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Focus on<br />
Gastroenterologic<br />
Diseases<br />
www.uspharmacist.com<br />
HEALTH SYSTEMS EDITION<br />
DECEMBER 2009<br />
THE JOURNAL FOR PHARMACISTS’ EDUCATION<br />
Overview of Hepatitis<br />
Colorectal Cancer:<br />
Screening Guidelines<br />
Gastrointestinal Bleeding<br />
Surgical Procedures<br />
for Weight Loss<br />
2 CE Credits<br />
Prescription Drug Abuse<br />
New Products in This Issue:<br />
Afinitor / Novartis Pharmaceuticals Corporation •<br />
Authorized Generics / Greenstone LLC • Brimonidine<br />
Tartrate Ophthalmic Solution / Falcon Pharmaceuticals •<br />
Distinctive Labeling / Baxter Healthcare • Embeda / King<br />
Pharmaceuticals • Injectables / Pfizer Injectables •<br />
Kapidex / Takeda Pharmaceuticals • Methenamine<br />
Hippurate / CorePharma LLC • Product Labeling / Teva<br />
Pharmaceuticals • Uloric / Takeda Pharmaceuticals<br />
FOR FREE CE, GO TO:<br />
www.uspharmacist.com<br />
A JOBSON PUBLICATION
Indication<br />
ULORIC is a xanthine oxidase (XO) inhibitor indicated for<br />
the chronic management of hyperuricemia in patients<br />
with gout. ULORIC is not recommended for the treatment<br />
of asymptomatic hyperuricemia.<br />
Important Safety Information<br />
• ULORIC is contraindicated in patients being treated<br />
with azathioprine, mercaptopurine, or theophylline.<br />
• An increase in gout flares is frequently observed<br />
during initiation of anti-hyperuricemic agents,<br />
including ULORIC. If a gout flare occurs during<br />
treatment, ULORIC need not be discontinued.<br />
Prophylactic therapy (i.e. - NSAIDs or colchicine)<br />
upon initiation of treatment may be beneficial for<br />
up to six months.<br />
• Cardiovascular Events: In randomized controlled studies,<br />
there was a higher rate of cardiovascular thromboembolic<br />
events (cardiovascular deaths, non-fatal myocardial<br />
infarctions, and non-fatal strokes) in patients treated<br />
with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than<br />
allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal<br />
relationship with ULORIC has not been established.<br />
Monitor for signs and symptoms of MI and stroke.<br />
• Liver Enzyme Elevations: In randomized controlled studies,<br />
transaminase elevations greater than 3 times the upper<br />
limit of normal (ULN) were observed (AST: 2%, 2%, and<br />
ULORIC ® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc.<br />
©2009 Takeda Pharmaceuticals North America, Inc. TXF-00319 08/09
ULORIC powerfully lowers<br />
serum uric acid levels for long-term<br />
control of gout.<br />
Powerfully lowers serum uric acid 1<br />
• In the largest phase 3 study (6 months):<br />
- 45% of patients who received ULORIC 40 mg achieved serum uric acid<br />
levels of
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for<br />
ULORIC ® (febuxostat) tablets<br />
INDICATIONS AND USAGE<br />
ULORIC ® is a xanthine oxidase (XO) inhibitor indicated for the chronic management<br />
of hyperuricemia in patients with gout.<br />
ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.<br />
CONTRAINDICATIONS<br />
ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine,<br />
or theophylline [see Drug Interactions].<br />
WARNINGS AND PRECAUTIONS<br />
Gout Flare<br />
After initiation of ULORIC, an increase in gout flares is frequently observed. This<br />
increase is due to reduction in serum uric acid levels resulting in mobilization of<br />
urate from tissue deposits.<br />
In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic<br />
treatment with an NSAID or colchicine is recommended.<br />
Cardiovascular Events<br />
In the randomized controlled studies, there was a higher rate of cardiovascular<br />
thrombo embolic events (cardiovascular deaths, non-fatal myocardial infarctions,<br />
and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y<br />
(95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see<br />
Adverse Reactions]. A causal relationship with ULORIC has not been established.<br />
Monitor for signs and symptoms of myocardial infarction (MI) and stroke.<br />
Liver Enzyme Elevations<br />
During randomized controlled studies, transaminase elevations greater than 3 times<br />
the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2%<br />
in ULORIC and allopurinol-treated patients, respectively). No dose-effect<br />
relationship for these transaminase elevations was noted. Laboratory<br />
assessment of liver function is recommended at, for example, 2 and 4 months<br />
following initiation of ULORIC and periodically thereafter.<br />
ADVERSE REACTIONS<br />
Clinical Trials Experience<br />
Because clinical trials are conducted under widely varying conditions, adverse<br />
reaction rates observed in the clinical trials of a drug cannot be directly compared<br />
to rates in the clinical trials of another drug and may not reflect the rates observed<br />
in practice.<br />
A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC<br />
40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients<br />
were treated for 6 months. For ULORIC 80 mg, 1377 subjects were treated for<br />
6 months, 674 patients were treated for 1 year and 515 patients were treated<br />
for 2 years.<br />
Most Common Adverse Reactions<br />
In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were<br />
6 to 12 months in duration, the following adverse reactions were reported by<br />
the treating physician as related to study drug. Table 1 summarizes adverse<br />
reactions reported at a rate of at least 1% in ULORIC treatment groups and at<br />
least 0.5% greater than placebo.<br />
Table 1: Adverse Reactions Occurring in 1% of ULORIC-Treated<br />
Patients and at Least 0.5% Greater than Seen in Patients<br />
Receiving Placebo in Controlled Studies<br />
Placebo ULORIC allopurinol*<br />
40 mg 80 mg<br />
daily daily<br />
Adverse Reactions (N=134) (N=757) (N=1279) (N=1277)<br />
Liver Function<br />
Abnormalities<br />
0.7% 6.6% 4.6% 4.2%<br />
Nausea 0.7% 1.1% 1.3% 0.8%<br />
Arthralgia 0% 1.1% 0.7% 0.7%<br />
Rash 0.7% 0.5% 1.6% 1.6%<br />
* Of the subjects who received allopurinol, 10 received 100 mg, 145 received<br />
200 mg, and 1122 received 300 mg, based on level of renal impairment.<br />
The most common adverse reaction leading to discontinuation from therapy<br />
was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC<br />
80 mg, and in 0.9% of allopurinol-treated subjects.<br />
In addition to the adverse reactions presented in Table 1, dizziness was reported<br />
in more than 1% of ULORIC-treated subjects although not at a rate more than<br />
0.5% greater than placebo.<br />
Less Common Adverse Reactions<br />
In phase 2 and 3 clinical studies the following adverse reactions occurred in less<br />
than 1% of subjects and in more than one subject treated with doses ranging from<br />
40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than<br />
1% of subjects) associated with organ systems from Warnings and Precautions.<br />
Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic<br />
purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly,<br />
throm bo cytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter,<br />
cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia;<br />
Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision<br />
blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain,<br />
constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis,<br />
gastro esophageal reflux disease, gastrointestinal discomfort, gingival pain,<br />
haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis,<br />
peptic ulcer, vomiting; General Disorders and Administration Site Conditions:<br />
asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait<br />
disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary<br />
Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly;<br />
Immune System Disorder: hypersensitivity; Infections and Infestations: herpes<br />
zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders:<br />
anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia,<br />
hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia,<br />
weight decreased/increased; Musculoskeletal and Connective Tissue Disorders:<br />
arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness,<br />
musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered<br />
taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache,<br />
hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental<br />
impairment, migraine, paresthesia, somnolence, transient ischemic attack,<br />
tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability,<br />
libido decreased, nervousness, panic attack, personality change; Renal and<br />
Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal<br />
failure, renal insufficiency, urgency, incontinence; Reproductive System and<br />
Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory,<br />
Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis,<br />
nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory<br />
tract congestion, sneezing, throat irritation, upper respiratory tract infection;<br />
Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis,<br />
dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal,<br />
hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin<br />
discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria;<br />
Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory<br />
Parameters: activated partial thromboplastin time prolonged, creatine increased,<br />
bicarbonate decreased, sodium increased, EEG abnormal, glucose increased,<br />
cholesterol increased, triglycerides increased, amylase increased, potassium<br />
increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin<br />
decreased, MCV increased, RBC decreased, creatinine increased, blood urea<br />
increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased,<br />
alkaline phosphatase increased, LDH increased, PSA increased, urine output<br />
increased/decreased, lymphocyte count decreased, neutrophil count decreased,<br />
WBC increased/decreased, coagulation test abnormal, low density lipoprotein<br />
(LDL) increased, prothrombin time prolonged, urinary casts, urine positive for<br />
white blood cells and protein.<br />
Cardiovascular Safety<br />
Cardiovascular events and deaths were adjudicated to one of the pre-defined<br />
endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular<br />
death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized<br />
controlled and long-term extension studies. In the Phase 3 randomized controlled<br />
studies, the incidences of adjudicated APTC events per 100 patient-years of exposure<br />
were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08),<br />
ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI<br />
0.16-1.53).<br />
In the long-term extension studies, the incidences of adjudicated APTC events were:<br />
ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).<br />
Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated<br />
patients. A causal relationship with ULORIC has not been established.<br />
Monitor for signs and symptoms of MI and stroke.<br />
DRUG INTERACTIONS<br />
Xanthine Oxidase Substrate Drugs<br />
ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that<br />
are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have<br />
not been conducted. Inhibition of XO by ULORIC may cause increased plasma<br />
concentrations of these drugs leading to toxicity [see Clinical Pharmacology].<br />
ULORIC is contraindicated in patients being treated with azathioprine,<br />
mercaptopurine, or theophylline [see Contraindications].<br />
Cytotoxic Chemotherapy Drugs<br />
Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been<br />
conducted. No data are available regarding the safety of ULORIC during<br />
cytotoxic chemotherapy.<br />
In Vivo Drug Interaction Studies<br />
Based on drug interaction studies in healthy subjects, ULORIC does not have<br />
clinically significant interactions with colchicine, naproxen, indomethacin,<br />
hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used<br />
concomitantly with these medications.
USE IN SPECIFIC POPULATIONS<br />
Pregnancy<br />
Pregnancy Category C: There are no adequate and well-controlled studies in<br />
pregnant women. ULORIC should be used during pregnancy only if the potential<br />
benefit justifies the potential risk to the fetus.<br />
Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg<br />
(40 and 51 times the human plasma exposure at 80 mg per day for equal body<br />
surface area, respectively) during organogenesis. However, increased neonatal<br />
mortality and a reduction in the neonatal body weight gain were observed when<br />
pregnant rats were treated with oral doses up to 48 mg per kg (40 times the<br />
human plasma exposure at 80 mg per day) during organogenesis and through<br />
lactation period.<br />
Nursing Mothers<br />
Febuxostat is excreted in the milk of rats. It is not known whether this drug is<br />
excreted in human milk. Because many drugs are excreted in human milk, caution<br />
should be exercised when ULORIC is administered to a nursing woman.<br />
Pediatric Use<br />
Safety and effectiveness in pediatric patients under 18 years of age have not<br />
been established.<br />
Geriatric Use<br />
No dose adjustment is necessary in elderly patients. Of the total number of subjects<br />
in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were<br />
75 and over. Comparing subjects in different age groups, no clinically significant<br />
differences in safety or effectiveness were observed but greater sensitivity of<br />
some older individuals cannot be ruled out. The C max and AUC 24 of febuxostat<br />
following multiple oral doses of ULORIC in geriatric subjects ( 65 years) were<br />
similar to those in younger subjects (18-40 years).<br />
Renal Impairment<br />
No dose adjustment is necessary in patients with mild or moderate renal<br />
impairment (Cl cr 30-89 mL per min). The recommended starting dose of ULORIC<br />
is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per<br />
dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.<br />
There are insufficient data in patients with severe renal impairment (Cl cr less<br />
than 30 mL per min); therefore, caution should be exercised in these patients.<br />
Hepatic Impairment<br />
No dose adjustment is necessary in patients with mild or moderate hepatic<br />
impairment (Child-Pugh Class A or B). No studies have been conducted in<br />
patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution<br />
should be exercised in these patients.<br />
Secondary Hyperuricemia<br />
No studies have been conducted in patients with secondary hyperuricemia (including<br />
organ transplant recipients); ULORIC is not recommended for use in patients whom<br />
the rate of urate formation is greatly increased (e.g., malignant disease and its<br />
treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine<br />
could, in rare cases, rise sufficiently to allow deposition in the urinary tract.<br />
OVERDOSAGE<br />
ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven<br />
days without evidence of dose-limiting toxicities. No overdose of ULORIC was<br />
reported in clinical studies. Patients should be managed by symptomatic and<br />
supportive care should there be an overdose.<br />
CLINICAL PHARMACOLOGY<br />
Pharmacodynamics<br />
Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC<br />
resulted in a dose dependent decrease in 24-hour mean serum uric acid<br />
concentrations, and an increase in 24-hour mean serum xanthine concentrations.<br />
In addition, there was a decrease in the total daily urinary uric acid excretion.<br />
Also, there was an increase in total daily urinary xanthine excretion. Percent<br />
reduction in 24-hour mean serum uric acid concentrations was between 40% to<br />
55% at the exposure levels of 40 mg and 80 mg daily doses.<br />
Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization<br />
as assessed by the QTc interval was evaluated in normal healthy subjects and in<br />
patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not<br />
demonstrate an effect on the QTc interval.<br />
Special Populations<br />
Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects<br />
with mild (Cl cr 50-80 mL per min), moderate (Cl cr 30-49 mL per min) or severe<br />
renal impairment (Cl cr 10-29 mL per min), the C max of febuxostat did not change<br />
relative to subjects with normal renal function (Cl cr greater than 80 mL per min).<br />
AUC and half-life of febuxostat increased in subjects with renal impairment in<br />
comparison to subjects with normal renal function, but values were similar<br />
among three renal impairment groups. Mean febuxostat AUC values were up to<br />
1.8 times higher in subjects with renal impairment compared to those with<br />
normal renal function. Mean C max and AUC values for 3 active metabolites<br />
increased up to 2- and 4-fold, respectively. However, the percent decrease in<br />
serum uric acid concentration for subjects with renal impairment was<br />
comparable to those with normal renal function (58% in normal renal function<br />
group and 55% in the severe renal function group).<br />
No dose adjustment is necessary in patients with mild to moderate renal<br />
impairment [see Dosage and Administration and Use in Specific Populations].<br />
The recommended starting dose of ULORIC is 40 mg once daily. For patients<br />
who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg,<br />
ULORIC 80 mg is recommended. There is insufficient data in patients with<br />
severe renal impairment; caution should be exercised in those patients [see Use<br />
in Specific Populations.<br />
ULORIC has not been studied in end stage renal impairment patients who are<br />
on dialysis.<br />
Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients<br />
with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic<br />
impairment, an average of 20-30% increase was observed for both C max and<br />
AUC 24 (total and unbound) in hepatic impairment groups compared to subjects<br />
with normal hepatic function. In addition, the percent decrease in serum uric<br />
acid concentration was comparable between different hepatic groups (62% in<br />
healthy group, 49% in mild hepatic impairment group, and 48% in moderate<br />
hepatic impairment group). No dose adjustment is necessary in patients with<br />
mild or moderate hepatic impairment. No studies have been conducted in<br />
subjects with severe hepatic impairment (Child-Pugh Class C); caution should<br />
be exercised in those patients [see Use in Specific Populations.<br />
NONCLINICAL TOXICOLOGY<br />
Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats<br />
and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary<br />
bladder was observed at 24 mg per kg (25 times the human plasma exposure<br />
at maximum recommended human dose of 80 mg per day) and 18.75 mg per<br />
kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and<br />
female mice, respectively. The urinary bladder neoplasms were secondary to<br />
calculus formation in the kidney and urinary bladder.<br />
Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal<br />
aberration assay in a Chinese hamster lung fibroblast cell line with and without<br />
metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay<br />
and chromosomal aberration test in human peripheral lymphocytes, and L5178Y<br />
mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat<br />
unscheduled DNA synthesis and rat bone marrow cells.<br />
Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day<br />
(approximately 35 times the human plasma exposure at 80 mg per day) had no<br />
effect on fertility and reproductive performance of male and female rats.<br />
Animal Toxicology<br />
A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals<br />
and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma<br />
exposure at 80 mg per day). A similar effect of calculus formation was noted in<br />
rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg<br />
(approximately 35 times the human plasma exposure at 80 mg per day).<br />
PATIENT COUNSELING INFORMATION<br />
[see FDA-Approved Patient Labeling in the full prescribing information]<br />
General Information<br />
Patients should be advised of the potential benefits and risks of ULORIC. Patients<br />
should be informed about the potential for gout flares, elevated liver enzymes and<br />
adverse cardiovascular events after initiation of ULORIC therapy.<br />
Concomitant prophylaxis with an NSAID or colchicine for gout flares should<br />
be considered.<br />
Patients should be instructed to inform their healthcare professional if they<br />
develop a rash, chest pain, shortness of breath or neurologic symptoms<br />
suggesting a stroke. Patients should be instructed to inform their healthcare<br />
professional of any other medications they are currently taking with ULORIC,<br />
including over-the-counter medications.<br />
Distributed by<br />
Takeda Pharmaceuticals America, Inc.<br />
Deerfield, IL 60015<br />
U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520.<br />
ULORIC ® is a registered trademark of Teijin Pharma Limited and used under<br />
license by Takeda Pharmaceuticals America, Inc.<br />
All other trademark names are the property of their respective owners<br />
©2009 Takeda Pharmaceuticals America, Inc.<br />
February 2009<br />
For more detailed information, see the full prescribing information for<br />
ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact<br />
Takeda Pharmaceuticals America, Inc. at 1.877.825.3327.<br />
PI1114 R1-Brf; February 2009<br />
L-TXF-0209-3
Straight Talk<br />
Making a Difference<br />
Earlier this year, I announced<br />
the launch of a new professional<br />
social network exclusively<br />
geared to the pharmacy<br />
community. Since its debut, many thousands<br />
of pharmacists, pharmacy technicians,<br />
and pharmacy students have<br />
shared their professional and personal<br />
experiences. It has given pharmacy professionals<br />
an outlet not only to express<br />
their feelings but also to share professional<br />
information and link up with colleagues<br />
with like interests. For me, one<br />
of the best things about PharmQD<br />
(www.pharmqd.com) is the stories and<br />
blogs. A couple of months ago, I asked<br />
site visitors to post stories and blogs<br />
relating how they made a difference in<br />
their patients’ lives. Many of the postings<br />
were very heartwarming and reinforced<br />
why we went into pharmacy in<br />
the first place. As we finish out another<br />
year and enjoy the holiday season with<br />
family, friends, and colleagues, I thought I would<br />
briefly share some of these stories with you.<br />
A pharmacist from New York told of her gut-wrenching<br />
experience of seeing the store she owned burn to the<br />
ground. But, as traumatic as that was, she expressed<br />
thanks to competitors, manufacturers, wholesalers, and<br />
customers who came to her aid while she was putting<br />
the pieces of her life back together. She wrote, “It was<br />
then that I realized I was participating in a profession<br />
that really did care about one another.” Then there was<br />
the pharmacist who, like many pharmacists, gave a talk<br />
at a local hospital on Parkinson’s disease. “It really makes<br />
you appreciate your health when you see someone literally<br />
trapped in their body,” he wrote. “While their mind<br />
is active, their body is holding them hostage.” A few<br />
weeks later, the pharmacist received a call from a gentleman<br />
who had attended the talk, who told him that the<br />
information he provided was personally very helpful.<br />
“That made me feel good,” the pharmacist said. “So<br />
often we go through our days not realizing how much<br />
people appreciate what we do. We have to remind ourselves<br />
and others of this more often.”<br />
Another pharmacist tells a story to which any retailer<br />
can easily relate. A patient came into the pharmacy to<br />
fill a prescription for a thyroid product in a strength<br />
that was on back order. The patient was ready to go on<br />
vacation and was in a bit of a panic, so<br />
the pharmacist secured approval from the<br />
doctor to “adjust” her dosage with the<br />
strengths in stock. “The patient was very<br />
pleased,” said the pharmacist. “It is experiences<br />
like these that make the downright<br />
nasty patients a lot easier to deal<br />
with.” One pharmacist tells of his experience<br />
of refusing to fill a prescription for a<br />
patient who was an obvious addict. To<br />
his amazement, 6 months later that<br />
patient came back to the store to basically<br />
say thank you for not filling the prescription.<br />
She told the pharmacist that she<br />
now attends Alcoholics Anonymous and<br />
Narcotics Anonymous. “I just couldn’t<br />
believe that out of a potentially bad situation,<br />
something so good happened,”<br />
commented the pharmacist.<br />
And finally, there is the story about a<br />
particularly difficult patient who regularly<br />
came into the pharmacy. When he<br />
became too weak to make the trip, the<br />
pharmacist started to personally deliver prescriptions to<br />
the man’s home after work. Each time he went to the<br />
client’s apartment, the pharmacist would chat with him.<br />
Eventually, the embittered man started to open up, and<br />
he told the pharmacist that he had no family and that<br />
his wife had recently passed away. The pharmacist continued<br />
to talk with him on subsequent visits, and the<br />
patient would tell his friends that the pharmacist was his<br />
“buddy.” Sadly, the patient was found on the floor of his<br />
apartment one day, felled by a fatal heart attack. “Say<br />
what you need to say,” advises the pharmacist. “When<br />
you get the chance, take it. Don’t let significant<br />
moments pass you by. It may seem like a little thing, but<br />
it can make a big difference. Say it before it is too late.”<br />
As we enjoy this festive holiday season and begin a<br />
new year, let me make sure I say what I need to say.<br />
And that would be “thank you” for being an important<br />
part of the U.S. <strong>Pharmacist</strong> family. Have a wonderful<br />
holiday season and, most important, a very<br />
healthy new year.<br />
Harold E. Cohen, RPh<br />
Editor-in-Chief<br />
hcohen@jobson.com<br />
4<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
HEALTH SYSTEMS EDITION<br />
Vol. 34 No. 12<br />
TEAR ALONG PERFORATION<br />
Pancreatitis<br />
Gallbladder<br />
Ga lstones<br />
Common<br />
bile duct<br />
Pancreatic<br />
duct<br />
Enzymes flow freely<br />
into the duodenum<br />
to aid in digestion<br />
PATIENT TEACHING AID<br />
Inflamed<br />
Pancreas<br />
Normal<br />
Pancreas<br />
DECEMBER 2009<br />
The Journal for <strong>Pharmacist</strong>s’ Education<br />
U.S. <strong>Pharmacist</strong> is a Peer-Reviewed Journal<br />
MEDICAL ILLUSTRATION: © KRISTEN WEINANDT MARZEJON 2009<br />
Duodenum<br />
(sma l intestine)<br />
Acute or Chronic<br />
Inflammation of<br />
Endocrine Gland<br />
Ga lstones, produced<br />
in the ga lbladder,<br />
can get lodged in the<br />
common bile duct,<br />
blocking the flow of<br />
pancreatic enzymes<br />
into the sma l intestine.<br />
Pancreatitis occurs<br />
when these blocked<br />
enzymes irritate the<br />
ce ls of the pancreas<br />
Pancreatitis is an inflammation of the pancreas, the gland<br />
behind the stomach that produces insulin and enzymes<br />
that help digest food. The pancreas can become inflamed<br />
as a result of alcoholism, ga lstones, or infection, among<br />
other reasons. The inflammation can develop quickly over<br />
a period of days (acute pancreatitis) or can develop and<br />
continue for years (chronic pancreatitis). It can be a mild<br />
inflammation that heals quickly with the proper treatment, or a severe condition that can lead to<br />
serious diseases such as diabetes, kidney failure, or cancer of the pancreas.<br />
Symptoms of acute pancreatitis include pain in the abdomen that can move to the lower back area.<br />
The pain often feels worse with eating, but better in the fetal position. Acute pancreatitis can also cause<br />
nausea and vomiting. In chronic pancreatitis, the abdominal pain is also a sociated with weight lo s and<br />
oily, foul-sme ling bowel movements. Laboratory tests of the blood, urine, and stool are performed to look<br />
for signs of inflammation and abnormal amounts of pancreatic enzymes. Other tests often performed in<br />
the diagnosis of pancreatitis include abdominal x-ray, ultrasound testing, CT scan, and MRI.<br />
Treatment depends on the type of pancreatitis, its cause, and its severity. Patients may require a<br />
hospital stay to treat pain and a low the pancreas to rest by restricting food and fluids by mouth.<br />
Patients are rehydrated with intravenous fluids and nutrition is restored with special feedings. The<br />
specific cause of the pancreatic inflammation will determine further treatment.<br />
Copyright Jobson Medical Information LLC, 2009 continued<br />
PTA0912 Pancrea 10_14bo.indd 1 10/15/09 12:25 PM<br />
COVER IMAGE:<br />
PATIENT TEACHING AID<br />
Pancreatitis. See page 25<br />
Illustration: © Keith Kasnot 2009<br />
www.kazstudios.com<br />
Though prevalence is declining, infection with<br />
the hepatitis B or C virus is a major health<br />
concern because it often leads to chronic liver<br />
failure and even death<br />
CE CREDITS<br />
Prescription Drug Abuse: Strategies to<br />
Reduce Diversion. See page 61<br />
THIS MONTH<br />
Editorial Focus: Gastroenterologic Diseases<br />
NEXT MONTH<br />
Editorial Focus: Neurologic Diseases<br />
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CE PROGRAMS ON THE<br />
U.S. PHARMACIST WEB SITE<br />
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FEATURES<br />
Senior Care<br />
Colorectal Cancer<br />
Screening . . . . . . . . . . . . . . 29<br />
Routine examinations, beginning at age 50,<br />
are the key to preventing this disease.<br />
Mary Ann E. Zagaria, PharmD, MS, CGP<br />
Overview of Hepatitis<br />
B and C Management . . . . . . . 32<br />
Although much effort has been dedicated<br />
to the eradication of these diseases through<br />
education and vaccination, viral hepatitis<br />
is still a worldwide problem.<br />
Justin Hooper, PharmD, BCPS,<br />
and Amy Martin, PharmD, BCPS<br />
Probiotics and Microflora . . . . 42<br />
There is a new focus on the role of<br />
beneficial bacteria to aid digestion,<br />
boost natural defenses, and fight off<br />
bacteria that could cause health problems.<br />
Max Sherman, RPh<br />
HEALTH SYSTEMS EDITION<br />
Pharmacy Law<br />
Gender Discrimination<br />
and Its Consequences . . .56<br />
There is no reason to differentiate<br />
compensation or enforcement of<br />
policies based on gender alone, as<br />
a female pharmacist and a large<br />
pharmacy chain have learned.<br />
Jesse C. Vivian, BS Pharm, JD<br />
●2 CE Credits<br />
Prescription Drug Abuse:<br />
Strategies to<br />
Reduce Diversion . . . . . . . . . 61<br />
<strong>Pharmacist</strong>s need to be aware of<br />
the potential for drug diversion, recognize<br />
the warning signs of possible misuse,<br />
and acknowledge a legal obligation<br />
to minimize drug abuse.<br />
Gerald Gianutsos, PhD, JD<br />
Law CE<br />
Surgical Procedures for Weight Loss . . . . . . . . . . . . . . . . . . . . . HS-2<br />
Bariatric surgery currently offers the best method of producing<br />
sustained weight reduction in morbidly obese individuals.<br />
Mea A. Weinberg, DMD, MSD, RPh, and Stuart L. Segelnick, DDS, MS<br />
In-Service Primers<br />
Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-12<br />
Early intervention to control bleeding is important in order to minimize mortality.<br />
Manouchehr Saljoughian, PharmD, PhD<br />
U.S. PHARMACIST ® (ISSN 01484818; USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postage<br />
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2009 by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Reproduction of articles without permission from the publisher is expressly prohibited.<br />
Acceptance of advertising by U.S. PHARMACIST does not constitute endorsement of the advertiser, its products or services. The opinions, statements and views expressed by contributors to<br />
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6<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
On behalf of the Mylan family, we wish you<br />
and your family a Happy holiday season ...<br />
and a healthy, prosperous New Year!<br />
800.RX.MYLAN • 800.796.9526 • www.mylanpharms.com<br />
©2009 Mylan Pharmaceuticals Inc. MYNMKT365A
U.S.<br />
<strong>Pharmacist</strong><br />
A Jobson Publication<br />
Senior Vice President–Editor-in-Chief<br />
Harold E. Cohen, RPh<br />
Executive Editor<br />
Robert Davidson<br />
Senior Editor<br />
Bonnie Ostrowski<br />
DECEMBER 2009<br />
The Journal for <strong>Pharmacist</strong>s’ Education<br />
U.S. <strong>Pharmacist</strong> is a Peer-Reviewed Journal<br />
Vol. 34 No. 12<br />
Senior Associate Editor<br />
Marjorie Borden<br />
Projects Editor<br />
Nancy Robertson, MS<br />
Consulting Clinical Editor<br />
Mary Gurnee, PharmD, RPh<br />
Senior Vice President–Publisher<br />
Harold E. Cohen, RPh (201) 623-0982<br />
Associate Publisher<br />
Jack McAleer (201) 623-0987<br />
East Coast Regional Sales Manager<br />
Mark Hildebrand (201) 623-0984<br />
Midwest/West Regional Sales Manager<br />
Megan Conley (773) 450-7339<br />
Marketing Manager<br />
Deborah Mortara (201) 623-0990<br />
Classified Advertising Sales<br />
Heather Brennan (800) 983-7737 x106<br />
Design Director<br />
Sharyl Sand Carow<br />
Production Manager<br />
Dina Romano (201) 623-0942<br />
Corporate Production Director<br />
John Anthony Caggiano<br />
Director, Continuing Education Processing<br />
Regina Combs (800) 825-4696<br />
Vice President, Circulation Director<br />
Emelda Barea<br />
Vice President,<br />
Creative Services and Production<br />
Monica Tettamanzi<br />
Chief Executive Officer<br />
Jeff MacDonald<br />
Chief Financial Officer<br />
Derek Winston<br />
CEO, Information Services Division<br />
Marc Ferrara<br />
Senior Vice President, Operations<br />
Jeff Levitz<br />
Vice President, Human Resources<br />
Lorraine Orlando<br />
DEPARTMENTS<br />
Straight Talk<br />
Making a Difference . . . . . . . . 4<br />
Harold E. Cohen, RPh<br />
What’s News. . . . . . . . . . . . . 10<br />
TrendWatch<br />
The Burden of<br />
Digestive Diseases . . . . . . . . 12<br />
The overall incidence of gastrointestinal<br />
disorders has led to increased prescription<br />
and OTC drug use.<br />
Somnath Pal, BS (Pharm), MS, MBA, PhD<br />
Costliest Prescriptions Dispensed for Treatment of Digestive Diseases<br />
Lansoprazole<br />
Esomeprazole<br />
Pantoprazole<br />
Rabeprazole<br />
Omeprazole<br />
Ranitidine<br />
Mesalamine<br />
5.9 9.2<br />
1.8 3.8<br />
6.3 8.4<br />
© JUPITERIMAGES<br />
15.5 25.2<br />
14.3 23.1<br />
8.6 11.4<br />
9.7 2.6<br />
0 5 10 15 20 25 30 35 40 45<br />
Percentage<br />
Prescriptions<br />
Cost<br />
Visit www.uspharmacist.com for features<br />
and departments available only online,<br />
including IBS Treatment Guidelines<br />
Consult Your <strong>Pharmacist</strong><br />
Strategies for the Relief<br />
of Bloating and Gas . . . . . . . . 16<br />
Various sources for this problem have<br />
been identified, including air swallowing,<br />
diet, lactose intolerance, and IBS.<br />
W. Steven Pray, PhD, DPh<br />
Annual Index 2009 . . . . . . . . . 50<br />
Contemporary<br />
Compounding<br />
Tamiflu Oral Suspension . . . . 54<br />
A liquid version of this influenza<br />
medication may be easily prepared<br />
using the capsule formulation.<br />
Loyd V. Allen, Jr, PhD<br />
Classified Advertising . . . . . . 71<br />
Career and business opportunities,<br />
products, and services for the pharmacist.<br />
Product News . . . . . . . . . . . . 73<br />
WEB-EXCLUSIVE ARTICLES<br />
U.S. <strong>Pharmacist</strong><br />
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New Products in This Issue<br />
Afinitor / Novartis Pharmaceuticals Corporation • Authorized Generics / Greenstone LLC • Brimonidine<br />
Tartrate Ophthalmic Solution / Falcon Pharmaceuticals • Embeda / King Pharmaceuticals • Kapidex /<br />
Takeda Pharmaceuticals • Methenamine Hippurate / CorePharma LLC • Uloric / Takeda Pharmaceuticals<br />
Health Systems <strong>Edition</strong>: Distinctive Labeling / Baxter Healthcare • Injectables / Pfizer Injectables •<br />
Product Labeling / Teva Pharmaceuticals<br />
8<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
We’re about to really open it up.<br />
E. FOUGERA & CO.<br />
A division of Nycomed US Inc., Melville, NY 11747 • Toll free: 800-645-9833 • www.fougera.com<br />
© 2009 Fougera. All rights reserved.<br />
Rev. 9/09
U.S. <strong>Pharmacist</strong><br />
Editorial Board of Advisors<br />
Joseph Bova, RPh<br />
Community Pharmacy Owner,<br />
Cary’s Pharmacy,<br />
Dobbs Ferry, New York;<br />
Member, NYS Board of Pharmacy<br />
Carmen Catizone, RPh<br />
Executive Director, National Association<br />
of Boards of Pharmacy<br />
John M. Coster, PhD, RPh<br />
Senior VP of Government Affairs<br />
National Community <strong>Pharmacist</strong>s Assoc.<br />
Hewitt (Ted) W. Matthews, PhD<br />
Dean, Southern School of Pharmacy,<br />
Mercer University, Atlanta<br />
David G. Miller, RPh<br />
Pharmacy Affairs, Merck & Co., Inc.,<br />
West Point, Pennsylvania<br />
Mario F. Sylvestri, PharmD, PhD<br />
Senior Director, Medical Science<br />
Liaisons, Amylin Pharmaceuticals<br />
Ray A. Wolf, PharmD<br />
Medical Education, Sanofi Aventis<br />
Mary Ann E. Zagaria,<br />
PharmD, MS, CGP<br />
Senior Care Consultant and<br />
President, MZ Associates, Inc.,<br />
Norwich, New York<br />
Contributing Editors<br />
Loyd V. Allen, Jr., PhD<br />
Connie Barnes, PharmD<br />
Bruce Berger, PhD<br />
R. Keith Campbell, RPh, CDE<br />
Patrick N. Catania, PhD, RPh<br />
R. Rebecca Couris, PhD, RPh<br />
Ed DeSimone, PhD, RPh<br />
Ronald W. Maddox, PharmD<br />
Somnath Pal, BS (Pharm), MBA, PhD<br />
W. Steven Pray, PhD, DPh<br />
M. Saljoughian, PharmD, PhD<br />
Jesse C. Vivian, BS Pharm, JD<br />
Send your comments via<br />
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Telephone: (201) 623-0999<br />
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Internet: www.uspharmacist.com<br />
What’s News<br />
Statins May Worsen Cardiac Symptoms<br />
San Diego, CA — New research shows that statin drugs may negatively impact<br />
some patients with cardiac disorders. A new study presented at the 75th annual<br />
international scientific assembly of the American College of Chest Physicians found<br />
that statins benefit patients with systolic heart failure (SHF), but not those with<br />
diastolic heart failure (DHF). These patients experienced increased dyspnea, fatigue,<br />
and decreased exercise tolerance. “It is possible that statins would help patients with<br />
systolic heart failure more than patients with diastolic heart failure due to the<br />
cholesterol-lowering and anti-inflammatory effects of statins,” said Lawrence P.<br />
Cahalin, PhD, PT, Northeastern University, Boston, Massachusetts. Despite the<br />
new data, researchers feel that the benefits of using statins in patients with SHF<br />
and DHF outweigh the risks.<br />
Dr. Regina Benjamin Confirmed as U.S. Surgeon General<br />
Washington, DC — U.S. Department of Health and Human Services Secretary<br />
Kathleen Sebelius announced that the U.S. Senate unanimously confirmed Regina<br />
Benjamin, MD, MBA, as the nation’s Surgeon General. Benjamin is founder and<br />
CEO of the Bayou La Batre Rural Health Clinic in Bayou La Batre, Alabama. She<br />
is the immediate past-chair of the Federation of State Medical Boards of the U.S.<br />
and previously served as associate dean for Rural Health at the University of South<br />
Alabama College of Medicine. In 2002, she became president of the Medical Association<br />
of the State of Alabama, making her the first African American woman to<br />
hold this position at a state medical society in the U.S. “Dr. Benjamin will quickly<br />
become America’s doctor as our next Surgeon General. Her deep knowledge and<br />
strong medical skills, her commitment to her patients, and her ability to inspire the<br />
people she interacts with every day will serve her well as Surgeon General,” Secretary<br />
Sebelius said.<br />
FDA Expands Approved Use of H1N1 Vaccines<br />
Silver Spring, MD — The FDA approved the use of the CSL Limited’s 2009<br />
H1N1 influenza vaccine to include children ages 6 months and older. Previously,<br />
this vaccine was approved only for use in adults ages 18 years and older. “Because<br />
children are among those most vulnerable to the 2009 H1N1 virus, having a<br />
broader range of children’s vaccines available is an important step in responding to<br />
the H1N1 outbreak,” said Margaret A. Hamburg, MD, FDA commissioner. The<br />
expanded approval also covers the company’s seasonal flu vaccine. Because CSL’s<br />
seasonal and H1N1 monovalent vaccines contain a small amount of egg protein,<br />
they should not be administered to anyone allergic to eggs or egg products. The<br />
vaccines will be available in single-dose, preservative-free, prefilled syringes and in<br />
multidose vials that contain thimerosal, a mercury derivative, as a preservative.<br />
Survey: Patients Do Not Treat Cold and Flu Symptoms Early Enough<br />
Scottsdale, AZ — A recent survey of 505 pharmacists found that 75% of pharmacists<br />
say most patients should purchase OTC cold and flu products at the first sign<br />
of symptoms, while only 26% of their patients take this proactive approach. Nine<br />
out of 10 of the surveyed pharmacists believe it is important for a patient to seek<br />
treatment early to help shorten the duration and severity of a cold. The survey also<br />
found that 85% of pharmacists agree the economy has increased patient questions<br />
about OTC products, and that 81% of pharmacists agree that more patients are<br />
opting to purchase OTC medications versus filling prescriptions for economic reasons.<br />
The survey was sponsored by Matrixx Initiatives, Inc., an OTC health care<br />
company and makers of Zicam products.<br />
10<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
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At the end of the<br />
20th century,<br />
there were changes in<br />
the incidence, prevalence,<br />
and overall<br />
impact of digestive diseases,<br />
as evidenced by<br />
the 2008 update to<br />
the National Institutes<br />
of Health publication<br />
on digestive diseases.<br />
Somnath Pal, BS (Pharm), MBA, PhD<br />
Professor of Pharmacy Administration,<br />
College of Pharmacy & Allied Health<br />
Professions, St. John’s University,<br />
Jamaica, New York<br />
Hospital and Ambulatory-Care<br />
Visits:<br />
Between 1983 and<br />
1988, rates of hospitalization<br />
for digestive<br />
diseases fell, a trend<br />
that occurred for all causes<br />
of hospitalization. Hospitalization<br />
rates were stable<br />
for the next 10 years and<br />
rose by 2004 to a rate<br />
equal to the previous peak<br />
rate in 1982. Between<br />
1998 and 2004, the hospitalization<br />
rate for all diseases<br />
increased to 35%.<br />
The largest contributions<br />
to the increase were made<br />
by gastroesophageal reflux<br />
disease (GERD), with an<br />
increase of 376 per<br />
100,000; viral hepatitis C<br />
(79/100,000); chronic constipation<br />
(62/100,000);<br />
and intestinal infection<br />
(41/100,000). Although<br />
overnight hospitalizations<br />
with a diagnosis of digestive<br />
disease decreased notably<br />
for peptic ulcer disease<br />
(PUD) and gallstones<br />
owing to a shift to sameday<br />
surgery, 25% of all<br />
hospital discharges in 1998<br />
had a diagnosis of digestive<br />
disease; this increased to<br />
30% in 2004.<br />
In 2004, there were<br />
35,684 ambulatory-care<br />
visits related to digestive<br />
diseases per 100,000 population.<br />
Visits were common<br />
for all age groups,<br />
with the highest rate in<br />
individuals aged 65 years<br />
and older. Rates were comparable<br />
between black<br />
patients and white patients<br />
and were 20% higher for<br />
females than for males.<br />
Costs: Total ambulatorycare<br />
costs (excluding<br />
ambulatory surgery) in<br />
2004 were $16 billion.<br />
Outpatient procedures<br />
constituted 50% of this<br />
TrendWatch<br />
The Burden of<br />
Digestive Diseases<br />
Costliest Prescriptions Dispensed for Treatment of Digestive Diseases<br />
Lansoprazole<br />
Esomeprazole<br />
Pantoprazole<br />
Rabeprazole<br />
Omeprazole<br />
Ranitidine<br />
Mesalamine<br />
© JUPITERIMAGES<br />
5.9 9.2<br />
1.8 3.8<br />
15.5 25.2<br />
14.3 23.1<br />
8.6 11.4<br />
6.3 8.4<br />
9.7 2.6<br />
0 5 10 15 20 25 30 35 40 45<br />
Percentage<br />
Prescriptions<br />
Cost<br />
amount. Abdominal-wall<br />
hernia (AWH), GERD,<br />
chronic constipation, gallstones,<br />
and diverticular disease<br />
were the biggest contributors<br />
to ambulatory<br />
costs. Diseases costing<br />
more than $1 billion were<br />
(in descending order) gallstones,<br />
AWH, diverticular<br />
disease, pancreatitis,<br />
colorectal cancer, appendicitis,<br />
liver disease, GERD,<br />
and PUD. The total cost<br />
of prescription drugs written<br />
during office visits was<br />
$12.3 billion, and more<br />
than half of this cost ($7.7<br />
billion) was associated with<br />
drugs prescribed for<br />
GERD. PUD, hepatitis C<br />
virus (HCV), and irritable<br />
bowel syndrome (IBS)<br />
were major contributors to<br />
the remaining drug cost.<br />
The chart shows the<br />
seven costliest prescription<br />
drugs for digestive diseases<br />
from retail pharmacies.<br />
The five proton pump<br />
inhibitors (prescribed<br />
for GERD) constituted<br />
51% of the total<br />
number of prescriptions,<br />
amounting to<br />
77% of total cost;<br />
mesalamine (inflammatory<br />
bowel disease)<br />
and ranitidine were<br />
the other top contributors.<br />
Other drugs adding<br />
to the cost were<br />
tegaserod (IBS, constipation),<br />
ribavirin, and<br />
peginterferon alpha 2a<br />
(HCV). The Consumer<br />
Healthcare Products<br />
Association estimates<br />
expenditures for OTC<br />
drugs for GERD, constipation,<br />
and diarrhea at $2.1<br />
billion, excluding complementary<br />
and alternative<br />
medicines.<br />
In 2004, the costliest<br />
prescriptions (n = 938,000)<br />
filled at retail pharmacies<br />
were for gastrointestinal<br />
(GI) infections; most were<br />
antimicrobials or GI-motility<br />
agents (e.g., promethazine).<br />
The next costliest<br />
prescriptions were for viral<br />
hepatitis (n = 637,000),<br />
but these were represented<br />
by a few drugs.<br />
Continued progress in<br />
improving the health of<br />
the population requires<br />
continued investment in<br />
digestive disease research,<br />
public-health initiatives,<br />
the health care system, and<br />
education of the public.<br />
12<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Teva’s<br />
Lansoprazole Delayed-<br />
Release Capsules USP<br />
AB Rated and Bioequivalent to<br />
Prevacid ® *<br />
Delayed-Release Capsules<br />
To place your order,<br />
call your wholesaler<br />
or distributor today.<br />
Please see brief summary<br />
of prescribing information<br />
on adjacent page.<br />
Lansoprazole Delayed-Release<br />
Capsules USP<br />
STRENGTH SIZE NDC#<br />
15 mg 30 00093-7350-56<br />
30 mg 30 00093-7351-56<br />
*Prevacid ® is a registered trademark of Takeda Pharmaceuticals, Inc.<br />
©2009, Teva Pharmaceuticals USA<br />
1090 Horsham Road • North Wales, PA 19454<br />
800.545.8800 • www.tevausa.com<br />
8498A
BRIEF SUMMARY<br />
LANSOPRAZOLE DELAYED-RELEASE CAPSULES<br />
USP<br />
4 CONTRAINDICATIONS<br />
Lansoprazole delayed-release capsules are contraindicated in<br />
patients with known severe hypersensitivity to any component of the<br />
formulation of lansoprazole delayed-release capsules.<br />
5 WARNINGS AND PRECAUTIONS<br />
Symptomatic response to therapy with lansoprazole does not<br />
preclude the presence of gastric malignancy.<br />
6 ADVERSE REACTIONS<br />
6.1 Clinical<br />
Worldwide, over 10,000 patients have been treated with lansoprazole in<br />
Phase 2 or Phase 3 clinical trials involving various dosages and durations<br />
of treatment. The adverse reaction profiles for lansoprazole delayedrelease<br />
capsules and lansoprazole for delayed-release oral suspension are<br />
similar. In general, lansoprazole treatment has been well-tolerated in both<br />
short-term and long-term trials.<br />
Because clinical trials are conducted under widely varying conditions,<br />
adverse reaction rates observed in the clinical trials of a drug cannot be<br />
directly compared to rates in the clinical trials of another drug and may<br />
not reflect the rates observed in clinical practice.<br />
The following adverse reactions were reported by the treating physician<br />
to have a possible or probable relationship to drug in 1% or more<br />
of lansoprazole-treated patients and occurred at a greater rate in<br />
lansoprazole-treated patients than placebo-treated patients in Table 1.<br />
Table 1: Incidence of Possibly or Probably Treatment-Related<br />
Adverse Reactions in Short-Term, Placebo-Controlled<br />
Lansoprazole Studies<br />
Body System/Adverse<br />
Event<br />
Body as a Whole<br />
Lansoprazole<br />
(N = 2768) %<br />
Placebo<br />
(N = 1023) %<br />
Abdominal Pain 2.1 1.2<br />
Digestive System<br />
Constipation 1.0 0.4<br />
Diarrhea 3.8 2.3<br />
Nausea 1.3 1.2<br />
Headache was also seen at greater than 1% incidence but was more<br />
common on placebo. The incidence of diarrhea was similar between<br />
patients who received placebo and patients who received 15 mg and<br />
30 mg of lansoprazole, but higher in the patients who received 60 mg<br />
of lansoprazole (2.9%, 1.4%, 4.2%, and 7.4%, respectively).<br />
The most commonly reported possibly or probably treatment-related<br />
adverse event during maintenance therapy was diarrhea.<br />
In the risk reduction study of lansoprazole for NSAID-associated<br />
gastric ulcers, the incidence of diarrhea for patients treated with<br />
lansoprazole, misoprostol, and placebo was 5%, 22%, and 3%,<br />
respectively.<br />
Another study for the same indication, where patients took either a<br />
COX-2 inhibitor or lansoprazole and naproxen, demonstrated that<br />
the safety profile was similar to the prior study. Additional reactions<br />
from this study not previously observed in other clinical trials with<br />
lansoprazole included contusion, duodenitis, epigastric discomfort,<br />
esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness,<br />
impaired gastric emptying, metaplasia, and renal impairment.<br />
Additional adverse experiences occurring in less than 1% of patients<br />
or subjects who received lansoprazole in domestic trials are shown<br />
below:<br />
Body as a Whole - abdomen enlarged, allergic reaction, asthenia, back<br />
pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills,<br />
edema, fever, flu syndrome, halitosis, infection (not otherwise specified),<br />
malaise, neck pain, neck rigidity, pain, pelvic pain<br />
Cardiovascular System - angina, arrhythmia, bradycardia,<br />
cerebrovascular accident/cerebral infarction, hypertension/<br />
hypotension, migraine, myocardial infarction, palpitations, shock<br />
(circulatory failure), syncope, tachycardia, vasodilation<br />
Digestive System - abnormal stools, anorexia, bezoar, cardiospasm,<br />
cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis,<br />
eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal<br />
discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis,<br />
gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder,<br />
gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis,<br />
increased appetite, increased salivation, melena, mouth ulceration,<br />
nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal<br />
moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus,<br />
thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis<br />
Endocrine System - diabetes mellitus, goiter, hypothyroidism<br />
Hemic and Lymphatic System - anemia, hemolysis, lymphadenopathy<br />
Metabolic and Nutritional Disorders – avitaminosis, gout,<br />
dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight<br />
gain/loss<br />
Musculoskeletal System - arthralgia, arthritis, bone disorder, joint<br />
disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia,<br />
ptosis, synovitis<br />
Nervous System - abnormal dreams, agitation, amnesia, anxiety,<br />
apathy, confusion, convulsion, dementia, depersonalization,<br />
depression, diplopia, dizziness, emotional lability, hallucinations,<br />
hemiplegia, hostility aggravated, hyperkinesia, hypertonia,<br />
hypesthesia, insomnia, libido decreased/increased, nervousness,<br />
neurosis, paresthesia, sleep disorder, somnolence, thinking<br />
abnormality, tremor, vertigo<br />
Respiratory System - asthma, bronchitis, cough increased, dyspnea,<br />
epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis,<br />
pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper<br />
respiratory inflammation/infection, rhinitis, sinusitis, stridor<br />
Skin and Appendages - acne, alopecia, contact dermatitis, dry skin,<br />
fixed eruption, hair disorder, maculopapular rash, nail disorder,<br />
pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria<br />
Special Senses - abnormal vision, amblyopia, blepharitis, blurred<br />
vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder,<br />
eye pain, glaucoma, otitis media, parosmia, photophobia, retinal<br />
degeneration/disorder, taste loss, taste perversion, tinnitus, visual<br />
field defect<br />
Urogenital System - abnormal menses, breast enlargement, breast<br />
pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia,<br />
impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia,<br />
menstrual disorder, penis disorder, polyuria, testis disorder, urethral<br />
pain, urinary frequency, urinary retention, urinary tract infection,<br />
urinary urgency, urination impaired, vaginitis.<br />
6.2 Postmarketing Experience<br />
Additional adverse experiences have been reported since lansoprazole<br />
has been marketed. The majority of these cases are foreign-sourced<br />
and a relationship to lansoprazole has not been established. Because<br />
these reactions were reported voluntarily from a population of<br />
unknown size, estimates of frequency cannot be made. These events<br />
are listed below by COSTART body system.<br />
Body as a Whole - anaphylactic/anaphylactoid reactions; Digestive<br />
System - hepatotoxicity, pancreatitis, vomiting; Hemic and Lymphatic<br />
System - agranulocytosis, aplastic anemia, hemolytic anemia,<br />
leukopenia, neutropenia, pancytopenia, thrombocytopenia, and<br />
thrombotic thrombocytopenic purpura; Musculoskeletal System -<br />
myositis; Skin and Appendages - severe dermatologic reactions including<br />
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal<br />
necrolysis (some fatal); Special Senses - speech disorder; Urogenital<br />
System - interstitial nephritis, urinary retention.<br />
6.4 Laboratory Values<br />
The following changes in laboratory parameters in patients who<br />
received lansoprazole were reported as adverse reactions:<br />
Abnormal liver function tests, increased SGOT (AST), increased SGPT<br />
(ALT), increased creatinine, increased alkaline phosphatase, increased<br />
globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal<br />
AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood<br />
urea increased, crystal urine present, eosinophilia, hemoglobin decreased,<br />
hyperlipemia, increased/decreased electrolytes, increased/decreased<br />
cholesterol, increased glucocorticoids, increased LDH, increased/<br />
decreased/abnormal platelets, increased gastrin levels and positive fecal<br />
occult blood. Urine abnormalities such as albuminuria, glycosuria, and<br />
hematuria were also reported. Additional isolated laboratory abnormalities<br />
were reported.<br />
In the placebo controlled studies, when SGOT (AST) and SGPT<br />
(ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients,<br />
who received placebo and lansoprazole, respectively, had enzyme<br />
elevations greater than three times the upper limit of normal range<br />
at the final treatment visit. None of these patients who received<br />
lansoprazole reported jaundice at any time during the study.<br />
7 DRUG INTERACTIONS<br />
Drugs With pH-Dependent Absorption Kinetics<br />
Lansoprazole causes long-lasting inhibition of gastric acid secretion.<br />
Lansoprazole and other PPIs are likely to substantially decrease the<br />
systemic concentrations of the HIV protease inhibitor atazanavir,<br />
which is dependent upon the presence of gastric acid for absorption,<br />
and may result in a loss of therapeutic effect of atazanavir and the<br />
development of HIV resistance. Therefore, lansoprazole and other<br />
PPIs should not be coadministered with atazanavir [see Clinical<br />
Pharmacology (12.5)].<br />
It is theoretically possible that lansoprazole and other PPIs may interfere<br />
with the absorption of other drugs where gastric pH is an important<br />
determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron<br />
salts, ketoconazole) [see Clinical Pharmacology (12.5)].<br />
Warfarin<br />
In a study of healthy subjects, coadministration of single or multiple<br />
60 mg doses of lansoprazole and warfarin did not affect the<br />
pharmacokinetics of warfarin nor prothrombin time [see Clinical<br />
Pharmacology (12.5)]. However, there have been reports of increased<br />
INR and prothrombin time in patients receiving PPIs and warfarin<br />
concomitantly. Increases in INR and prothrombin time may lead to<br />
abnormal bleeding and even death. Patients treated with PPIs and<br />
warfarin concomitantly may need to be monitored for increases in INR<br />
and prothrombin time [see Clinical Pharmacology (12.5)].<br />
Tacrolimus<br />
Concomitant administration of lansoprazole and tacrolimus may<br />
increase whole blood levels of tacrolimus, especially in transplant<br />
patients who are intermediate or poor metabolizers of CYP2C19.<br />
Theophylline<br />
A minor increase (10%) in the clearance of theophylline was observed<br />
following the administration of lansoprazole concomitantly with<br />
theophylline. Although the magnitude of the effect on theophylline<br />
clearance is small, individual patients may require additional titration<br />
of their theophylline dosage when lansoprazole is started or stopped<br />
to ensure clinically effective blood levels [see Clinical Pharmacology<br />
(12.5)].<br />
8 USE IN SPECIFIC POPULATIONS<br />
8.1 Pregnancy<br />
Teratogenic Effects<br />
Pregnancy category B<br />
Reproduction studies have been performed in pregnant rats at oral<br />
doses up to 40 times the recommended human dose and in pregnant<br />
rabbits at oral doses up to 16 times the recommended human dose<br />
and have revealed no evidence of impaired fertility or harm to the fetus<br />
due to lansoprazole. There are, however, no adequate or well-controlled<br />
studies in pregnant women. Because animal reproduction studies are<br />
not always predictive of human response, this drug should be used<br />
during pregnancy only if clearly needed [see Nonclinical Toxicology<br />
(13.2)].<br />
8.3 Nursing Mothers<br />
Lansoprazole or its metabolites are excreted in the milk of rats. It is<br />
not known whether lansoprazole is excreted in human milk. Because<br />
many drugs are excreted in human milk, because of the potential for<br />
serious adverse reactions in nursing infants from lansoprazole, and<br />
because of the potential for tumorigenicity shown for lansoprazole<br />
in rat carcinogenicity studies, a decision should be made whether to<br />
discontinue nursing or to discontinue lansoprazole, taking into account<br />
the importance of lansoprazole to the mother.<br />
8.4 Pediatric Use<br />
The safety and effectiveness of lansoprazole have been established<br />
in pediatric patients 1 to 17 years of age for short-term treatment of<br />
symptomatic GERD and erosive esophagitis.<br />
One to 11 Years of Age<br />
In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric<br />
patients (1 to 11 years of age) with GERD were assigned, based on<br />
body weight, to receive an initial dose of either lansoprazole 15 mg<br />
daily if ≤ 30 kg or lansoprazole 30 mg daily if greater than 30 kg<br />
administered for 8 to 12 weeks. The lansoprazole dose was increased<br />
(up to 30 mg twice daily) in 24 of 66 pediatric patients after 2 or more<br />
weeks of treatment if they remained symptomatic. At baseline 85%<br />
of patients had mild to moderate overall GERD symptoms (assessed<br />
by investigator interview), 58% had non-erosive GERD and 42% had<br />
erosive esophagitis (assessed by endoscopy).<br />
After 8 to 12 weeks of lansoprazole treatment, the intent-to-treat<br />
analysis demonstrated an approximate 50% reduction in frequency<br />
and severity of GERD symptoms.<br />
Twenty-one of 27 erosive esophagitis patients were healed at 8<br />
weeks and 100% of patients were healed at 12 weeks by endoscopy<br />
(Table 2).<br />
Table 2: GERD Symptom Improvement and Erosive Esophagitis<br />
Healing Rates in Pediatric Patients Age 1 to 11<br />
GERD<br />
Final Visit a % (n/N)<br />
Symptomatic GERD<br />
Improvement in Overall GERD<br />
76% (47/62<br />
Symptoms b<br />
c )<br />
Erosive Esophagitis<br />
Improvement in Overall GERD<br />
81% (22/27)<br />
Symptoms b<br />
Healing Rate 100% (27/27)<br />
a<br />
At Week 8 or Week 12<br />
b<br />
Symptoms assessed by patients diary kept by caregiver.<br />
c<br />
No data were available for 4 pediatric patients.<br />
In a study of 66 pediatric patients in the age group 1 year to 11 years<br />
old after treatment with lansoprazole given orally in doses of 15 mg<br />
daily to 30 mg twice daily, increases in serum gastrin levels were<br />
similar to those observed in adult studies. Median fasting serum<br />
gastrin levels increased 89% from 51 pg/mL at baseline to 97 pg/<br />
mL [interquartile range (25 th to 75 th percentile) of 71 to 130 pg/mL]<br />
at the final visit.<br />
The pediatric safety of lansoprazole delayed-release capsules has<br />
been assessed in 66 pediatric patients aged 1 to 11 years of age. Of<br />
the 66 patients with GERD 85% (56/66) took lansoprazole for 8 weeks<br />
and 15% (10/66) took it for 12 weeks.<br />
The most frequently reported (2 or more patients) treatment-related<br />
adverse reactions in patients 1 to 11 years of age (N = 66) were<br />
constipation (5%) and headache (3%).<br />
Twelve to 17 Years of Age<br />
In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent<br />
patients (12 to 17 years of age) with symptomatic GERD were treated<br />
with lansoprazole for 8 to 12 weeks. Baseline upper endoscopies<br />
classified these patients into two groups: 64 (74%) nonerosive GERD<br />
and 23 (26%) erosive esophagitis (EE). The nonerosive GERD patients<br />
received lansoprazole 15 mg daily for 8 weeks and the EE patients<br />
received lansoprazole 30 mg daily for 8 to 12 weeks. At baseline, 89% of<br />
these patients had mild to moderate overall GERD symptoms (assessed<br />
by investigator interviews). During 8 weeks of lansoprazole treatment,<br />
adolescent patients experienced a 63% reduction in frequency and a<br />
69% reduction in severity of GERD symptoms based on diary results.<br />
Twenty-one of 22 (95.5%) adolescent erosive esophagitis patients<br />
were healed after 8 weeks of lansoprazole treatment. One patient<br />
remained unhealed after 12 weeks of treatment (Table 3).<br />
Table 3: GERD Symptom Improvement and Erosive Esophagitis<br />
Healing Rates in Pediatric Patients Age 12 to 17<br />
GERD<br />
Final Visit % (n/N)<br />
Symptomatic GERD (All Patients)<br />
Improvement in Overall GERD<br />
73.2% (60/82)<br />
Symptoms a<br />
b<br />
Nonerosive GERD<br />
Improvement in Overall GERD<br />
71.2% (42/59)<br />
Symptoms a<br />
b<br />
Erosive Esophagitis<br />
Improvement in Overall GERD<br />
78.3% (18/23)<br />
Symptoms a<br />
Healing Rate c<br />
95.5% (21/22) c<br />
a<br />
Symptoms assessed by patient diary (parents/caregivers as<br />
necessary).<br />
b<br />
No data available for 5 patients.<br />
c<br />
Data from one healed patient was excluded from this analysis due<br />
to timing of final endoscopy.<br />
In these 87 adolescent patients, increases in serum gastrin levels<br />
were similar to those observed in adult studies, median fasting serum<br />
gastrin levels increased 42% from 45 pg/mL at baseline to 64 pg/<br />
mL [interquartile range (25 th to 75 th percentile) of 44 to 88 pg/mL]<br />
at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL.)<br />
The safety of lansoprazole delayed-release capsules has been<br />
assessed in these 87 adolescent patients. Of the 87 adolescent<br />
patients with GERD, 6% (5/87) took lansoprazole for less than 6<br />
weeks, 93% (81/87) for 6 to 10 weeks, and 1% (1/87) for greater<br />
than 10 weeks.<br />
The most frequently reported (at least 3%) treatment-related adverse<br />
reactions in these patients were headache (7%), abdominal pain<br />
(5%), nausea (3%) and dizziness (3%). Treatment-related dizziness,<br />
reported in this package insert as occurring in less than 1% of<br />
adult patients, was reported in this study by 3 adolescent patients<br />
with nonerosive GERD, who had dizziness concurrently with other<br />
reactions (such as migraine, dyspnea, and vomiting).<br />
8.5 Geriatric Use<br />
No dosage adjustment of lansoprazole is necessary in geriatric<br />
patients. The incidence rates of lansoprazole-associated adverse<br />
reactions and laboratory test abnormalities are similar to those seen<br />
in younger patients [see Clinical Pharmacology (12.4)].<br />
8.6 Renal Impairment<br />
No dosage adjustment of lansoprazole is necessary in patients with<br />
renal impairment. The pharmacokinetics of lansoprazole in patients<br />
with various degrees of renal impairment were not substantially<br />
different compared to those in subjects with normal renal function<br />
[see Clinical Pharmacology (12.4)].<br />
8.7 Hepatic Impairment<br />
In patients with various degrees of chronic hepatic impairment, an<br />
increase in the mean AUC of up to 500% was observed at steady state<br />
compared to healthy subjects. Consider dose reduction in patients with<br />
severe hepatic impairment [see Clinical Pharmacology (12.4)].<br />
8.8 Gender<br />
Over 4,000 women were treated with lansoprazole. Ulcer healing<br />
rates in females were similar to those in males. The incidence rates<br />
of adverse reactions in females were similar to those seen in males<br />
[see Clinical Pharmacology (12.4)].<br />
8.9 Race<br />
The pooled mean pharmacokinetic parameters of lansoprazole from<br />
twelve U.S. Phase 1 studies (N = 513) were compared to the mean<br />
pharmacokinetic parameters from two Asian studies (N = 20). The<br />
mean AUCs of lansoprazole in Asian subjects were approximately<br />
twice those seen in pooled U.S. data; however, the inter-individual<br />
variability was high. The C max values were comparable.
12 CLINICAL PHARMACOLOGY<br />
12.4 Specific Populations<br />
Pediatric Use<br />
One to 17 years of age<br />
The pharmacokinetics of lansoprazole were studied in pediatric patients<br />
with GERD aged 1 to 11 years and 12 to 17 years in two separate<br />
clinical studies. In children aged 1 to 11 years, lansoprazole was dosed<br />
15 mg daily for subjects weighing ≤ 30 kg and 30 mg daily for subjects<br />
weighing greater than 30 kg. Mean C max and AUC values observed on<br />
Day 5 of dosing were similar between the two dose groups and were<br />
not affected by weight or age within each weight-adjusted dose group<br />
used in the study. In adolescent subjects aged 12 to 17 years, subjects<br />
were randomized to receive lansoprazole at 15 mg or 30 mg daily.<br />
Mean C max and AUC values of lansoprazole were not affected by body<br />
weight or age; and nearly dose-proportional increases in mean C max and<br />
AUC values were observed between the two dose groups in the study.<br />
Overall, lansoprazole pharmacokinetics in pediatric patients aged 1<br />
to 17 years were similar to those observed in healthy adult subjects.<br />
Geriatric Use: The clearance of lansoprazole is decreased in the<br />
elderly, with elimination half-life increased approximately 50% to<br />
100%. Because the mean half-life in the elderly remains between<br />
1.9 to 2.9 hours, repeated once daily dosing does not result in<br />
accumulation of lansoprazole. Peak plasma levels were not increased<br />
in the elderly. No dosage adjustment is necessary in the elderly [see<br />
Use in Specific Populations (8.5)].<br />
Renal Impairment: In patients with severe renal impairment, plasma<br />
protein binding decreased by 1.0% to 1.5% after administration of 60<br />
mg of lansoprazole. Patients with renal impairment had a shortened<br />
elimination half-life and decreased total AUC (free and bound). The AUC<br />
for free lansoprazole in plasma, however, was not related to the degree<br />
of renal impairment; and the C max and t max (time to reach the maximum<br />
concentration) were not different than the C max and t max from subjects<br />
with normal renal function. No dosage adjustment is necessary in<br />
patients with renal impairment [see Use in Specific Populations (8.6)].<br />
Hepatic Impairment: In patients with various degrees of chronic hepatic<br />
impairment, the mean plasma half-life of lansoprazole was prolonged<br />
from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up<br />
to 500% was observed at steady state in hepatically-impaired patients<br />
compared to healthy subjects. Consider dose reduction in patients with<br />
severe hepatic impairment [see Use in Specific Populations (8.7)].<br />
Gender: In a study comparing 12 male and 6 female human subjects<br />
who received lansoprazole, no gender differences were found in<br />
pharmacokinetics and intragastric pH results [see Use in Specific<br />
Populations (8.5)].<br />
12.5 Drug-Drug Interactions<br />
It is theoretically possible that lansoprazole may interfere with<br />
the absorption of other drugs where gastric pH is an important<br />
determinant of bioavailability (e.g., ketoconazole, ampicillin esters,<br />
iron salts, digoxin).<br />
Lansoprazole is metabolized through the cytochrome P 450 system,<br />
specifically through the CYP3A and CYP2C19 isozymes. Studies have<br />
shown that lansoprazole does not have clinically significant interactions<br />
with other drugs metabolized by the cytochrome P 450 system, such as<br />
warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol,<br />
prednisone, diazepam, or clarithromycin in healthy subjects. These<br />
compounds are metabolized through various cytochrome P 450<br />
isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.<br />
Atazanavir: Lansoprazole causes long-lasting inhibition of gastric<br />
acid secretion. Lansoprazole substantially decreases the systemic<br />
concentrations of the HIV protease inhibitor atazanavir, which is<br />
dependent upon the presence of gastric acid for absorption, and may<br />
result in a loss of therapeutic effect of atazanavir and the development of<br />
HIV resistance. Therefore, lansoprazole, or other proton pump inhibitors,<br />
should not be coadministered with atazanavir.<br />
Theophylline: When lansoprazole was administered concomitantly<br />
with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the<br />
clearance of theophylline was seen. Because of the small magnitude<br />
and the direction of the effect on theophylline clearance, this<br />
interaction is unlikely to be of clinical concern. Nonetheless, individual<br />
patients may require additional titration of their theophylline dosage<br />
when lansoprazole is started or stopped to ensure clinically effective<br />
blood levels.<br />
Warfarin: In a study of healthy subjects neither the pharmacokinetics<br />
of warfarin enantiomers nor prothrombin time were affected<br />
following single or multiple 60 mg doses of lansoprazole. However,<br />
there have been reports of increased International Normalized Ratio<br />
(INR) and prothrombin time in patients receiving proton pump<br />
inhibitors, including lansoprazole, and warfarin concomitantly.<br />
Increases in INR and prothrombin time may lead to abnormal<br />
bleeding and even death. Patients treated with proton pump<br />
inhibitors and warfarin concomitantly may need to be monitored for<br />
increases in INR and prothrombin time.<br />
Methotrexate and 7-hydromethotrexate: In an open-label, singlearm,<br />
eight-day, pharmacokinetic study of 28 adult rheumatoid<br />
arthritis patients (who required the chronic use of 7.5 to 15 mg of<br />
methotrexate given weekly), administration of 7 days of naproxen<br />
500 mg twice daily and lansoprazole 30 mg daily had no effect on the<br />
pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While<br />
this study was not designed to assess the safety of this combination<br />
of drugs, no major adverse reactions were noted.<br />
Amoxicillin: Lansoprazole has also been shown to have no clinically<br />
significant interaction with amoxicillin.<br />
Sucralfate: In a single-dose crossover study examining lansoprazole<br />
30 mg and omeprazole 20 mg each administered alone and<br />
concomitantly with sucralfate 1 gram, absorption of the proton<br />
pump inhibitors was delayed and their bioavailability was reduced<br />
by 17% and 16%, respectively, when administered concomitantly<br />
with sucralfate. Therefore, proton pump inhibitors should be taken<br />
at least 30 minutes prior to sucralfate. In clinical trials, antacids<br />
were administered concomitantly with lansoprazole and there was no<br />
evidence of a change in the efficacy of lansoprazole.<br />
13 NONCLINICAL TOXICOLOGY<br />
13.1 Carcinogenesis, Mutagenesis, Impairment of<br />
Fertility<br />
In two 24 month carcinogenicity studies, Sprague-Dawley rats were<br />
treated with oral lansoprazole doses of 5 to 150 mg/kg/day - about<br />
1 to 40 times the exposure on a body surface (mg/m 2 ) basis of a 50<br />
kg person of average height [1.46 m 2 body surface area (BSA)] given<br />
the recommended human dose of 30 mg/day. Lansoprazole produced<br />
dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and<br />
ECL cell carcinoids in both male and female rats. It also increased<br />
the incidence of intestinal metaplasia of the gastric epithelium in<br />
both sexes. In male rats, lansoprazole produced a dose-related<br />
increase of testicular interstitial cell adenomas. The incidence of these<br />
adenomas in rats receiving doses of 15 to 150 mg/kg/day (4 to 40<br />
times the recommended human dose based on BSA) exceeded the<br />
low background incidence (range = 1.4 to 10%) for this strain of rat.<br />
In a 24 month carcinogenicity study, CD-1 mice were treated with<br />
oral lansoprazole doses of 15 to 600 mg/kg/day, 2 to 80 times the<br />
recommended human dose based on BSA. Lansoprazole produced<br />
a dose-related increased incidence of gastric ECL cell hyperplasia. It<br />
also produced an increased incidence of liver tumors (hepatocellular<br />
adenoma plus carcinoma). The tumor incidences in male mice treated<br />
with 300 and 600 mg/kg/day (40 to 80 times the recommended<br />
human dose based on BSA) and female mice treated with 150 to<br />
600 mg/kg/day (20 to 80 times the recommended human dose<br />
based on BSA) exceeded the ranges of background incidences in<br />
historical controls for this strain of mice. Lansoprazole treatment<br />
produced adenoma of rete testis in male mice receiving 75 to<br />
600 mg/kg/day (10 to 80 times the recommended human dose<br />
based on BSA).<br />
A 26 week p53 (+/-) transgenic mouse carcinogenicity study was<br />
not positive.<br />
Lansoprazole was not genotoxic in the Ames test, the ex vivo rat<br />
hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo<br />
mouse micronucleus test, or the rat bone marrow cell chromosomal<br />
aberration test. It was positive in in vitro human lymphocyte<br />
chromosomal aberration assays.<br />
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the<br />
recommended human dose based on BSA) was found to have no<br />
effect on fertility and reproductive performance of male and female rats.<br />
13.2 Animal Toxicology and/or Pharmacology<br />
Reproductive Toxicology Studies<br />
Reproduction studies have been performed in pregnant rats at oral<br />
lansoprazole doses up to 150 mg/kg/day [40 times the recommended<br />
human dose (30 mg/day) based on body surface area (BSA)] and<br />
pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day<br />
(16 times the recommended human dose based on BSA) and have<br />
revealed no evidence of impaired fertility or harm to the fetus due<br />
to lansoprazole.<br />
17 PATIENT COUNSELING INFORMATION<br />
Patients should be informed of the following:<br />
17.1 Information for Patients<br />
Lansoprazole is available as a capsule and is available in 15 mg and<br />
30 mg strengths. Directions for use specific to the route and available<br />
methods of administration for this dosage form is presented below<br />
[see Dosage and Administration (2.3)].<br />
• Lansoprazole delayed-release capsules should be taken before<br />
eating.<br />
• Lansoprazole delayed-release capsules SHOULD NOT BE<br />
CRUSHED OR CHEWED.<br />
Administration Options<br />
Lansoprazole Delayed-Release Capsules<br />
• Lansoprazole delayed-release capsules should be swallowed<br />
whole.<br />
• Alternatively, for patients who have difficulty swallowing capsules,<br />
lansoprazole delayed-release capsules can be opened and<br />
administered as follows:<br />
• Open capsule.<br />
• Sprinkle intact granules on one tablespoon of either applesauce,<br />
ENSURE ® pudding, cottage cheese, yogurt or strained pears.<br />
• Swallow immediately.<br />
• Lansoprazole delayed-release capsules may also be emptied into<br />
a small volume of either apple juice, orange juice or tomato juice<br />
and administered as follows:<br />
• Open capsule.<br />
• Sprinkle intact granules into a small volume of either apple juice,<br />
orange juice or tomato juice (60 mL — approximately 2 ounces).<br />
• Mix briefly.<br />
• Swallow immediately.<br />
• To ensure complete delivery of the dose, the glass should be<br />
rinsed with two or more volumes of juice and the contents<br />
swallowed immediately.<br />
USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED<br />
CLINICALLY AND IS THEREFORE NOT RECOMMENDED.<br />
ENSURE ® is a registered trademark of Abbott Laboratories.<br />
Manufactured In Israel By:<br />
TEVA PHARMACEUTICAL IND. LTD.<br />
Jerusalem, 91010, Israel<br />
Manufactured For:<br />
TEVA PHARMACEUTICALS USA<br />
Sellersville, PA 18960<br />
Rev. B 11/2009
Consult Your <strong>Pharmacist</strong><br />
Strategies for the<br />
Relief of Bloating and Gas<br />
Patients often consider<br />
pharmacists as<br />
professionals to whom<br />
they can confide embarrassing<br />
medical problems<br />
in the hope that the<br />
pharmacist will provide<br />
some assistance. One<br />
such problem is abdominal<br />
bloating, often<br />
thought to be due to<br />
excess intestinal gas.<br />
However, patients may<br />
also experience abdominal<br />
discomfort they attribute<br />
to gas, but can be caused<br />
by several serious medical<br />
conditions.<br />
Prevalence of<br />
Bloating and Gas<br />
The prevalence of intestinal<br />
gas and bloating is<br />
unknown, as reliable<br />
large-scale studies do not<br />
exist. However, bloating<br />
and flatulence (defined as<br />
excessive air or other gas<br />
in the stomach and/or<br />
intestines) are two of the<br />
most common complaints<br />
for which patients seek<br />
medical care. 1<br />
Manifestations of<br />
Bloating and Gas<br />
Bloating and gas can<br />
cause several complaints<br />
or coexist with them.<br />
W. Steven Pray, PhD, DPh<br />
Bernhardt Professor, Nonprescription<br />
Products and Devices<br />
College of Pharmacy, Southwestern<br />
Oklahoma State University<br />
Weatherford, Oklahoma<br />
Undigested food passes from the small intestine into the large<br />
intestine, where bacteria break it down, producing gas that<br />
eventually exits through the rectum.<br />
Patients complain of<br />
excessive belching (eructation).<br />
2 Belching is a normal<br />
response during or<br />
after a meal, especially<br />
one that was eaten so rapidly<br />
that the patient also<br />
swallowed air. However,<br />
some patients swallow air<br />
intentionally to facilitate<br />
belching, a practice that<br />
can develop into an<br />
unconscious habit. Thus,<br />
if people burp excessively,<br />
they may be chronic air<br />
swallowers. Patients may<br />
deny that they swallow air<br />
as a nervous habit, forcing<br />
physicians to give them a<br />
mirror to observe the episodes<br />
themselves.<br />
Flatulence is a common<br />
and logical consequence<br />
of intestinal gas.<br />
Average patients with no<br />
© JOHN M. DAUGHERTY / PHOTO RESEARCHERS, INC<br />
pathology or underlying<br />
medical condition produce<br />
1 to 4 pints of<br />
intestinal gas per day and<br />
flatulate 14 to 23 times<br />
daily. 2,3<br />
Abdominal distention<br />
is an increase in abdominal<br />
girth that is frequently<br />
ascribed to excessive intestinal<br />
gas. 2,4 This perception<br />
is often incorrect, as<br />
many such patients have<br />
normal amounts of gas.<br />
Rather, investigators<br />
believe that these patients<br />
have a heightened awareness<br />
of intestinal gas.<br />
Thus, even normal volumes<br />
of gas cause troublesome<br />
symptoms.<br />
Abdominal pain is<br />
another complaint often<br />
thought to be due to<br />
gas. 2,3 It may arise from<br />
either side of the colon,<br />
mimicking such conditions<br />
as heart disease, gallstones,<br />
and appendicitis.<br />
Possible Causes of<br />
Bloating and Gas<br />
Various sources of excess<br />
gas have been identified,<br />
including air swallowing,<br />
diet, lactose intolerance,<br />
and irritable bowel syndrome<br />
(IBS).<br />
Aerophagia: Aerophagia,<br />
or air swallowing, has<br />
long been thought to be<br />
responsible for bloating<br />
and gas, as previously<br />
described. 5,6 But there<br />
had been little evidence<br />
to support the hypothesis,<br />
as logical as it sounds.<br />
However, in 2009, investigators<br />
confirmed the<br />
hypothesis by assessing<br />
swallowing frequency in<br />
general and air swallowing<br />
frequency in particular<br />
in patients with suspected<br />
aerophagia. 5 They<br />
identified a group of<br />
patients with typical<br />
complaints of bloating,<br />
abdominal distention,<br />
flatulence, and/or excessive<br />
belching. Abdominal<br />
x-rays confirmed the<br />
presence of excessive<br />
abdominal gas, the presumed<br />
source of the<br />
complaints. The researchers<br />
carried out 24-hour<br />
pH-impedance monitor-<br />
16<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
✁<br />
PATIENT INFORMATION<br />
Bloating and Gas: Not a Laughing Matter<br />
Bloating and intestinal gas are not considered polite subjects<br />
for discussion. Rather, they are very often a source of humor<br />
and ridicule. This aversion to discussing such subjects means<br />
that many patients suffer needlessly, when just a little advice<br />
can go a long way in improving their quality of life.<br />
© JUPITERIMAGES<br />
Swallowing Air<br />
When you swallow air, it<br />
must either be burped<br />
up or expelled as gas.<br />
Several problems can<br />
cause one to swallow air.<br />
Dentures that do not fit<br />
well cause you to<br />
swallow more saliva,<br />
which is mixed with air<br />
bubbles. If this is a<br />
possible cause, you<br />
should see the dental<br />
professional who fitted<br />
your dentures to have<br />
them adjusted. If you<br />
have postnasal discharge,<br />
you tend to swallow<br />
more than normal,<br />
allowing more air to<br />
enter your stomach.<br />
Judicious use of a nasal<br />
decongestant (e.g.,<br />
Sudafed, Afrin) may<br />
help. Smoking cigarettes,<br />
cigars, or pipes and<br />
using chewing tobacco<br />
can increase salivation<br />
and contribute to<br />
excessive bloating, as can<br />
talking too much.<br />
Some people belch<br />
excessively, either as a<br />
nervous habit or perhaps<br />
as a source of humor. To<br />
accomplish intentional<br />
belching, the person<br />
often first swallows<br />
air, followed by the<br />
belching. However, he or<br />
she seldom releases all of<br />
the swallowed air, and it<br />
becomes flatulence.<br />
Dietary Issues<br />
Eating too rapidly causes<br />
you to swallow extra air.<br />
You should slow your<br />
eating and chew the<br />
food thoroughly before<br />
swallowing it. Chewing<br />
gum and sucking on<br />
hard candy also increase<br />
the amount of swallowed<br />
air, so these practices<br />
should be reduced.<br />
An easy way to help<br />
minimize bloating and<br />
gas is to focus on<br />
carbonated beverages<br />
(e.g., Coke, Pepsi).<br />
Manufacturers<br />
intentionally add<br />
carbonation to all of<br />
these sodas to give the<br />
products their “fizz.”<br />
When the bottle or can<br />
is agitated before being<br />
opened, everyone knows<br />
what the result will<br />
PHARMACY STAMP<br />
be—a great deal of<br />
bubbly drink on the<br />
floor. As a person drinks<br />
the beverage, the<br />
carbonation bubbles<br />
enter the stomach. If<br />
they are not belched out,<br />
they become excess<br />
flatulence. Many people<br />
could reduce gas<br />
problems dramatically by<br />
simply eliminating all<br />
carbonated beverages. If<br />
a person refuses to take<br />
this simple step, perhaps<br />
he or she can be<br />
convinced to allow the<br />
drinks to sit out on the<br />
counter at room<br />
temperature for several<br />
hours, which allows<br />
them to go flat and thus<br />
reduces the amount of<br />
swallowed gas.<br />
The same advice can<br />
be given to beer<br />
drinkers. Beer contains<br />
gas, as indicated by the<br />
frothy head that<br />
develops when it is<br />
poured. You should<br />
completely eliminate it<br />
from your diet to see if<br />
your symptoms improve.<br />
A major dietary cause<br />
of gas is beans, as well as<br />
other foods with<br />
indigestible components,<br />
such as cabbage,<br />
cauliflower, and broccoli.<br />
Your intestinal bacteria<br />
use these components as<br />
foods, producing gas as a<br />
by-product.<br />
Lactose intolerance<br />
also contributes to gas<br />
and bloating. It is best<br />
to avoid dairy products<br />
or to take supplements<br />
that contain lactase, such<br />
as Lactaid.<br />
Consult Your<br />
<strong>Pharmacist</strong><br />
There are several OTC<br />
products you can take to<br />
help relieve symptoms.<br />
Your pharmacist can<br />
assist you by advising on<br />
the use of simethicone<br />
(e.g., Gas-X, Mylanta<br />
Gas, Phazyme), which<br />
eases elimination of gas.<br />
Beano, a product that<br />
reduces the amount of<br />
gas, is a liquid solution<br />
that can be applied<br />
directly to food or taken<br />
as a tablet prior to<br />
eating.<br />
Remember, if you have questions, Consult Your <strong>Pharmacist</strong>.<br />
17<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
YOU’RE USED TO ANSWERING JUST ABOUT ANY QUESTION CUSTOMERS COME UP WITH.<br />
Teaching customers about Humalog ® KwikPen doesn’t change that. Humalog KwikPen is part of the Humalog ® approach,<br />
designed to help fit mealtime therapy into a patient’s life. And now, the maker of Humalog is offering a complimentary Humalog<br />
KwikPen Pharmacy Kit with a demonstration pen to help educate your customers and information to answer<br />
their questions.<br />
For more details or to order a kit, visit www.kwikpenpharmkit.com.<br />
Humalog is for use in patients with diabetes mellitus for the control of hyperglycemia.<br />
Hypoglycemia is the most common adverse effect associated with insulins, including Humalog.<br />
For complete safety profile, please see Important Safety Information on adjacent page and accompanying<br />
Brief Summary of full Prescribing Information.<br />
Please see full user manual that accompanies the pen.
Indication<br />
Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control<br />
of hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination<br />
with sulfonylureas in patients with type 2 diabetes.<br />
Important Safety Information<br />
Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one<br />
of its excipients.<br />
Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of<br />
action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or<br />
immediately after a meal.<br />
Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longeracting<br />
insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is<br />
recommended for all patients with diabetes.<br />
The safety and effectiveness of Humalog in patients less than 3 years of age have not been established.<br />
There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or<br />
nursing women.<br />
Starting or changing insulin therapy should be done cautiously and only under medical supervision.<br />
Hypoglycemia<br />
Hypoglycemia is the most common adverse effect associated with insulins, including Humalog.<br />
Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change<br />
from time to time. Severe hypoglycemia can cause seizures and may be life-threatening.<br />
Other Side Effects<br />
Other potential side effects associated with the use of insulins include: hypokalemia, weight gain,<br />
lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening.<br />
Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia<br />
or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal<br />
impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level).<br />
For additional safety profile and other important prescribing considerations, see accompanying Brief<br />
Summary of full Prescribing Information.<br />
Please see full user manual that accompanies the pen.<br />
Humalog ® is a registered trademark of Eli Lilly and Company and is available by prescription only.<br />
Humalog ® KwikPen is a trademark of Eli Lilly and Company and is available by prescription only.<br />
HI59613 0909 PRINTED IN USA ©2009, LILLY USA, LLC. ALL RIGHTS RESERVED.
HUMALOG ®<br />
INSULIN LISPRO INJECTION (rDNA ORIGIN)<br />
BRIEF SUMMARY: Consult package insert for complete prescribing information.<br />
INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with<br />
diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of<br />
action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in<br />
regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used<br />
without a longer-acting insulin when used in combination therapy with sulfonylurea agents.<br />
Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other<br />
insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients<br />
with type 2 diabetes.<br />
CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to<br />
Humalog or any of its excipients.<br />
WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well<br />
as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given<br />
within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog,<br />
patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when<br />
using an external insulin pump).<br />
External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed<br />
with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s<br />
instructions and the “PATIENT INFORMATION” leaflet before using Humalog.<br />
Physicians should carefully evaluate information on external insulin pump use in the Humalog physician<br />
package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or<br />
ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary.<br />
The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients<br />
Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION).<br />
Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog.<br />
As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose<br />
monitoring is recommended for all patients with diabetes and is particularly important for patients using an<br />
external insulin pump.<br />
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin<br />
strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the<br />
need for a change in dosage.<br />
PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects<br />
associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care<br />
should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are<br />
fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to<br />
serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects<br />
associated with the use of all insulins.<br />
As with all insulin preparations, the time course of Humalog action may vary in different individuals or at<br />
different times in the same individual and is dependent on site of injection, blood supply, temperature, and<br />
physical activity.<br />
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual<br />
meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress.<br />
Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the<br />
administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of<br />
hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of<br />
hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes,<br />
diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control.<br />
Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment.<br />
Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of<br />
Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary.<br />
Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching<br />
at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances,<br />
these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor<br />
injection technique.<br />
Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may<br />
cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure,<br />
rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be lifethreatening.<br />
Localized reactions and generalized myalgias have been reported with the use of cresol as an<br />
injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients<br />
receiving Humulin R ® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053).<br />
Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro<br />
were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the<br />
antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy.<br />
Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter),<br />
Disetronic ® D-TRON ®2,3 or D-TRONplus ®2,3 cartridge adapter, and Humalog in the external insulin pump<br />
reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external<br />
insulin pump should not be exposed to temperatures above 37°C (98.6°F).<br />
In the D-TRON ®2,3 or D-TRONplus ®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However,<br />
as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be<br />
selected every 48 hours or less.<br />
When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see<br />
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of<br />
Insulins, DOSAGE AND ADMINISTRATION, and Storage).<br />
Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and<br />
alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection<br />
technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose<br />
monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia,<br />
and periodic assessment for diabetes complications.<br />
Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.<br />
Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (
Consult Your <strong>Pharmacist</strong><br />
ing on subjects, discovering<br />
that swallowing frequency<br />
for the 24-hour<br />
period was normal (741<br />
+/- 71 episodes), but the<br />
number of air swallows<br />
and gastric belches was<br />
excessive (521 +/- 63 and<br />
126 +/-37, respectively).<br />
Thus, the advice presented<br />
in this month’s<br />
Patient Information section<br />
regarding air swallowing<br />
may be beneficial<br />
for these patients.<br />
Diet: Diet is a major<br />
cause of bloating and gas.<br />
One of the most common<br />
dietary issues is eating<br />
foods that cannot be<br />
digested in the gastrointestinal<br />
(GI) tract due to<br />
a lack of the necessary<br />
enzymes. 1,2<br />
If certain food residues<br />
(mostly carbohydrates)<br />
reach the large intestine,<br />
normal bacterial residents<br />
utilize them as food<br />
sources, producing carbon<br />
dioxide, hydrogen, and<br />
sometimes methane as byproducts.<br />
1,2 Exactly which<br />
foods cause gas varies<br />
from person to person.<br />
Some patients’ bowel<br />
microorganisms destroy<br />
hydrogen, lessening their<br />
intestinal gas burden. 2<br />
Nevertheless, some foods<br />
are universally identified<br />
as gas producers.<br />
Carbohydrate-containing<br />
foods are among the<br />
most common culprits in<br />
causing intestinal gas,<br />
whereas fatty foods and<br />
proteins are seldom<br />
responsible. 1,2,7 Raffinose<br />
A Dictator and His Flatulence<br />
It is remarkable how often flatulence is used for its shock<br />
value. In 1945, a high-ranking Nazi officer communicated<br />
a candid portrait of Adolf Hitler to a British agent. 16 The<br />
top-secret papers were to have been destroyed immediately,<br />
but they were not. Their discovery in 2009 after a<br />
house clearance gave new insights into Hitler’s habits and<br />
behaviors. Although the papers also contained critically<br />
important insights into the tyrant’s personality, the headlines<br />
focused on Hitler’s flatulence, a relatively minor matter<br />
presumably of little interest to historians.<br />
is one such complex<br />
sugar, being found in the<br />
indigestible seed coatings<br />
of beans, cabbage, brussels<br />
sprouts, broccoli, asparagus,<br />
other vegetables, and<br />
whole grains. 2 Fructose is<br />
another offender, found<br />
in onions, artichokes,<br />
pears, and wheat; it is also<br />
used as an artificial sweetener.<br />
Sorbitol is also an<br />
artificial sweetener, but it<br />
is a naturally occurring<br />
component of apples,<br />
pears, peaches, and<br />
prunes. Sorbitol is a cause<br />
of “Halloween diarrhea,”<br />
a phenomenon experienced<br />
by many children<br />
who consume large<br />
amounts of candy on<br />
Halloween night. Numerous<br />
patients also report<br />
that psyllium ingested to<br />
ensure regularity causes<br />
gas (e.g., Metamucil,<br />
Konsyl). These patients<br />
may benefit by switching<br />
to methylcellulose, an<br />
FDA-approved fiber supplement<br />
that is not fermented<br />
by colonic bacteria<br />
(e.g., Citrucel).<br />
Lactose Intolerance:<br />
Lactose intolerance (LI)<br />
is another type of carbohydrate<br />
malabsorption,<br />
discussed separately<br />
because of its different<br />
etiologies. 1 Lactase found<br />
in the brush border cells<br />
of the small intestine is<br />
essential for breaking lactose<br />
down into its component<br />
sugars for absorption.<br />
Lactase deficiency is<br />
the underlying defect<br />
behind LI.<br />
There are two major<br />
types of LI. They share<br />
the same consequences, in<br />
that undigested lactose<br />
reaches the intestinal tract,<br />
where the colonic microbiota<br />
digest it, producing<br />
gas, diarrhea, bloating,<br />
borborygmus, and a host<br />
of other complaints,<br />
beginning as early as 30<br />
minutes after ingestion. 8,9<br />
The more common type<br />
of LI is the primary form,<br />
experienced by most of<br />
the world’s peoples,<br />
including those of African,<br />
Native American, and<br />
Asian heritage. In primary<br />
LI, lactase activity drops<br />
sharply after weaning<br />
from breast milk, until it<br />
is virtually absent. Drinking<br />
milk or ingesting dairy<br />
products causes the symptoms<br />
to begin.<br />
Some people also suffer<br />
from secondary LI. They<br />
normally produce lactase<br />
as adults, but an environmental<br />
insult or surgical<br />
procedure compromises<br />
their ability to do so. Possible<br />
causes of secondary<br />
LI include chemotherapy,<br />
diarrheal diseases, small<br />
intestine resection, or<br />
celiac disease. 1 <strong>Pharmacist</strong>s<br />
can direct patients with<br />
suspected LI to lactasecontaining<br />
supplements<br />
(e.g., Lactaid) or lactosefree<br />
dairy products.<br />
Irritable Bowel Syndrome:<br />
IBS causes abdominal<br />
pain, cramping, bloating,<br />
constipation, and diarrhea.<br />
10-12 About 20% of<br />
Americans suffer from<br />
IBS, perhaps due to<br />
colonic hypersensitivity to<br />
specific foods or in<br />
response to stressful situations.<br />
11 <strong>Pharmacist</strong>s should<br />
refer patients with suspected<br />
IBS to a physician<br />
for a full evaluation, but<br />
they can also advise<br />
patients to keep a food<br />
diary to help identify<br />
dietary causes of IBS.<br />
Elimination of certain<br />
foods and drinks (e.g.,<br />
chocolate, alcohol, caffeine,<br />
cola, tea, peppers,<br />
onions) may be all that is<br />
needed to provide relief.<br />
Nonprescription<br />
Products<br />
<strong>Pharmacist</strong>s can recommend<br />
two types of nonprescription<br />
products<br />
other than lactose-intolerance<br />
products. One<br />
21<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Consult Your <strong>Pharmacist</strong><br />
group of products contains<br />
simethicone, a nontoxic<br />
and hypoallergenic<br />
ingredient that is FDA<br />
approved as safe and<br />
effective in breaking<br />
down bubbles or froth in<br />
the GI tract, although<br />
the total amount of gas<br />
remains the same. 1<br />
Simethicone’s usefulness<br />
may be due to several<br />
factors. Some patients<br />
may experience abdominal<br />
discomfort as normal<br />
amounts of intestinal gas<br />
move through them.<br />
Reducing froth may<br />
allow the gas to pass<br />
through more readily.<br />
Further, patients using<br />
simethicone may be able<br />
to eliminate gas in several<br />
larger episodes, reducing<br />
the perception of excessive<br />
gas. Products with<br />
simethicone include<br />
Mylanta Gas, Phazyme,<br />
and Gas-X. The dosage is<br />
typically 1 or 2 units as<br />
needed after meals and at<br />
bedtime.<br />
Alpha-galactosidase is<br />
another means to prevent<br />
bloating and gas. 1,13 This<br />
is an enzyme derived<br />
from Aspergillus niger, and<br />
it has the ability to break<br />
down the oligosaccharide<br />
linkages that humans cannot<br />
digest. The patient is<br />
then able to absorb the<br />
single-component sugar<br />
residues. In research<br />
exploring the enzyme’s<br />
efficacy, subjects ingested<br />
two meals of meatless<br />
chili composed of several<br />
types of beans, cabbage,<br />
cauliflower, and onions. 14<br />
They were given either a<br />
placebo or the commercially<br />
available alphagalactosidase<br />
product,<br />
known as Beano. Beano<br />
reduced the number of<br />
flatulence events at all<br />
times except for 2 hours<br />
postingestion. The effect<br />
was most pronounced 5<br />
hours after the meal. 14<br />
To use Beano solution,<br />
the patient places approximately<br />
5 drops on the<br />
first bite of troublesome<br />
food, such as beans, cabbage,<br />
cauliflower, broccoli,<br />
grains, cereals, nuts,<br />
seeds, and whole-grain<br />
breads. 13 That amount<br />
usually covers a half-cup<br />
serving of food. If the<br />
meal consists of two or<br />
three servings of the food,<br />
the patient should place<br />
10 to 15 drops on the<br />
meal. However, if the<br />
patient still experiences<br />
flatulence, the amount<br />
can be adjusted upward<br />
until an effective dose is<br />
reached. The patient may<br />
also swallow or chew a<br />
Beano tablet with the<br />
first bite of food or crumble<br />
it onto the first bite.<br />
One tablet usually digests<br />
a half-cup serving; more<br />
tablets can be used for<br />
larger portions. Patients<br />
cannot cook with Beano<br />
because of heat-induced<br />
enzyme degradation.<br />
Patients with galactosemia<br />
should consult a<br />
physician prior to use<br />
since enzymatic degradation<br />
of oligosaccharides<br />
produces galactose. Beano<br />
is labeled only for<br />
patients aged 12 years<br />
and above. While it<br />
appears to be safe during<br />
pregnancy and breastfeeding,<br />
there are no studies<br />
to confirm that observation.<br />
At one time, the<br />
manufacturer recommended<br />
that patients<br />
allergic to molds not use<br />
Beano, but the present<br />
view is that the caution is<br />
not supported by medical<br />
literature. 13<br />
Addition Diets<br />
<strong>Pharmacist</strong>s can also<br />
advise patients to undergo<br />
an addition diet. 15 With<br />
this method, the patient<br />
eliminates all foods and<br />
drinks that are thought to<br />
produce symptoms. If<br />
symptoms improve, the<br />
patient continues the diet<br />
for several days until<br />
reaching a perceived normal<br />
level, a state known<br />
as normoflatulence. 15 Then<br />
one new food or drink is<br />
added, and the patient<br />
records the results in a<br />
diary, paying particular<br />
attention to the intensity<br />
of the symptoms.<br />
Patients should discontinue<br />
any troublesome<br />
food for the duration of<br />
the addition diet and<br />
add another suspected<br />
food or drink after 48<br />
hours. After several<br />
weeks of following this<br />
simple procedure, the<br />
patient begins to build a<br />
profile of difficult foods.<br />
Eventually all suspected<br />
foods will be identified,<br />
and the patient will have<br />
a much better idea of<br />
how to choose foods and<br />
drinks, even when visiting<br />
a restaurant.<br />
REFERENCES<br />
1. Pray WS. Nonprescription Product Therapeutics.<br />
2nd ed. Baltimore, MD: Lippincott<br />
Williams & Wilkins; 2006.<br />
2. Gas in the digestive tract. NIDDK.<br />
http://digestive.niddk.nih.gov/ddiseases/pubs/<br />
gas/. Accessed October 29, 2009.<br />
3. Gas—flatulence. MedlinePlus. www.nlm.nih.<br />
gov/medlineplus/ency/article/003124.htm.<br />
Accessed October 29. 2009.<br />
4. Agrawal A, Whorwell PJ. Review article:<br />
abdominal bloating and distension in functional<br />
gastrointestinal disorders—epidemiology and<br />
explorations of possible mechanisms. Aliment<br />
Pharmacol Ther. 2008;27:2-10.<br />
5. Hemmink GJ, Weusten BL, Bredenoord AJ,<br />
et al. Aerophagia: excessive air swallowing demonstrated<br />
by esophageal impedance monitoring.<br />
Clin Gastroenterol Hepatol. 2009;7:1127-1129.<br />
6. Azpiroz F. Intestinal gas dynamics: mechanisms<br />
and clinical relevance. Gut. 2005;54:<br />
893-895.<br />
7. Hernot DC, Boileau TW, Bauer LL, et al.<br />
In vitro fermentation profiles, gas production<br />
rates, and microbiota modulation as affected by<br />
certain fructans, galactooligosaccharides, and<br />
polydextrose. J Agric Food Chem. 2009;57:<br />
1354-1361.<br />
8. Saulnier DM, Kolida S, Gibson GR.<br />
Microbiology of the human intestinal tract and<br />
approaches for its dietary modulation.<br />
Curr Pharm Des. 2009;15:1403-1414.<br />
9. Ozdemir O, Mete E, Catal F, et al. Food<br />
intolerances and eosinophilic esophagitis in<br />
childhood. Dig Dis Sci. 2009;54:8-14.<br />
10. Gasbarrini A, Lauritano EC, Garcovich M,<br />
et al. New insights into the pathophysiology of<br />
IBS: intestinal microflora, gas production and<br />
gut motility. Eur Rev Med Pharmacol Sci.<br />
2008;12(suppl 1):111-117.<br />
11. Irritable bowel syndrome. NIDDK.<br />
http://digestive.niddk.nih.gov/ddiseases/pubs/<br />
ibs/. Accessed October 29, 2009.<br />
12. Rana SV, Sharma S, Sinha SK, et al. Incidence<br />
of predominant methanogenic flora in<br />
irritable bowel syndrome patients and apparently<br />
healthy controls from North India. Dig<br />
Dis Sci. 2009;54:132-135.<br />
13. Beano FAQs. GlaxoSmithKline.<br />
www.beanogas.com/FAQ.aspx. Accessed<br />
October 29, 2009.<br />
14. Ganiats TG, Norcross WA, Halverson AL,<br />
et al. Does Beano prevent gas? A double-blind<br />
crossover study of oral alpha-galactosidase to<br />
treat dietary oligosaccharide intolerance. J Fam<br />
Pract. 1994;39:441-445.<br />
15. Clearfield HR. Clinical intestinal gas syndromes.<br />
Prim Care. 1996;23:621-628.<br />
16. Adolf Hitler had poor table manners and<br />
suffered flatulence. Telegraph. February 17,<br />
2009. www.telegraph.co.uk/news/newstopics/<br />
howaboutthat/4678840/Adolf-Hitler-had-poortable-manners-and-suffered-flatulence.html.<br />
Accessed October 29, 2009.<br />
22<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Brimonidine Tartrate Ophthalmic Solution, 0.15%<br />
Sterile<br />
DESCRIPTION<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% (1.5 mg brimonidine tartrate per mL equivalent to 1.0 mg<br />
brimonidine free base per mL) is a relatively selective alpha-2-adrenergic agonist for ophthalmic use. The<br />
chemical name of brimonidine tartrate is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. It is an<br />
off-white to pale yellow powder. It has a molecular weight of 442.24 as the tartrate salt, and is both soluble in<br />
water (1.5 mg/mL) and in the product vehicle (3.0 mg/mL) at pH 7.2. The structural formula is:<br />
Formula: C 11<br />
H 10<br />
BrN 5<br />
4<br />
H 6<br />
O 6<br />
CAS Number: 59803-98-4<br />
HN<br />
N<br />
NH<br />
Br<br />
In solution, Brimonidine Tartrate Ophthalmic Solution, 0.15% has a clear, greenish-yellow color. It has an<br />
osmolality of 250 – 350 mOsmol/kg and a pH of 6.6-7.4.<br />
Each mL of Brimonidine Tartrate Ophthalmic Solution, 0.15% contains: Active ingredient: brimonidine tartrate<br />
0.15% (1.5 mg/mL) Inactives: povidone; boric acid; sodium borate; calcium chloride; magnesium chloride;<br />
potassium chloride; mannitol; sodium chloride; POLYQUAD* 0.001% (0.01 mg/mL); purified water; with<br />
hydrochloric acid and/or sodium hydroxide to adjust pH.<br />
CLINICAL PHARMACOLOGY<br />
Mechanism of Action: Brimonidine Tartrate Ophthalmic Solution, 0.15% is an alpha-2 adrenergic receptor<br />
agonist. It has a peak ocular hypotensive effect occurring at two hours post-dosing. Fluorophotometric studies<br />
in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous<br />
humor production and increasing uveoscleral outflow.<br />
Pharmacokinetics:<br />
In a pharmacokinetic study, 14 healthy subjects (4 males and 10 females) received a single topical ocular<br />
administration of Brimonidine Tartrate Ophthalmic Solution, 0.15%, one drop per eye. The peak plasma<br />
concentrations (C max<br />
) and AUC 0-inf<br />
max<br />
was 1.7 ± 0.7<br />
hours after dosing. The systemic half-life was approximately 2.1 hours.<br />
Brimonidine is metabolized primarily by the liver. In vitro metabolism data from human microsomal fractions and<br />
liver slices indicate that brimonidine undergoes extensive hepatic metabolism.<br />
Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87%<br />
of an orally administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% of the<br />
radioactivity recovered in the urine.<br />
Special Populations<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% has not been studied in patients with hepatic or renal impairment.<br />
Because of the low systemic drug exposure following topical ocular administration of Brimonidine Tartrate Ophthalmic<br />
Solution, 0.15%, no dose adjustment is necessary when treating patients with hepatic or renal impairment.<br />
Clinical Evaluations:<br />
Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the<br />
likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering intraocular<br />
pressure with minimal effect on cardiovascular and pulmonary parameters.<br />
A clinical study was conducted to evaluate the safety and efficacy of Brimonidine Tartrate Ophthalmic Solution,<br />
0.15% compared to Alphagan ® P** administered three-times-daily in patients with open-angle glaucoma or<br />
ocular hypertension. The results indicated that Brimonidine Tartrate Ophthalmic Solution, 0.15% is equivalent in<br />
IOP-lowering effect to Alphagan ® P (brimonidine tartrate ophthalmic solution), 0.15%, and effectively lowers IOP<br />
in patients with open-angle glaucoma or ocular hypertension by 2 - 6 mm Hg.<br />
INDICATIONS AND USAGE<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% is indicated for the lowering of intraocular pressure in patients<br />
with open-angle glaucoma or ocular hypertension.<br />
CONTRAINDICATIONS<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% is contraindicated in patients with hypersensitivity to<br />
brimonidine tartrate or any component of this medication. It is also contraindicated in patients receiving<br />
monoamine oxidase (MAO) inhibitor therapy.<br />
PRECAUTIONS<br />
General:<br />
Although Brimonidine Tartrate Ophthalmic Solution, 0.15% had minimal effect on the blood pressure of patients<br />
in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% has not been studied in patients with hepatic or renal<br />
impairment; caution should be used in treating such patients.<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% should be used with caution in patients with depression,<br />
cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis<br />
obliterans. Patients prescribed IOP-lowering medication should be routinely monitored for IOP.<br />
N<br />
N<br />
COOH<br />
H<br />
HO<br />
C<br />
C<br />
OH<br />
H<br />
COOH<br />
Information for Patients:<br />
As with other drugs in this class, Brimonidine Tartrate Ophthalmic Solution, 0.15% may cause fatigue and/or<br />
drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential<br />
for a decrease in mental alertness.<br />
Drug Interactions:<br />
Although specific drug interaction studies have not been conducted with Brimonidine Tartrate Ophthalmic<br />
Solution, 0.15%, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates,<br />
opiates, sedatives, or anesthetics) should be considered. Alpha-2 agonists, as a class, may reduce pulse and<br />
blood pressure. Caution in using concomitant drugs such as beta-blockers (ophthalmic and systemic), antihypertensives<br />
and/or cardiac glycosides is advised.<br />
Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not<br />
known whether the concurrent use of these agents with Brimonidine Tartrate Ophthalmic Solution, 0.15% in<br />
humans can interfere with its IOP-lowering effect. No data on the level of circulating catecholamines after<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% administration are available. Caution, however, is advised in<br />
patients taking tricyclic antidepressants, which can affect the metabolism and uptake of circulating amines.<br />
Carcinogenesis, Mutagenesis, and Impairment of Fertility:<br />
No compound-related carcinogenic effects were observed in either mice or rats following a 21-month and a<br />
24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to<br />
2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved 60 and 50 times, respectively, the plasma drug<br />
concentration estimated in humans treated with one drop of Brimonidine Tartrate Ophthalmic Solution, 0.15%<br />
into both eyes.<br />
Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames<br />
test, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, a host-mediated assay and cytogenic<br />
studies in mice, and dominant lethal assay.<br />
Pregnancy: Teratogenic Effects: Pregnancy Category: B<br />
Reproductive studies performed in rats and rabbits with oral doses of 0.66 mg base/kg revealed no evidence<br />
of harm to the fetus due to Brimonidine Tartrate Ophthalmic Solution, 0.15%. Dosing at this level produced an<br />
exposure in rats and rabbits that is 80 and 40 times higher than the exposure seen in humans, respectively.<br />
There are no adequate and well-controlled studies in pregnant women. In animal studies, brimonidine crossed<br />
the placenta and entered into the fetal circulation to a limited extent. Brimonidine Tartrate Ophthalmic Solution,<br />
0.15% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to<br />
the fetus.<br />
Nursing Mothers:<br />
It is not known whether this drug is excreted in human milk. In animal studies, brimonidine tartrate was excreted<br />
in breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into<br />
account the importance of the drug to the mother.<br />
Pediatric Use:<br />
In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most<br />
commonly observed adverse events with brimonidine tartrate ophthalmic solution 0.2% dosed three-timesdaily<br />
were somnolence (50%-83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients<br />
7 years of age or older (>20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of<br />
patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.<br />
The safety and effectiveness of brimonidine tartrate ophthalmic solution have not been studied in pediatric<br />
patients below the age of 2 years. Brimonidine tartrate ophthalmic solution is not recommended for use in<br />
pediatric patients under the age of 2 years. (Also refer to ADVERSE REACTIONS section.)<br />
Geriatric Use:<br />
No overall differences in safety or effectiveness have been observed between elderly and other adult patients.<br />
ADVERSE REACTIONS<br />
Adverse events occurring in approximately 10-20% of the subjects included: allergic conjunctivitis, conjunctival<br />
hyperemia, and eye pruritis.<br />
Adverse events occurring in approximately 5-9% of the subjects included: burning sensation, conjunctival<br />
folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance.<br />
Events occurring in approximately 1-4% of subjects included: allergic reaction, arthralgia, arthritis, asthenia,<br />
blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, chest pain, conjunctival edema,<br />
conjunctival hemorrhage, conjunctivitis, cough, dizziness, diabetes mellitus, dyspepsia, dyspnea, epiphora, eye<br />
discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular<br />
conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, hypotension,<br />
infection, insomnia, joint disorder, keratitis, lid disorder, osteoporosis, pharyngitis, photophobia, rash, rhinitis,<br />
sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect,<br />
vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity.<br />
The following events were reported in less than 1% of subjects: corneal erosion, nasal dryness, and taste<br />
perversion.<br />
The following events have been identified during post-marketing use of brimonidine tartrate ophthalmic<br />
solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates<br />
of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness,<br />
frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination<br />
of these factors, include: bradycardia; iritis; miosis; skin reactions (including erythema, eyelid pruritis, rash, and<br />
vasodilation); and tachycardia. Apnea, bradycardia, hypotension, hypothermia, hypotonia, and somnolence have<br />
been reported in infants receiving brimonidine tartrate ophthalmic solutions.<br />
OVERDOSAGE<br />
No information is available on overdosage in humans. Treatment of an oral overdose includes supportive and<br />
symptomatic therapy; a patent airway should be maintained.<br />
DOSAGE AND ADMINISTRATION<br />
The recommended dose is one drop of Brimonidine Tartrate Ophthalmic Solution, 0.15% in the affected eye(s)<br />
three-times-daily, approximately 8 hours apart.<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% may be used concomitantly with other topical ophthalmic drug<br />
products to lower intraocular pressure. If more than one topical ophthalmic product is being used, the products<br />
should be administered at least 5 minutes apart.<br />
HOW SUPPLIED<br />
Brimonidine Tartrate Ophthalmic Solution, 0.15% is supplied sterile in opaque white LDPE plastic bottles and<br />
natural tips with purple polypropylene caps as follows:<br />
5 mL in 8 mL bottle NDC 61314-144-05<br />
10 mL in 10 mL bottle NDC 61314-144-10<br />
15 mL in 15 mL bottle NDC 61314-144-15<br />
Storage: Store at 15°-25° C (59° - 77°F).<br />
Rx Only<br />
Distributed by:<br />
Falcon Pharmaceuticals, Ltd.<br />
Fort Worth, Texas 76134<br />
Manufactured by:<br />
Alcon Laboratories, Inc.<br />
Fort Worth, Texas 76134<br />
Printed in USA<br />
*POLYQUAD is a registered trademark of Alcon Research, Ltd.<br />
**ALPHAGAN P is a registered trademark of Allergan, Inc.<br />
349040-1008
Brimonidine Tartrate Ophthalmic Solution, 0.15%<br />
(compares to Alphagan ® P Ophthalmic Solution, 0.15%)*<br />
First-Time Generic<br />
NEW STRENGTH<br />
Seeing is Believing.<br />
Introducing Brimonidine Tartrate Ophthalmic Solution, 0.15%.<br />
A lower price alternative that is AT Rated and therapeutically<br />
equivalent to Alphagan® P* Ophthalmic Solution, 0.15%.<br />
Available 5 mL, 10 mL, and 15 mL DROP-TAINER®** dispensers.<br />
© 2009 Falcon Pharmaceuticals, Ltd.<br />
PLEASE SEE FULL PRESCRIBING INFORMATION ON ADJACENT PAGE<br />
*Alphagan ® P is a registered trademark of Allergan, Inc.<br />
** DROP-TAINER is a registered trademark of Alcon Research, Ltd.
PATIENT TEACHING AID<br />
Pancreatitis<br />
Enzymes flow freely<br />
into the duodenum<br />
to aid in digestion<br />
Gallbladder<br />
Normal<br />
Pancreas<br />
TEAR ALONG PERFORATION<br />
MEDICAL ILLUSTRATION: © KRISTEN WEINANDT MARZEJON 2009<br />
Gallstones<br />
Common<br />
bile duct<br />
Pancreatic<br />
duct<br />
Duodenum<br />
(small intestine)<br />
Acute or Chronic<br />
Inflammation of<br />
Endocrine Gland<br />
Pancreatitis is an inflammation of the pancreas, the gland<br />
behind the stomach that produces insulin and enzymes<br />
that help digest food. The pancreas can become inflamed<br />
as a result of alcoholism, gallstones, or infection, among<br />
other reasons. The inflammation can develop quickly over<br />
a period of days (acute pancreatitis) or can develop and<br />
continue for years (chronic pancreatitis). It can be a mild<br />
inflammation that heals quickly with the proper treatment, or a severe condition that can lead to<br />
serious diseases such as diabetes, kidney failure, or cancer of the pancreas.<br />
Symptoms of acute pancreatitis include pain in the abdomen that can move to the lower back area.<br />
The pain often feels worse with eating, but better in the fetal position. Acute pancreatitis can also cause<br />
nausea and vomiting. In chronic pancreatitis, the abdominal pain is also associated with weight loss and<br />
oily, foul-smelling bowel movements. Laboratory tests of the blood, urine, and stool are performed to look<br />
for signs of inflammation and abnormal amounts of pancreatic enzymes. Other tests often performed in<br />
the diagnosis of pancreatitis include abdominal x-ray, ultrasound testing, CT scan, and MRI.<br />
Treatment depends on the type of pancreatitis, its cause, and its severity. Patients may require a<br />
hospital stay to treat pain and allow the pancreas to rest by restricting food and fluids by mouth.<br />
Patients are rehydrated with intravenous fluids and nutrition is restored with special feedings. The<br />
specific cause of the pancreatic inflammation will determine further treatment.<br />
Copyright Jobson Medical Information LLC, 2009<br />
Inflamed<br />
Pancreas<br />
Gallstones, produced<br />
in the gallbladder,<br />
can get lodged in the<br />
common bile duct,<br />
blocking the flow of<br />
pancreatic enzymes<br />
into the small intestine.<br />
Pancreatitis occurs<br />
when these blocked<br />
enzymes irritate the<br />
cells of the pancreas<br />
continued
PATIENT TEACHING AID<br />
Alcohol Abuse and Smoking Are<br />
Major Risk Factors for the Disease<br />
The pancreas is responsible for producing hormones and<br />
enzymes that help regulate blood sugar and food digestion.<br />
The digestive enzymes produced in the pancreas are not activated<br />
until after they are released by the pancreas into the<br />
small intestine. If these enzymes become active while they are<br />
still in the pancreas, they can irritate the pancreatic tissue and<br />
lead to inflammation. Conditions that can cause the digestive<br />
enzymes to inflame the pancreas include excess alcohol, gallstones,<br />
infections, trauma to the abdomen, or pancreatic<br />
Inflammation occurs when<br />
pancreatic enzymes irritate<br />
the cells of the organ.<br />
cancer. People with ulcers, elevated triglycerides, cystic fibrosis, or a family history of pancreatitis<br />
and those who smoke are also at higher risk. People with frequent bouts of acute pancreatitis<br />
can develop scar tissue in the pancreas, leading to chronic pancreatitis.<br />
Presentation and Diagnosis<br />
Symptoms of acute pancreatitis include significant upper abdominal pain, nausea, and vomiting.<br />
In severe cases, patients may become dehydrated and go into shock when other organs begin to<br />
fail or the pancreas begins to bleed internally. Chronic pancreatitis also causes abdominal pain, but<br />
it is more often associated with digestive problems and oily, foul-smelling bowel movements. Patients<br />
with long-standing pancreatitis often lose weight due to a lack of digestive enzymes needed to break<br />
down nutrients from food. Diabetes can also result from chronic inflammation of the pancreas,<br />
since the scar tissue in the pancreas means that there are fewer healthy cells to produce insulin.<br />
Pancreatitis can also lead to infection of the inflamed tissue in the pancreas, requiring surgery.<br />
Diagnosis is based on a series of tests to measure the effect of the inflammation in blood,<br />
urine, and stool samples. Studies that allow a view of the pancreas include x-rays, CT scans,<br />
ultrasound procedures, and MRIs.<br />
Treatment Options<br />
Treatment of an acute episode of pancreatitis usually means stabilizing the patient in the hospital<br />
to allow the pancreas to rest. This means that no food or liquids can be taken by mouth for<br />
several days, during which time fluids are administered intravenously and abdominal pain is<br />
treated. When the inflammation and pain begin to subside, the patient can begin drinking and<br />
eating soft foods, and eventually resume a more normal diet. In cases of chronic pancreatitis, a<br />
low-fat, highly nutritious diet is necessary, and pancreatic enzyme supplements may be prescribed<br />
for use before meals to help break down food into useful nutrients. Alcohol is a significant cause<br />
of pancreatitis and should be avoided completely. Smoking is another risk factor for pancreatitis,<br />
and smoking cessation is an important way to help prevent future attacks. Patients with a history<br />
of pancreatitis should drink plenty of fluids daily to prevent dehydration.<br />
Depending on the cause of pancreatitis, other procedures may be needed to avoid future bouts<br />
of inflammation and the development of chronic pancreatitis. If a bile duct blockage or gallstones<br />
were a cause of the condition, surgery may be indicated to correct the problem. If alcohol was<br />
the cause, an abstinence program may be needed to help prevent future damage. Infected tissue<br />
or pockets of fluid known as pseudocysts may require surgical removal.<br />
Diagnosis and treatment of acute or chronic pancreatitis can also be performed using a procedure<br />
known as endoscopic retrograde cholangiopancreatography (ERCP). ERCP uses a tiny camera<br />
on the end of a tube to view the pancreas without a surgical incision. The tube is inserted down<br />
the throat and through the stomach and small intestine to the pancreas, where the area can be<br />
seen and minor surgical procedures can be performed to correct the cause of the pancreatitis.<br />
If you have questions about pancreatic enzyme supplements or pain medications prescribed<br />
for pancreatitis, ask your pharmacist.
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HEALTH SYSTEMS EDITION<br />
Surgical<br />
Procedures for<br />
Weight Loss<br />
Obesity is a chronic condition characterized by<br />
an extreme accumulation of fat that exceeds the<br />
body’s skeletal and physical standards. 1 It is<br />
insidious, with symptoms slowly becoming evident over<br />
a prolonged period of time. Morbid (clinically severe)<br />
obesity, which involves an increased risk of coexisting<br />
disease, is defined as having at least 100 lb. of excess<br />
weight, being 20% or more above ideal body weight, or<br />
having a body-mass index (BMI) of 35 kg/m 2 or higher. 2,3<br />
(BMI, a measure of body fat based on height and weight,<br />
is calculated as weight [kg]/height [m] 2 . 3,4 ) At this stage,<br />
obesity becomes a health risk and treatment options must<br />
be contemplated. 5 Weight-loss, or bariatric, surgery is<br />
considered for the morbidly obese patient when all conventional<br />
therapy—including behavioral modification,<br />
diet therapy, exercise, and medication—has failed.<br />
Obesity: Epidemiology and Screening<br />
In the last 20 years, there has been a dramatic increase<br />
in the prevalence of obesity in the United States. 2 In<br />
1991, no state had an obesity rate higher than 20%. 4<br />
According to 2008 statistics, obesity prevalence in adults<br />
increased in 37 states, with Mississippi having the highest<br />
rate (31.7%) and Colorado having the lowest rate<br />
(18.4%). In every state except Colorado, more than 20%<br />
of adults are obese. 4<br />
In 1994, according to the National Health and Nutrition<br />
Examination Survey III, approximately 55% of U.S.<br />
adults (about 97 million) were obese. 6 In 2007, it was<br />
estimated that about 66% of adults are overweight or obese;<br />
16% of children and adolescents are overweight and 34%<br />
are at risk for becoming overweight. 7 The prevalence of<br />
severe obesity in the U.S. between 1999 and 2002 was<br />
greater in women than in men. 8 In the U.S., approximately<br />
280,000 deaths are attributed to obesity, which will soon<br />
exceed smoking as the primary preventable cause of death. 9<br />
Mea A. Weinberg, DMD, MSD, RPh<br />
Clinical Associate Professor<br />
Stuart L. Segelnick, DDS, MS<br />
Clinical Associate Professor<br />
Department of Periodontology and Implant Dentistry<br />
New York University College of Dentistry<br />
New York, New York<br />
© JUPITERIMAGES<br />
Surgical Treatment Options<br />
Introduced in the 1950s, bariatric<br />
surgery currently offers the best<br />
method of producing sustained weight<br />
loss in morbidly obese individuals. 10<br />
A consensus statement by the American<br />
Society for Metabolic and Bariatric<br />
Surgery (ASMBS) concluded that bariatric surgery<br />
is the most effective treatment for morbid obesity and<br />
that it can result in improvement or complete resolution<br />
of obesity comorbidities. 11-13 In 2002, 63,000 bariatric<br />
surgeries were performed in the U.S.; in 2006, an estimated<br />
177,600 patients underwent the procedure, according<br />
to the ASMBS. Fewer than 1% of individuals who<br />
meet the criteria for weight-loss surgery actually undergo<br />
the procedure. It is advisable for severely obese patients<br />
to have surgery early to prevent the development of other<br />
medical conditions, such as diabetes and hypertension. 14<br />
Three types of bariatric surgery exist (TABLE 1). Restrictive<br />
surgery limits food intake by making the stomach<br />
smaller. Malabsorptive surgery hinders calorie absorption<br />
by shortening the duodenum and/or altering where the<br />
duodenum connects to the stomach, thereby limiting<br />
the amount of food digested or absorbed. The third type<br />
of surgery is a combination of the first two. Restrictive<br />
procedures, which are performed least often, result in<br />
the most significant weight loss by reducing the amount<br />
of food eaten and slowing the speed of gastric emptying. 15<br />
The mechanism by which weight<br />
loss occurs after bariatric surgery is<br />
most likely an interplay between<br />
mechanical effects of the surgery and<br />
neurohormonal feedback loops<br />
involved in body-weight homeostasis.<br />
16,17 The amount of weight loss<br />
HS-2<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
IN THE TREATMENT OF MRSA BACTEREMIA AND MRSA COMPLICATED SKIN INFECTIONS<br />
INSIDE.OUTSIDE.ON HIS SIDE.<br />
n Landmark clinical trial of CUBICIN 6 mg/kg once daily demonstrated<br />
efficacy in S. aureus bacteremia caused by MRSA and MSSA<br />
n Proven clinical success of CUBICIN 4 mg/kg once daily in S. aureus<br />
complicated skin infections —both MRSA and MSSA<br />
INDICATIONS AND IMPORTANT SAFETY INFORMATION<br />
CUBICIN is indicated for the following infections:<br />
Complicated skin and skin structure infections caused by susceptible<br />
isolates of the following Gram-positive microorganisms: S. aureus (including<br />
methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus<br />
agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and<br />
Enterococcus faecalis (vancomycin-susceptible isolates only). Combination<br />
therapy may be clinically indicated if the documented or presumed<br />
pathogens include Gram-negative or anaerobic organisms.<br />
S. aureus bloodstream infections (bacteremia), including those with<br />
right-sided infective endocarditis, caused by methicillin-susceptible and<br />
methicillin-resistant isolates. Combination therapy may be clinically indicated<br />
if the documented or presumed pathogens include Gram-negative or<br />
anaerobic organisms.<br />
The efficacy of CUBICIN in patients with left-sided infective endocarditis due<br />
to S. aureus has not been demonstrated. The clinical trial of CUBICIN in<br />
patients with S. aureus bloodstream infections included limited data from<br />
patients with left-sided infective endocarditis; outcomes in these patients<br />
were poor. CUBICIN has not been studied in patients with prosthetic valve<br />
endocarditis or meningitis.<br />
Patients with persisting or relapsing S. aureus infection or poor clinical<br />
response should have repeat blood cultures. If a culture is positive for<br />
www.cubicin.com<br />
©2007 Cubist Pharmaceuticals, Inc.<br />
3974071907 September 2007<br />
CUBICIN is a registered trademark of Cubist Pharmaceuticals,Inc.<br />
S. aureus, MIC susceptibility testing of the isolate should be performed<br />
using a standardized procedure, as well as diagnostic evaluation to rule<br />
out sequestered foci of infection. Appropriate surgical intervention (eg,<br />
debridement, removal of prosthetic devices, valve replacement surgery)<br />
and/or consideration of a change in antibiotic regimen may be required.<br />
CUBICIN is not indicated for the treatment of pneumonia.<br />
Clostridium difficile-associated diarrhea (CDAD) has been reported with the<br />
use of nearly all antibacterial agents, including CUBICIN, and may range in<br />
severity from mild diarrhea to fatal colitis. CDAD has been reported to occur<br />
over 2 months post-antibiotic treatment. If CDAD is suspected, antibiotic<br />
treatment may need to be suspended.<br />
Patients receiving CUBICIN should be monitored for the development of<br />
muscle pain or weakness, particularly of the distal extremities. In patients<br />
who receive CUBICIN, creatine phosphokinase (CPK) levels should be<br />
monitored weekly, and more frequently in patients who received recent prior<br />
or concomitant therapy with an HMG-CoA reductase inhibitor. In patients<br />
with renal insufficiency, both renal function and CPK should be monitored<br />
more frequently. Patients who demonstrate unexplained elevations in CPK<br />
while receiving CUBICIN should be monitored more frequently.<br />
CUBICIN should be discontinued in patients with unexplained signs and<br />
symptoms of myopathy in conjunction with CPK elevation >1000 U/L<br />
(~5X ULN), or in patients without reported symptoms who have marked<br />
elevations in CPK >2000 U/L (≥10X ULN).<br />
Most adverse events reported in CUBICIN clinical trials were mild to moderate<br />
in intensity. The most common CUBICIN adverse events were anemia,<br />
constipation, diarrhea, nausea,<br />
vomiting, injection-site reactions,<br />
and headache.<br />
Please see Brief Summary<br />
of Prescribing Information<br />
on adjacent page.
Brief summary of prescribing information.<br />
INDICATIONS AND USAGE CUBICIN (daptomycin for injection) is indicated<br />
for the following infections (see also DOSAGE AND ADMINISTRATION and<br />
CLINICAL STUDIES in full prescribing information): Complicated skin<br />
and skin structure infections (cSSSI) caused by susceptible isolates<br />
of the following Gram-positive microorganisms: Staphylococcus aureus<br />
(including methicillin-resistant isolates), Streptococcus pyogenes, S. agalactiae,<br />
S. dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin-susceptible<br />
isolates only). Combination therapy may be clinically<br />
indicated if the documented or presumed pathogens include Gram-negative<br />
or anaerobic organisms. Staphylococcus aureus bloodstream infections<br />
(bacteremia), including those with right-sided infective endocarditis,<br />
caused by methicillin-susceptible and methicillin-resistant isolates. Combination<br />
therapy may be clinically indicated if the documented or presumed<br />
pathogens include Gram-negative or anaerobic organisms. The efficacy of<br />
CUBICIN in patients with left-sided infective endocarditis due to S. aureus<br />
has not been demonstrated. The clinical trial of CUBICIN in patients with<br />
S. aureus bloodstream infections included limited data from patients with<br />
left-sided infective endocarditis; outcomes in these patients were poor (see<br />
CLINICAL STUDIES in full prescribing information). CUBICIN has not been<br />
studied in patients with prosthetic valve endocarditis or meningitis. Patients<br />
with persisting or relapsing S. aureus infection or poor clinical response<br />
should have repeat blood cultures. If a culture is positive for S. aureus,MIC<br />
susceptibility testing of the isolate should be performed using a standardized<br />
procedure, as well as diagnostic evaluation to rule out sequestered foci<br />
of infection (see PRECAUTIONS). CUBICIN is not indicated for the treatment<br />
of pneumonia. Appropriate specimens for microbiological examination<br />
should be obtained in order to isolate and identify the causative pathogens<br />
and to determine their susceptibility to daptomycin. Empiric therapy may<br />
be initiated while awaiting test results. Antimicrobial therapy should be<br />
adjusted as needed based upon test results. To reduce the development<br />
of drug-resistant bacteria and maintain the effectiveness of CUBICIN and<br />
other antibacterial drugs, CUBICIN should be used only to treat or prevent<br />
infections that are proven or strongly suspected to be caused by susceptible<br />
bacteria.When culture and susceptibility information are available, they<br />
should be considered in selecting or modifying antibacterial therapy. In the<br />
absence of such data, local epidemiology and susceptibility patterns may<br />
contribute to the empiric selection of therapy.<br />
CONTRAINDICATIONS CUBICIN is contraindicated in patients with<br />
known hypersensitivity to daptomycin.<br />
WARNINGS Clostridium difficile–associated diarrhea (CDAD) has been<br />
reported with use of nearly all antibacterial agents, including CUBICIN,<br />
and may range in severity from mild diarrhea to fatal colitis. Treatment<br />
with antibacterial agents alters the normal flora of the colon, leading to<br />
overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute<br />
to the development of CDAD. Hypertoxin-producing strains of C.<br />
difficile cause increased morbidity and mortality, since these infections<br />
can be refractory to antimicrobial therapy and may require colectomy.<br />
CDAD must be considered in all patients who present with diarrhea following<br />
antibiotic use. Careful medical history is necessary because CDAD<br />
has been reported to occur over 2 months after the administration of<br />
antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic<br />
use not directed against C. difficile may need to be discontinued.<br />
Appropriate fluid and electrolyte management, protein supplementation,<br />
antibiotic treatment of C. difficile, and surgical evaluation should be instituted<br />
as clinically indicated.<br />
PRECAUTIONS General The use of antibiotics may promote the selection<br />
of non-susceptible organisms. Should superinfection occur during therapy,<br />
appropriate measures should be taken. Prescribing CUBICIN in the absence<br />
of a proven or strongly suspected bacterial infection is unlikely to provide<br />
benefit to the patient and increases the risk of the development of drugresistant<br />
bacteria. Persisting or Relapsing S. aureus Infection Patients<br />
with persisting or relapsing S. aureus infection or poor clinical response<br />
should have repeat blood cultures. If a culture is positive for S. aureus,MIC<br />
susceptibility testing of the isolate should be performed using a standardized<br />
procedure, as well as diagnostic evaluation to rule out sequestered foci<br />
of infection. Appropriate surgical intervention (eg, debridement, removal of<br />
prosthetic devices, valve replacement surgery) and/or consideration of a<br />
change in antibiotic regimen may be required. Failure of treatment due to<br />
persisting or relapsing S. aureus infections was assessed by the Adjudication<br />
Committee in 19/120 (15.8%) CUBICIN-treated patients (12 with<br />
MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients<br />
(9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal<br />
semi-synthetic penicillin). Among all failures, 6 CUBICINtreated<br />
patients and 1 vancomycin-treated patient developed increasing<br />
MICs (reduced susceptibility) by central laboratory testing on or following<br />
therapy. Most patients who failed due to persisting or relapsing S. aureus<br />
infection had deep-seated infection and did not receive necessary surgical<br />
intervention (see CLINICAL STUDIES in full prescribing information).<br />
Skeletal Muscle In a Phase 1 study examining doses up to 12 mg/kg<br />
q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations<br />
were observed. In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg,<br />
elevations in CPK were reported as clinical adverse events in 15/534<br />
(2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated<br />
patients. In the S. aureus bacteremia/endocarditis trial, at a<br />
dose of 6 mg/kg, elevations in CPK were reported as clinical adverse<br />
events in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116<br />
(500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24<br />
(16.7%) treated with comparator developed further increases in CPK while<br />
on therapy. In this same population, no patients developed myopathy.<br />
CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experience<br />
an increased incidence of CPK elevations or myopathy relative to<br />
those treated with comparator (N=24). In the S. aureus bacteremia/endocarditis<br />
study, 3 (2.6%) CUBICIN-treated patients, including 1 with trauma<br />
associated with a heroin overdose and 1 with spinal cord compression, had<br />
an elevation in CPK >500 U/L with associated musculoskeletal symptoms.<br />
None of the patients in the comparator group had an elevation in CPK<br />
>500 U/L with associated musculoskeletal symptoms. CUBICIN should be<br />
discontinued in patients with unexplained signs and symptoms of myopathy<br />
in conjunction with CPK elevation >1,000 U/L (~5x ULN), or in patients<br />
without reported symptoms who have marked elevations in CPK >2,000<br />
U/L (10x ULN). In addition, consideration should be given to temporarily<br />
suspending agents associated with rhabdomyolysis, such as HMG-CoA<br />
reductase inhibitors, in patients receiving CUBICIN. In a Phase 1 study examining<br />
doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence<br />
of nerve conduction deficits or symptoms of peripheral neuropathy was<br />
observed. In a small number of patients in Phase 1 and Phase 2 studies at<br />
doses up to 6 mg/kg, administration of CUBICIN was associated with<br />
decreases in nerve conduction velocity and with adverse events (eg, paresthesias,<br />
Bell’s palsy) possibly reflective of peripheral or cranial neuropathy.<br />
Nerve conduction deficits were also detected in a similar number of comparator<br />
subjects in these studies. In Phase 3 cSSSI and communityacquired<br />
pneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patients<br />
and 7/1,018 (0.7%) comparator-treated patients experienced paresthesias.<br />
New or worsening peripheral neuropathy was not diagnosed in any of<br />
these patients. In the S. aureus bacteremia/endocarditis trial, a total of<br />
11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse<br />
events related to the peripheral nervous system. All of the events were<br />
classified as mild to moderate in severity; most were of short duration and<br />
resolved during continued treatment with CUBICIN or were likely due to an<br />
alternative etiology. In animals, effects of CUBICIN on peripheral nerve were<br />
observed (see ANIMAL PHARMACOLOGY in full prescribing information).<br />
Therefore, physicians should be alert to the possibility of signs and symptoms<br />
of neuropathy in patients receiving CUBICIN. Drug Interactions<br />
Warfarin Concomitant administration of CUBICIN (6 mg/kg q24h for 5<br />
days) and warfarin (25 mg single oral dose) had no significant effect on the<br />
pharmacokinetics of either drug, and the INR was not significantly altered.<br />
As experience with the concomitant administration of CUBICIN and warfarin<br />
is limited, anticoagulant activity in patients receiving CUBICIN and warfarin<br />
should be monitored for the first several days after initiating therapy with<br />
CUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions in<br />
full prescribing information). HMG-CoA Reductase Inhibitors Inhibitors<br />
of HMG-CoA reductase may cause myopathy, which is manifested as<br />
muscle pain or weakness associated with elevated levels of CPK. There<br />
were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial<br />
in which 10 healthy subjects on stable simvastatin therapy were treated<br />
concurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S.<br />
aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients who<br />
received prior or concomitant therapy with an HMG-CoA reductase inhibitor<br />
developed CPK elevations >500 U/L. Experience with co-administration of<br />
HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore,<br />
consideration should be given to temporarily suspending use of HMG-CoA<br />
reductase inhibitors in patients receiving CUBICIN (see ADVERSE<br />
REACTIONS, Post-Marketing Experience). Drug-Laboratory Test<br />
Interactions There are no reported drug-laboratory test interactions.<br />
Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term<br />
carcinogenicity studies in animals have not been conducted to evaluate the<br />
carcinogenic potential of daptomycin. However, neither mutagenic nor<br />
clastogenic potential was found in a battery of genotoxicity tests, including<br />
the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal<br />
aberrations in Chinese hamster ovary cells, an in vivo micronucleus<br />
assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange<br />
assay in Chinese hamsters. Daptomycin did not affect the fertility or<br />
reproductive performance of male and female rats when administered<br />
intravenously at doses up to 150 mg/kg/day, which is approximately 9<br />
times the estimated human exposure level based upon AUCs. Pregnancy<br />
Teratogenic Effects: Pregnancy Category B Reproductive and teratology<br />
studies performed in rats and rabbits at doses of up to 75 mg/kg, 2 and<br />
4 times the 6 mg/kg human dose, respectively, on a body surface area<br />
basis, have revealed no evidence of harm to the fetus due to daptomycin.<br />
There are, however, no adequate and well-controlled studies in pregnant<br />
women. Because animal reproduction studies are not always predictive of<br />
human response, this drug should be used during pregnancy only if clearly<br />
needed. Nursing Mothers It is not known if daptomycin is excreted in<br />
human milk. Caution should be exercised when CUBICIN is administered to<br />
nursing women. Pediatric Use Safety and efficacy of CUBICIN in patients<br />
under the age of 18 have not been established. Geriatric Use Of the 534<br />
patients treated with CUBICIN in Phase 3 controlled clinical trials of cSSSI,<br />
27.0% were 65 years of age or older and 12.4% were 75 years of age or<br />
older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled<br />
clinical trial of S. aureus bacteremia/endocarditis, 25.0% were 65 years of<br />
age or older and 15.8% were 75 years of age or older. In Phase 3 clinical<br />
studies of cSSSI and S. aureus bacteremia/endocarditis, lower clinical success<br />
rates were seen in patients 65 years of age compared with those<br />
SURGICAL PROCEDURES FOR WEIGHT LOSS<br />
Table 1<br />
Different Types of Bariatric Surgical Procedures<br />
Surgical<br />
Procedure Type Features Advantages Disadvantages/Risks<br />
Roux-en-Y Restrictive/ Pouch created with staples/band High percentage Heartburn, nausea,<br />
gastric bypass malabsorptive on stomach; section of duodenum of weight loss diarrhea, infection,<br />
attached to pouch; food bypasses<br />
abdominal hernia,<br />
much of duodenum, resulting in<br />
abdominal obstruction,<br />
inability to absorb calories and<br />
gallstones (rare)<br />
nutrients. Pouch size: 1 oz.<br />
Laparoscopic Restrictive Inflatable silicone band placed Adjustable, reversible, Less weight loss than<br />
adjustable around upper end of stomach, minimally invasive, with gastric bypass<br />
gastric band creating small pouch and narrow less pain, outpatient, surgery, harder to<br />
surgery passage into rest of stomach. fewer nutritional maintain loss, vomiting,<br />
Pouch size:
HEALTH SYSTEMS EDITION<br />
Table 2<br />
NIH Guidelines for Patient<br />
Selection for Bariatric Surgery<br />
• ≥100 lb. excess weight<br />
• BMI ≥40 kg/m 2 without obesity-associated<br />
comorbidities (e.g., diabetes, cardiovascular disease,<br />
arthritis, obstructive sleep apnea)<br />
• BMI 35.0-39.9 kg/m 2 with 1 or more associated<br />
medical problems<br />
• Previous failed weight-loss attempts (e.g., nonsurgical<br />
interventions: diet control, behavioral modification,<br />
exercise)<br />
BMI: body-mass index; NIH: National Institutes of Health.<br />
Source: Reference 29.<br />
and the patient’s weight is considered to be stable.<br />
Combined surgery is more likely to result in long-term<br />
nutritional deficiencies, so it is important to monitor<br />
patients. Deficiencies of the fat-soluble vitamins (A, D,<br />
E, and K) and calcium, zinc, and selenium are common<br />
after gastric bypass. 23 There is an increased incidence of<br />
anemia owing to decreased levels of iron, vitamin B 12<br />
,<br />
and folic acid. 24 Patients should take a supplemental<br />
multivitamin containing B 12<br />
and folic acid.<br />
Purely Restrictive Surgery: Approved by the FDA in<br />
June 2001 for patients over 18 years of age, laparoscopic<br />
adjustable gastric band surgery (LAGBS) is a minimally<br />
invasive procedure for the severely obese that, unlike<br />
gastric bypass surgery, offers the advantages of being<br />
adjustable and reversible (band can be removed). LAGBS<br />
seems to be increasing in popularity in the U.S. 25 This<br />
type of surgery is easier to perform and has a lower<br />
complication rate than malabsorptive surgery. The surgery,<br />
which usually takes about 1 hour, is done on an outpatient<br />
basis or involves an overnight stay.<br />
After small incisions are made, a laparoscope is used<br />
to visualize placement and to suture an adjustable/<br />
inflatable hollow silicone gastric band around the top<br />
5% of the stomach, creating a small upper pouch and<br />
a large lower pouch. No staples are used. The band is<br />
connected to a port that is placed subcutaneously in<br />
the stomach via small incisions; the port can be accessed<br />
to inflate or deflate the balloon in the band, which<br />
changes the size of the band accordingly. The diameter<br />
of the band obstructs or restricts the passage of food.<br />
The band is inflated or adjusted by adding saline to or<br />
removing it from the port. As the patient eats, the upper<br />
pouch fills and the patient feels full sooner. The pouch<br />
initially can hold only about 1 oz. of food, but later<br />
expands to hold up to 3 oz. The normal digestive process<br />
is not altered. Most patients return to normal<br />
activities within a few weeks. 22<br />
SURGICAL PROCEDURES FOR WEIGHT LOSS<br />
Postsurgical instructions include a liquid diet for about<br />
2 weeks, followed by soft foods and then solid foods. It<br />
is highly recommended that the patient follow a personalized<br />
nutrition plan and exercise program. Within the<br />
first 2 years, there is a weight loss of about 50% to 60%. 26<br />
LABGS is also safe and effective as reoperative surgery<br />
in obese patients who require additional weight loss after<br />
previous bariatric surgery. 27<br />
Weight loss is not as dramatic as with restrictive/<br />
malabsorptive surgery, and some patients regain weight<br />
quickly. Vomiting results from poor chewing, rapid eating,<br />
exceeding pouch capacity, or drinking shortly after<br />
eating; repeated vomiting may cause the pouch to stretch,<br />
enabling weight gain. 28 Because adjustments involve<br />
needle puncture of the access port, there is an increased<br />
chance of infection. The procedure is contraindicated in<br />
patients with Crohn’s disease, large hiatal hernia, or a<br />
history of gastric ulcers.<br />
Vertical banded gastroplasty (VBG) uses both a band<br />
and staples to create a small stomach pouch that empties<br />
into the lower pouch. Once the most common restrictive<br />
operation, VBG is not often used today because longterm<br />
weight loss is minimal.<br />
Purely Malabsorptive Surgery: In biliopancreatic bypass<br />
with duodenal switch, the stomach is reduced and the<br />
small pouch that remains is connected directly to the<br />
end of the ileum, thus bypassing the duodenum and<br />
jejunum entirely. This procedure is performed infrequently<br />
because of the high risk of nutritional deficiencies.<br />
Criteria for Surgery<br />
The patient-selection guidelines for bariatric surgery<br />
developed by the National Institutes of Health (NIH)<br />
are listed in TABLE 2. A candidate for weight-loss surgery<br />
must meet these criteria. 29 The risk of death if a patient<br />
does not undergo the surgery may outweigh the risks<br />
Table 3<br />
Adverse Effects and<br />
Complications of Bariatric Surgery<br />
Adverse Effects<br />
Nausea<br />
Vomiting<br />
Diarrhea<br />
Nutritional/vitamin<br />
deficiencies<br />
Gallstones<br />
Source: Reference 34.<br />
Complications<br />
Internal hernia<br />
Leakage from staples<br />
Wound infection from band/port<br />
Gastric bleeding<br />
Stomal stenosis<br />
Small-bowel obstruction<br />
Marginal ulcer<br />
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HEALTH SYSTEMS EDITION<br />
SURGICAL PROCEDURES FOR WEIGHT LOSS<br />
from possible complications of the procedure.<br />
Mortality from bariatric surgery is relatively rare. 38<br />
In 2007, a survey of 1,343 U.S. bariatric surgeons The mortality rate differs according to the type of surgical<br />
procedure: 0.15% for VBG and 0.54% for gastric<br />
was published. A questionnaire examining clinical predictors<br />
of patient selection was mailed to participants. The bypass. 38 The most common cause of death is pulmonary<br />
survey concluded that the influences of patient age, embolism. 38<br />
gender, insurance status, social support, and functional A recent study documented a 30-day mortality rate<br />
status on the decision to operate were mitigated by of 0.9% postsurgery and a 6.4% mortality rate at 5 years.<br />
comorbidities and BMI. 30<br />
Mortality increased substantially with age (>65 years),<br />
The patient must be prepared to make significant and coronary heart disease was the leading cause of death<br />
lifestyle changes after having bariatric surgery. These include overall. 39 Another study found that rates of hospitalization<br />
doubled in the first 3 years after gastric bypass<br />
proper diet, physical activity, and health care practices<br />
necessary for any surgical weight-loss system to work. surgery and that many admissions were directly related<br />
to the procedure, including ventral hernia repair and<br />
Considerations in Adolescents and Older Adults gastric revision (e.g., surgery for staple-line failure). 40<br />
Bariatric surgery is an option for obese adolescents. Assessment of the risks of weight-loss surgery should<br />
However, emotional and physical long-term effects of include operative, perioperative, and long-term complications.<br />
The rate of complications in the early post-<br />
the surgery on the adolescent patient should be considered.<br />
Although weight-loss surgery can yield outstanding operative period (wound infection; leaking from stomach<br />
into abdominal cavity [peritonitis]; leaking from<br />
improvements in comorbid conditions in adults, it is not<br />
clear whether similar improvements occur in adolescents. 31 staple lines or from Y connection; saline solution leaking<br />
from port; stomal stenosis; marginal ulcers; consti-<br />
Bariatric surgery has not been a common therapy in<br />
adolescents, largely because the long-term effects (e.g., pation; staple-line dehiscence; pulmonary problems;<br />
nutritional deficiencies) are unknown. Within the last deep thrombophlebitis) may be as high as 10% or<br />
few years, many hospitals have been conducting FDAapproved<br />
studies of LABGS. Currently, only gastric bypass be necessary to control operative bleeding. Sometimes<br />
more. 41 In fewer than 1% of patients, splenectomy may<br />
surgery is approved for patients under 18 years of age. 32 a second operation may be necessary, which increases<br />
Bariatric surgery should be considered for an adolescent<br />
only after the patient has unsuccessfully tried to lose A recent study found that patients who undergo<br />
mortality and morbidity rates.<br />
weight for least 6 months. The candidate should have a LAGBS may have lower short-term morbidity than those<br />
BMI of 40 or more, be at least 13 years old (girls) or 15 treated with RGB, but reoperation rates may be higher<br />
years old (boys), and have serious comorbid conditions. 32 among LAGBS patients. 42<br />
Bariatric surgery in adults aged 60 years and older is<br />
effective. However, older patients may develop more Postoperative Drug-Absorption Alterations<br />
pre- and postoperative problems and achieve less weight Considering the changes made to the upper GI-tract<br />
loss than younger patients. 33<br />
anatomy in bariatric surgery, specific nutritional and<br />
absorptive side effects should be expected and managed<br />
Complications, Risks, and Adverse Effects appropriately to avoid complications and decreased drug<br />
Negative effects of bariatric surgery may be classified into efficacy. 43 All weight-loss procedures reduce the size and<br />
true complications associated with the operation and surface area of the stomach, which decreases the amount<br />
adverse effects related to alterations in upper-gastrointestinal<br />
(GI) anatomy (TABLE 3). 34<br />
the drug to remain in contact with the GI mucosal lin-<br />
of drug absorption and increases transit time; this causes<br />
Nausea and vomiting are common adverse effects. ing longer. Patients should not take drugs with the<br />
The patient can minimize their occurrence by eating a potential to cause ulcers (nonsteroidal anti-inflammatories,<br />
aspirin, oral bisphosphonates). 44 Alternative analge-<br />
meal without interruption, chewing meticulously, never<br />
drinking with meals, and waiting 2 hours after consuming<br />
solid food before drinking. 34<br />
agents (e.g., calcitonin nasal spray) should be recomsics<br />
(e.g., acetaminophen, narcotics) and osteoporosis<br />
The prevention of secondary complications of morbid<br />
obesity is an important goal of management. In the intestine, reducing the surface area for drug absorption.<br />
mended. 43 RGB bypasses a major portion of the small<br />
majority of cases, the results of surgery outweigh the Therefore, a drug’s route of administration, formulation<br />
risks, and the consensus is that surgery is the most (liquid vs. tablet/capsule), or dosage must be altered. 43<br />
effective treatment for severe obesity. 35 However, successful<br />
postsurgical weight loss does not preclude com-<br />
intestine for extended periods are likely to exhibit decreased<br />
Drugs with long absorptive phases that remain in the<br />
plications, and questions persist regarding efficacy and bioavailability in bypass-surgery patients. For that reason,<br />
safety. 1,34,35 In 2006, approximately 40% of patients products with prolonged dissolution times, such as extendedrelease<br />
formulations, should be avoided in this group. 43<br />
who underwent bariatric surgery developed complications<br />
within 6 months. 36,37 Iron must be absorbed in the ferrous state in the acidic<br />
HS-8<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
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HEALTH SYSTEMS EDITION<br />
stomach, but because bypass patients have reduced acid<br />
production, iron must be taken with vitamin C. This<br />
acidifies the stomach contents, allowing for better absorption.<br />
43,45 The small stomach pouch created during the<br />
bypass procedure produces less gastric acid and hydrochloric<br />
acid; this may reduce the absorption of calcium<br />
carbonate, but the citrate salt is unaffected. 43<br />
Drugs that may potentially cause decreased absorption<br />
in these patients include enalapril and ketoconazole, for<br />
which an alternative agent should be prescribed. With<br />
ramipril, metoprolol, metformin, olanzapine, quetiapine,<br />
ramipril, simvastatin, and zolpidem, the patient should<br />
be monitored for reduced drug efficacy. 43<br />
Conclusion and Future Trends<br />
The growing epidemic of overweight and obesity is a<br />
serious health problem in the U.S., with more than 5<br />
million Americans having a BMI exceeding 35. 46 Severe<br />
obesity is a chronic condition that is difficult to treat,<br />
and weight loss can be hard to maintain. There are many<br />
SURGICAL PROCEDURES FOR WEIGHT LOSS<br />
different approaches to weight management; bariatric<br />
surgery should be considered only when all other methods<br />
have failed.<br />
Surgery can result in profound weight loss in adults,<br />
which in turn may spur a significant improvement in<br />
comorbid conditions. Methods of bariatric surgery have<br />
improved over the past 25 years, but questions about<br />
safety and efficacy remain. Although concerns exist<br />
regarding bariatric procedures in adolescents, surgery is<br />
gaining acceptance as a treatment option in this population.<br />
Preoperatively, it is essential to stress to the bariatric<br />
surgical candidate the importance of healthy eating<br />
and exercise behaviors. 47<br />
In 2003, the National Institute of Diabetes and Digestive<br />
and Kidney Diseases of the NIH formed a partnership<br />
with researchers called the Longitudinal Assessment<br />
of Bariatric Surgery. The goal of this consortium is to<br />
plan and conduct studies that will lead to a better understanding<br />
of bariatric surgery and its impact on the health<br />
and well-being of patients with extreme obesity.<br />
REFERENCES<br />
1. Schwartz MW, Brunzell JD. Regulation of body adiposity and the problem of obesity.<br />
Arterioscler Thromb Vasc Biol. 1997;17:233-238.<br />
2. Centers for Disease Control and Prevention. U.S. obesity trends. www.cdc.gov/nccdphp/<br />
dnpa/obesity/trend/maps/index.htm. Accessed August 14, 2009.<br />
3. U.S. Preventive Services Task Force. Screening for obesity in adults: recommendations and<br />
rationale. Ann Intern Med. 2003;139:930-932.<br />
4. Trust for America’s Health. F as in fat 2008: how obesity policies are failing in America.<br />
www.healthyamericans.org. Accessed August 14, 2009.<br />
5. Pentin PL, Nashelsky J. What are the indications for bariatric surgery? J Fam Pract.<br />
2005;54:633-634.<br />
6. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the<br />
United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord. 1998;22:<br />
39-47.<br />
7. Wang Y, Beydoun MA. The obesity epidemic in the United States—gender, age, socioeconomic,<br />
racial/ethnic, and geographic characteristics: a systematic review and meta-regression<br />
analysis. Epidemiol Rev. 2007;29:6-28.<br />
8. Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among<br />
US children, adolescents, and adults, 1999-2002. JAMA. 2004;291:2847-2850.<br />
9. Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the<br />
United States. JAMA. 1999;282:1530-1538.<br />
10. Brolin RE. Bariatric surgery and long-term control of morbid obesity. JAMA.<br />
2002;288:2793-2796.<br />
11. Buchwald H. Consensus conference statement. Bariatric surgery for morbid obesity:<br />
health implications for patients, health professionals, and third-party payers. Surg Obes Relat<br />
Dis. 2005;1:371-381.<br />
12. Christou NV, Sampalis JS, Liberman M, et al. Surgery decreases long-term mortality,<br />
morbidity, and health care use in morbidly obese patients. Ann Surg. 2004;240:416-424.<br />
13. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and<br />
meta-analysis. JAMA. 2004;292:1724-1737.<br />
14. Sugerman H, Wolfe LG, Sica DA, Clore JN. Diabetes and hypertension in severe obesity<br />
and effects of gastric bypass-induced weight loss. Ann Surg. 2003;237:751-758.<br />
15. Wyles SM, Ahmed AR. Tips and tricks in bariatric surgical procedures: a review article.<br />
Minerva Chir. 2009;64:253-264.<br />
16. Duell PB. Bariatric surgery for morbid obesity [letter]. JAMA. 2003;289:1779.<br />
17. Schwartz MW, Woods SC, Porte D, et al. Central nervous system control of food intake.<br />
Nature. 2000;404:661-667.<br />
18. Olbers T, Björkman S, Lindroos A, et al. Body composition, dietary intake, and energy<br />
expenditure after laparoscopic Roux-en-Y gastric bypass and laparoscopic vertical banded gastroplasty:<br />
a randomized clinical trial. Ann Surg. 2006;244:715-722.<br />
19. Santry HP, Lauderdale DS, Cagney KA, et al. Predictors of patient selection in bariatric<br />
surgery. Ann Surg. 2007;245:59-67.<br />
20. Puzziferri N, Austrheim-Smith IT, Wolfe BM, et al. Three-year follow-up of a prospective<br />
randomized trial comparing laparoscopic versus open gastric bypass. Ann Surg. 2006;243:<br />
181-188.<br />
21. Johansson H-E, Öhrvall M, Haenni A, et al. Gastric bypass alters the dynamics and metabolic<br />
effects of insulin and proinsulin secretion. Diabet Med. 2007;24:1213-1220.<br />
22. Matarasso A, Roslin MS, Kurian M. Bariatric surgery: an overview of obesity surgery.<br />
Plast Reconstr Surg. 2007;119:1357-1362.<br />
23. Gong K, Gagner M, Pomp A, et al. Micronutrient deficiencies after laparoscopic gastric<br />
bypass: recommendations. Obes Surg. 2008;18:1062-1066.<br />
24. Slater GH, Ren CJ, Siegel N, et al. Serum fat-soluble vitamin deficiency and abnormal<br />
calcium metabolism after malabsorptive bariatric surgery. J Gastrointest Surg. 2004;8:48-55.<br />
25. Favretti F, Ashton D, Busetto L, et al. The gastric band: first-choice procedure for obesity<br />
surgery. World J Surg. 2009;33:2039-2048.<br />
26. Zinzindohoue F, Chevallier JM, Douard R, et al. Laparoscopic gastric banding: a minimally<br />
invasive surgical treatment for morbid obesity: prospective study of 500 consecutive<br />
patients. Ann Surg. 2003;237:1-9.<br />
27. Gentileschi P, Lirosi F, Benavoli D, et al. Laparoscopic reoperative approach after open<br />
bariatric surgery. Chir Ital. 2009;61:137-141.<br />
28. Kral JG. ABC of obesity. Management: part III—surgery. BMJ. 2006;333:900-903.<br />
29. NHLBI Obesity Education Initiative. Clinical Guidelines on the Identification, Evaluation,<br />
and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda, MD:<br />
National Heart, Lung, and Blood Institute; 1998. NIH Publication No. 98-4083.<br />
30. Santry HP, Lauderdale DS, Cagney KA, et al. Predictors of patient selection in bariatric<br />
surgery. Ann Surg. 2007;245:59-67.<br />
31. Inge TH. Bariatric surgery for morbidly obese adolescents: is there a rationale for early<br />
intervention? Growth Horm IGF Res. 2006;(suppl A):S15-S19.<br />
32. Inge TH, Krebs NF, Garcia VF, et al. Bariatric surgery for severely overweight adolescents:<br />
concerns and recommendations. Pediatrics. 2004;114:217-223.<br />
33. Sugerman HJ, DeMaria EJ, Kellum JM, et al. Effects of bariatric surgery in older<br />
patients. Ann Surg. 2004;240:243-247.<br />
34. Pandolfino JE, Krishnamoorthy B, Lee TJ. Gastrointestinal complications of obesity surgery.<br />
MedGenMed. 2004;6:15.<br />
35. Mitka M. Surgery useful for morbid obesity, but safety and efficacy questions linger.<br />
JAMA. 2006;296:1575-1577.<br />
36. Encinosa WE, Bernard DM, Chen CC, Steiner CA. Healthcare utilization and outcomes<br />
after bariatric surgery. Med Care. 2006;44:706-712.<br />
37. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery.<br />
N Engl J Med. 2007;357:753-761.<br />
38. Morino M, Toppino M, Forestieri P, et al. Mortality after bariatric surgery: analysis of<br />
13,871 morbidly obese patients from a national registry. Ann Surg. 2007;246:1002-1009.<br />
39. Omalu BI, Buhari AM, Schauer PR, Kuller LH. Death rates and causes of death after<br />
bariatric surgery for Pennsylvania residents, 1995 to 2004. Arch Surg. 2007;142:923-928.<br />
40. Zingmond DS, McGory ML, Ko CY. Hospitalization before and after gastric bypass surgery.<br />
JAMA. 2005;294;1918-1924.<br />
41. Virji A, Murr MM. Caring for patients after bariatric surgery. Am Fam Physician.<br />
2006;73:1403-1408.<br />
42. Tice JA, Karliner L, Walsh J, et al. Gastric banding or bypass? A systematic review comparing<br />
the two most popular bariatric procedures. Am J Med. 2008;1221:885-893.<br />
43. Miller AD, Smith KM. Medication and nutrient administration considerations after bariatric<br />
surgery. Am J Health Syst Pharm. 2006;63:1852-1857.<br />
44. Sapala JA, Wood MH, Sapala MA, Flake TM. Marginal ulcer after gastric bypass: a prospective<br />
3-year study of 173 patients. Obes Surg. 1998;8:505-516.<br />
45. Rhode BM, Shustik C, Christou NV, MacLean LD. Iron absorption and therapy after<br />
gastric bypass. Obes Surg. 1999;9:17-21.<br />
46. Dalla Vecchia CF, Susin C, Rösing CK, et al. Overweight and obesity as risk indicators<br />
for periodontitis in adults. J Periodontol. 2005;76:1721-1728.<br />
47. Balduf LM, Kohn GP, Galanko JA, Farrell TM. The impact of socioeconomic factors on<br />
patient preparation for bariatric surgery. Obes Surg. 2009;19:1089-1095.<br />
10<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
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HEALTH SYSTEMS EDITION<br />
In-Service Primers<br />
Early intervention to<br />
control bleeding is<br />
important in order to<br />
minimize mortality,<br />
particularly in<br />
elderly patients.<br />
Gastrointestinal (GI) bleeding<br />
can originate anywhere<br />
from the pharynx to the<br />
rectum and can be occult or overt. It<br />
differs from internal bleeding, where<br />
blood leaks from the blood vessels in<br />
such a way that the bleeding cannot<br />
be seen outside of the body. GI<br />
bleeding has a variety of causes, and<br />
a review of patient medical history<br />
and a physical examination can distinguish<br />
between the macroscopic<br />
and microscopic forms. The manifestations<br />
depend on the location<br />
and rate of bleeding, from nearly<br />
undetectable to acute and life-threatening.<br />
Upper endoscopy or colonoscopy<br />
are generally considered the<br />
best methods to identify the source<br />
of bleeding. 1<br />
History of present illness should<br />
be reviewed to ascertain quantity<br />
and frequency of blood passage.<br />
However, quantity can be difficult to<br />
assess because even small amounts<br />
(5-10 mL) of rectal bleeding or<br />
modest amounts of vomited blood<br />
are alarming to a patient. Wh ether<br />
blood was passed with initial emesis<br />
Manouchehr Saljoughian, PharmD, PhD<br />
Department of Pharmacy Services<br />
Alta Bates Summit Medical Center<br />
Berkeley, California<br />
Gastrointestinal<br />
Bleeding<br />
AN ALARMING SIGN<br />
or only after several nonbloody vomiting<br />
episodes could indicate different<br />
causes. 1<br />
To evaluate the patient, there are<br />
a number of symptoms that need to<br />
be reviewed after GI bleeding. These<br />
include presence of abdominal discomfort,<br />
weight loss, easy bleeding<br />
or bruising, previous colonoscopy<br />
results, and symptoms of anemia<br />
(weakness, fatigue, dizziness). Past<br />
medical history should also inquire<br />
about previously diagnosed or undiagnosed<br />
GI bleeding, inflammatory<br />
bowel disease (IBD), bleeding diatheses,<br />
and liver disease.<br />
Several drugs increase the likelihood<br />
of bleeding, including nonsteroidal<br />
anti-inflammatory drugs<br />
(NSAIDs), warfarin, and heparin.<br />
Chronic liver disease due to excessive<br />
use of alcohol can also cause bleeding.<br />
GI bleeding may also precipitate<br />
hepatic encephalopathy (brain and<br />
nervous system damage caused by<br />
liver failure) or hepatorenal syndrome<br />
(kidney failure secondary to<br />
liver disease). 2<br />
Types of GI Bleeding<br />
Upper GI Bleeding: Hematemesis is<br />
vomiting of red-colored blood and<br />
indicates upper GI bleeding, usually<br />
from an arterial source or varix. It is<br />
considered a medical emergency, and<br />
the most vital distinction is whether<br />
there is blood loss sufficient to cause<br />
shock. The bleeding is similar to<br />
dark brown emesis, with granular<br />
material that resembles coffee<br />
grounds. This results from upper GI<br />
bleeding that has slowed or stopped,<br />
with conversion of red hemoglobin<br />
to brown hematin by gastric acid. 3<br />
There are many causes for<br />
hematemesis, including irritation or<br />
erosion of the lining of the esophagus<br />
or stomach; bleeding ulcer<br />
located in the stomach, duodenum,<br />
or esophagus; vomiting of ingested<br />
blood after hemorrhage in the oral<br />
cavity, nose, or throat; vascular malfunctions<br />
of the GI tract; and<br />
tumors of the stomach or esophagus.<br />
Minimal Blood Loss: In this case,<br />
the patient is administered a proton<br />
pump inhibitor such as omeprazole,<br />
given a blood transfusion, and kept<br />
nil per os (Latin, “nothing by<br />
mouth”) until endoscopy can be<br />
arranged for further investigation.<br />
Significant Blood Loss: In a hemodynamically<br />
significant case of<br />
hematemesis (e.g., hypovolemic<br />
shock), resuscitation is an immediate<br />
priority to prevent cardiac arrest.<br />
Fluids and/or blood are administered,<br />
preferably by central venous<br />
catheter, and the patient is prepared<br />
for emergency endoscopy. If the<br />
source of bleeding cannot be identified<br />
endoscopically, a surgical option<br />
is usually sought for laparotomy. 3<br />
Lower GI Bleeding: Hematochezia<br />
is the passage of gross blood<br />
from the rectum and usually indicates<br />
lower GI bleeding. It is distinguished<br />
from melena, which is stool<br />
with blood that has been altered by<br />
the gut flora and appears “tarry”<br />
black. It is also different from bright<br />
red blood per rectum, which is<br />
caused by hemorrhoidal or fissure<br />
problems and is a local rectal bleeding.<br />
Hematochezia might also result<br />
from vigorous upper GI bleeding<br />
with rapid transit of blood through<br />
the intestines. Most common causes<br />
HS-12<br />
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GASTROINTESTINAL BLEEDING<br />
HEALTH SYSTEMS EDITION<br />
in adults are diverticulosis and hemorrhoids,<br />
both relatively benign,<br />
although this bleeding might be a<br />
warning sign for colorectal cancer.<br />
Hematochezia in newborn infants<br />
may be due to swallowed maternal<br />
blood at the time of delivery. In the<br />
most serious cases, it can also be an<br />
initial symptom of necrotizing<br />
enterocolitis, a serious condition<br />
affecting premature infants. In<br />
young adults, IBD, particularly<br />
ulcerative colitis, is a serious cause of<br />
hematochezia that must be further<br />
investigated for rapid treatment. 1-3<br />
Melena: Melena is a black, tarry<br />
stool that is caused by GI bleeding.<br />
The black color is due to the oxidation<br />
of blood hemoglobin during<br />
the bleeding in the ileum and colon.<br />
Melena also refers to stools or vomit<br />
stained black by blood pigment or<br />
dark blood products and may indicate<br />
upper GI bleeding. Bleeding<br />
from a lower source that occurs<br />
slowly enough to allow for oxidation<br />
is also associated with melena. About<br />
100 to 200 mL of blood in the<br />
upper GI tract is required to cause<br />
melena, which can remain for several<br />
days after bleeding has stopped. 4<br />
Black stool that does not contain<br />
occult blood may result from ingestion<br />
of iron, bismuth, or various<br />
foods and should not be mistaken<br />
for melena. Peptic ulcer disease is the<br />
main cause of melena, but secondary<br />
causes include bleeding from the<br />
upper GI tract as in gastritis or<br />
esophageal varices or even from the<br />
ascending colon. Overdosing of certain<br />
drugs (e.g., warfarin, clopidogrel,<br />
or long-term use of NSAIDS)<br />
may also be a cause. Melena is not<br />
considered a medical emergency, but<br />
patients should be carefully monitored<br />
to find the cause and assessed<br />
for further treatment. 3<br />
Etiology<br />
GI bleeding of any cause is more<br />
likely and severe in patients with<br />
chronic liver disease from alcohol<br />
abuse or hepatitis. It also occurs<br />
more commonly in patients with<br />
hereditary coagulation disorders or<br />
in those taking certain drugs. Drugs<br />
associated with GI bleeding include<br />
heparin, warfarin, aspirin, certain<br />
NSAIDs, clopidogrel, and selective<br />
serotonin reuptake inhibitors, which<br />
cause platelet depletion and reduce<br />
the ability to form clots. About 20%<br />
to 30% of GI bleeding is due to<br />
duodenal ulcers and gastric or duodenal<br />
erosions. 4<br />
Varices and erosive esophagitis are<br />
responsible for 10% to 20% of<br />
upper GI bleeds. For the lower GI,<br />
the bleeding depends on the age<br />
group, but it is mainly due to anal<br />
fissures, diverticulitis, irritable bowel<br />
syndrome, colitis, Crohn’s disease,<br />
and colonic polyps or carcinoma. 5<br />
Evaluation and Diagnosis<br />
The first step in the diagnosis of GI<br />
bleeding is to stabilize the patient’s<br />
airways and administer IV fluids or<br />
transfuse blood. Bloody nasogastric<br />
aspirate indicates active upper GI<br />
bleeding, but about 10% of patients<br />
have no blood in the nasogastric<br />
aspirate. 4 Then the focus should be<br />
on vital signs and any indication for<br />
hypovolemia (e.g., tachycardia,<br />
tachypnea, oliguria, confusion) or<br />
anemia (e.g., fatigue, pale skin,<br />
headache, coldness in the hands and<br />
feet, diaphoresis). In cases of lesser<br />
bleedings, the tachycardia and orthostatic<br />
changes (i.e., pulse, blood pressure)<br />
are milder but need immediate<br />
attention, especially in the elderly. 6<br />
When the patient is stable, the<br />
signs and symptoms of external<br />
bleeding disorders, such as black and<br />
blue spots on the skin (petechiae,<br />
ecchymoses), are sought. Other signs<br />
to look for are ascites and erythema<br />
(chronic liver disease) and splenomegaly<br />
and dilated abdominal wall<br />
veins (portal hypertension).<br />
In all patients with GI bleeding, a<br />
digital rectal examination is necessary<br />
to search for stool color, masses,<br />
and fissures. Anoscopy is done to<br />
diagnose hemorrhoids. Chemical<br />
testing of a stool specimen for occult<br />
blood completes the examination if<br />
gross blood is not present. In about<br />
50% of patients, peptic ulcer can be<br />
the cause of GI bleeding. 4 Epigastric<br />
abdominal discomfort that is<br />
relieved by food or antacids suggests<br />
peptic ulcer disease. These patients<br />
may or may not have pain. 6<br />
Bloody diarrhea, fever, and<br />
abdominal pain suggest ischemic<br />
colitis, ulcerative colitis, Crohn’s disease,<br />
or an infectious colitis. Fresh<br />
blood only on stools suggests rectal<br />
hemorrhoids or fissures, whereas<br />
blood mixed with the stool indicates<br />
bleeding from a distal or farthest<br />
area of the colon. Occult blood in<br />
the stool may be the first sign of a<br />
polyp, particularly in middle-aged<br />
patients. A CBC should be obtained<br />
in patients with occult blood loss. 6<br />
With more significant bleeding,<br />
coagulation monitoring such as<br />
platelet count, prothrombin time<br />
(PT), and partial thromboplastin<br />
time (PTT), and liver function tests<br />
such as aspartate aminotransferase<br />
(AST), alanine aminotransferase<br />
(ALT), bilirubin, alkaline phosphatase<br />
(ALP), and albumin, are done<br />
in certain patients. In most cases ,<br />
one or more diagnostic procedures<br />
are required.<br />
Although endoscopy is therapeutic<br />
as well as diagnostic, it should be<br />
done rapidly for significant upper<br />
GI bleeding. Angiography is useful<br />
in the diagnosis of upper GI bleeding<br />
and permits certain therapeutic<br />
maneuvers (e.g., embolization, vasoconstrictor<br />
infusion).<br />
Flexible sigmoidoscopy and anoscopy<br />
may be all that is required<br />
acutely for patients with symptoms<br />
typical of hemorrhoidal bleeding. All<br />
other patients with hematochezia<br />
should have a colonoscopy, which<br />
can be done electively after routine<br />
preparation unless there is significant<br />
ongoing bleeding. If colonoscopy<br />
cannot visualize the source and<br />
ongoing bleeding is sufficiently rapid<br />
(>0.5 to 1 mL/min), angiography<br />
may localize the source. 5,6<br />
Endoscopy is the preferred choice<br />
for occult bleeding, because diagno-<br />
HS-14<br />
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GASTROINTESTINAL BLEEDING<br />
HEALTH SYSTEMS EDITION<br />
sis of this type of bleeding may be<br />
difficult, due to heme-positive stools<br />
from bleeding anywhere in the GI<br />
tract. Double-contrast barium enema<br />
and sigmoidoscopy can also be used<br />
for the lower tract when colonoscopy<br />
is unavailable or the patient<br />
refuses the procedure. 4<br />
Treatment<br />
Both hematemesis and hematochezia<br />
should be considered an emergency.<br />
Admission to an intensive care unit,<br />
with consultation by a gastroenterologist<br />
and a surgeon, is recommended<br />
for all patients with severe GI bleeding.<br />
General treatment is directed at<br />
maintenance of the airway and restoration<br />
of circulating volume. Hemostasis<br />
and other treatments depend<br />
on the cause of the bleeding. 7,8<br />
Airway: A major cause of morbidity<br />
and mortality in patients with<br />
active upper GI bleeding is aspiration<br />
of blood with subsequent respiratory<br />
problems. To prevent these<br />
issues, endotracheal intubation<br />
should be considered in patients<br />
who have inadequate gag reflexes or<br />
are obtunded or unconscious—particularly<br />
if they will be undergoing<br />
upper endoscopy. 4<br />
Fluid Replacement: IV fluids are<br />
initiated for any patient with hypovolemia<br />
or hemorrhagic shock.<br />
Patients requiring further resuscitation<br />
should receive transfusion with<br />
packed red blood cells (RBCs).<br />
Transfusions continue until intravascular<br />
volume is restored and then are<br />
given as needed to replace ongoing<br />
blood loss. Platelet count should be<br />
monitored closely, since platelet<br />
transfusion may be required with<br />
severe bleeding. Patients who a re<br />
taking antiplatelet drugs (e.g.,<br />
clopid ogrel) and aspirin may have<br />
platelet dysfunction, often resulting<br />
in increased bleeding. Platelet transfusion<br />
should be considered when<br />
patients taking these drugs have<br />
severe, ongoing bleeding. Fresh frozen<br />
plasma should be transfused<br />
after every 4 units of packed RBCs. 4<br />
Hemostasis: Early intervention to<br />
control bleeding is important in<br />
order to minimize mortality, particularly<br />
in elderly patients. Specific<br />
therapy depends on the bleeding<br />
site. Fo r peptic ulcer, ongoing bleeding<br />
or rebleeding is treated with<br />
endoscopic coagulation. Nonbleeding<br />
vessels that are visible within an<br />
ulcer crater are also treated. If endoscopy<br />
does not stop the bleeding and<br />
medical management does not control<br />
gastric acid secretion, then surgery<br />
is performed. 4<br />
Severe, ongoing hematochezia<br />
from diverticula or angiomas can<br />
sometimes be controlled colonoscopically<br />
by electrocautery, coagulation<br />
with a heater probe, or injection<br />
with dilute epinephrine. Polyps can<br />
be removed by snare or cautery. If<br />
these methods are ineffective or<br />
unfeasible, angiography with embolization<br />
or vasopressin infusion may<br />
be successful. 4 Angiography can also<br />
be used to localize the source of<br />
bleeding more accurately. Surgery<br />
may be used in patients with continued<br />
bleeding, but localization of the<br />
bleeding site is very important.<br />
Acute or chronic bleeding of internal<br />
hemorrhoids stops spontaneously in<br />
most cases. Patients with refractory<br />
bleeding are treated via anoscopy<br />
with rubber band ligation, injection,<br />
coagulation, or surger y. 8<br />
Typically, a healthy person can<br />
endure a loss of 10% to 15% of the<br />
total blood volume without serious<br />
medical difficulties, and blood donation<br />
typically takes 8% to 10% of<br />
the donor’s blood volume. 4<br />
GI Bleeding in the Elderly<br />
I n the elderly (age ≥65 years), hemorrhoids<br />
and colorectal cancer are<br />
the most common causes of minor<br />
bleeding. Peptic ulcer, diverticular<br />
disease, and angiodysplasia are the<br />
most common causes of major<br />
bleeding. Approximately 35% to<br />
45% of all cases of acute upper GI<br />
hemorrhage occur in elderly persons.<br />
These patients increasingly account<br />
for the 10% of deaths that result<br />
from a bleeding episode each year. 4<br />
El derly patients tolerate massive<br />
GI bleeding poorly. Diagnosis must<br />
be made quickly, and treatment<br />
must be started sooner than in<br />
younger patients, who can better tolerate<br />
repeated episodes of bleeding. 9<br />
Endoscopic Safety<br />
Although upper endoscopy and<br />
colonoscopy are generally considered<br />
to be safe in the elderly, the risk of<br />
complications (including hemorrhage,<br />
aspiration pneumonia, myocardial<br />
infarction, and perforation) is<br />
greater than that with younger<br />
patients. Approximately 30% to<br />
40% of patients who undergo GI<br />
endoscopy are older than 70 years. 4<br />
On an emergency basis, therapeutic<br />
endoscopy is generally riskier than<br />
diagnostic endoscopy. Therefore,<br />
elderly patients—especially those<br />
with such comorbidities as obesity<br />
and cardiovascular, pulmonary, renal,<br />
hepatic, metabolic, or neurologic disorders—require<br />
careful evaluation<br />
before, and intensive monitoring<br />
during, the procedure. Endoscopy<br />
can be done in patients taking aspirin<br />
or NSAIDs who do not have a<br />
preexisting bleeding disorder.<br />
REFERENCES<br />
1. Ghosh S, Watts D, Kinnear M. Management of<br />
gastrointestinal haemorrhage. Postgrad Med J.<br />
2002;78:4-14.<br />
2. Rockey DC, Auslander A, Greenberg PD. Detection<br />
of upper gastrointestinal blood with fecal occult<br />
blood tests. Am J Gastroenterol. 1999;94:344-350.<br />
3. Marignani M, Angeletti S, Filippi L, et al. Occult and<br />
obscure bleeding, iron deficiency anemia, and other gastrointestinal<br />
stories. Int J Mol Med. 2005;15:129-135.<br />
4. Gastrointestinal bleeding. MedlinePlus. www.nlm.<br />
nih.gov/medlineplus/gastrointestinalbleeding.html.<br />
Accessed November 4, 2009.<br />
5. Raju GS, Nath SK. Capsule endoscopy. Curr<br />
Gastroenterol Rep. 2005;7:358-364.<br />
6. Triester SL, Leighton JA, Leontiadis GI, et al. A<br />
meta-analysis of the yield of capsule endoscopy compared<br />
to other diagnostic modalities in patients with<br />
obscure gastrointestinal bleeding. Am J Gastroenterol.<br />
2005;100:2407-2418.<br />
7. Carey EJ, Fleischer DE. Investigation of the small<br />
bowel in gastrointestinal bleeding—enteroscopy and<br />
capsule endoscopy. Gastroenterol Clin North Am.<br />
2005;34:719-734.<br />
8. Gastrointestinal bleeding. Mayo Clinic.<br />
www.mayoclinic.org/gastrointestinal-bleeding.<br />
Accessed November 2, 2009.<br />
9. Allison JE, Tekawa IS, Ransom LJ, Adrain AL. A<br />
comparison of fecal occult-blood tests for colorectalcancer<br />
screening. N Engl J Med. 1996;334:155-159.<br />
HS-16<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
TOUGH AS EVER, BUT<br />
A BIT MORE REFINED<br />
Now, patients who use colchicine for gout flares can get<br />
the efficacy they need from gentle COLCRYS.<br />
Important Safety Information<br />
COLCRYS (colchicine, USP) tablets are<br />
indicated for prophylaxis and the treatment<br />
of gout fl ares.<br />
COLCRYS is contraindicated in patients<br />
with renal or hepatic impairment who are<br />
concurrently prescribed P-gp inhibitors<br />
or strong inhibitors of CYP3A4 as lifethreatening<br />
or fatal toxicity has been<br />
reported. Dose adjustments of COLCRYS<br />
may be required when co-administered<br />
with P-gp or CYP3A4 inhibitors. The most<br />
common adverse events in clinical trials<br />
for the prophylaxis and treatment of gout<br />
were diarrhea and pharyngolaryngeal<br />
pain. Rarely, myelosuppression, thrombocytopenia,<br />
and leukopenia have been<br />
reported in patients taking colchicine.<br />
Rhabdomyolysis has been occasionally<br />
observed, especially when colchicine is<br />
prescribed in combination with other drugs<br />
known to cause this effect. Monitoring is<br />
recommended for patients with a history<br />
of blood dyscrasias or rhabdomyolysis.<br />
You are encouraged to report negative<br />
side effects of prescription drugs to the<br />
FDA. Visit www.fda.gov/medwatch or call<br />
1.800.FDA.1088.<br />
You may also report negative side effects<br />
to the manufacturer of COLCRYS by calling<br />
1.888.351.3786.<br />
Please see brief summary on adjacent<br />
page.<br />
Distributed by AR Scientific, Inc.<br />
A URL Pharma company. Philadelphia, PA<br />
www.urlpharma.com<br />
©2009 URL Pharma, Inc. All rights reserved.<br />
COL-097 Nov 2009 Printed in USA.<br />
www.COLCRYS.com | 1.888.351.3786
COLCRYS (colchicine, USP) tablets for oral use<br />
Brief Summary of full Prescribing Information<br />
The following is a brief summary only. Please see full Prescribing<br />
Information for complete product information.<br />
INDICATIONS AND USAGE<br />
COLCRYS TM (colchicine, USP) tablets are indicated for prophylaxis and<br />
the treatment of gout flares.<br />
Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of<br />
gout flares.<br />
Treatment of Gout Flares: COLCRYS is indicated for treatment of acute<br />
gout flares when taken at the first sign of a flare.<br />
Familial Mediterranean fever (FMF): COLCRYS is indicated in adults<br />
and children 4 years or older for treatment of familial Mediterranean<br />
fever (FMF).<br />
CONTRAINDICATIONS<br />
Patients with renal or hepatic impairment should not be given COLCRYS in<br />
conjunction with P-gp or strong CYP3A4 inhibitors. In these patients,<br />
life-threatening and fatal colchicine toxicity has been reported with colchicine<br />
taken in therapeutic doses.<br />
WARNINGS AND PRECAUTIONS<br />
Fatal Overdose: Fatal overdoses, both accidental and intentional, have<br />
been reported in adults and children who have ingested colchicine.<br />
COLCRYS should be kept out of the reach of children.<br />
Blood Dyscrasias: Myelosuppression, leukopenia, granulocytopenia,<br />
thrombocytopenia, pancytopenia, and aplastic anemia have been reported<br />
with colchicine used in therapeutic doses.<br />
Drug Interactions: Colchicine is a P-gp and CYP3A4 substrate. Lifethreatening<br />
and fatal drug interactions have been reported in patients<br />
treated with colchicine given with P-gp and strong CYP3A4 inhibitors.<br />
If treatment with a P-gp or strong CYP3A4 inhibitor is required in<br />
patients with normal renal and hepatic function, the patient’s dose of<br />
colchicine may need to be reduced or interrupted [see DRUG<br />
INTERACTIONS]. Use of COLCRYS in conjunction with P-gp or strong<br />
CYP3A4 inhibitors is contraindicated in patients with renal or hepatic<br />
impairment [see CONTRAINDICATIONS].<br />
Monitor for toxicity and if present consider temporary interruption or<br />
discontinuation of COLCRYS.<br />
Neuromuscular Toxicity: Colchicine-induced neuromuscular toxicity<br />
and rhabdomyolysis have been reported with chronic treatment in<br />
therapeutic doses. Patients with renal dysfunction and elderly patients,<br />
even those with normal renal and hepatic function, are at increased risk.<br />
Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin,<br />
gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves<br />
associated with myotoxicity) or cyclosporine with COLCRYS may potentiate<br />
the development of myopathy [see DRUG INTERACTIONS]. Once<br />
colchicine is stopped, the symptoms generally resolve within 1 week to<br />
several months.<br />
ADVERSE REACTIONS<br />
Prophylaxis of Gout Flares: The most commonly reported adverse reaction<br />
in clinical trials of colchicine for the prophylaxis of gout was diarrhea.<br />
Treatment of Gout Flares: The most common adverse reactions reported<br />
in the clinical trial with COLCRYS for treatment of gout flares were diarrhea<br />
(23%) and pharyngolaryngeal pain (3%).<br />
FMF: Gastrointestinal tract adverse effects are the most frequent side<br />
effects in patients initiating COLCRYS, usually presenting within 24 hours,<br />
and occurring in up to 20% of patients given therapeutic doses. Typical<br />
symptoms include cramping, nausea, diarrhea, abdominal pain, and<br />
vomiting. These events should be viewed as dose-limiting if severe as they<br />
can herald the onset of more significant toxicity.<br />
DRUG INTERACTIONS<br />
COLCRYS is a substrate of the efflux transporter P-glycoprotein (P-gp). Of<br />
the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the<br />
metabolism of colchicine. If COLCRYS is administered with drugs that<br />
inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations<br />
of colchicine are likely. Fatal drug interactions have been reported.<br />
Physicians should ensure that patients are suitable candidates for<br />
treatment with COLCRYS and remain alert for signs and symptoms of<br />
toxicities related to increased colchicine exposure as a result of a drug<br />
interaction. Signs and symptoms of COLCRYS toxicity should be evaluated<br />
promptly and, if toxicity is suspected, COLCRYS should be discontinued<br />
immediately. See full Prescribing Information for a complete list of reported<br />
potential interactions.<br />
USE IN SPECIFIC POPULATIONS<br />
• In the presence of mild to moderate renal or hepatic impairment, adjustment<br />
of dosing is not required for treatment of gout flare, prophylaxis of gout<br />
flare, and FMF but patients should be monitored closely.<br />
• In patients with severe renal impairment for prophylaxis of gout flares the<br />
starting dose should be 0.3 mg/day, for gout flares no dose adjustment is<br />
required but a treatment course should be repeated no more than once<br />
every 2 weeks. In FMF patients, start with 0.3 mg/day and any increase in<br />
dose should be done with close monitoring.<br />
• In patients with severe hepatic impairment, a dose reduction may be<br />
needed in prophylaxis of gout flares and FMF patients; while a dose<br />
reduction may not be needed in gout flares, a treatment course should be<br />
repeated no more than once every 2 weeks.<br />
• For patients undergoing dialysis, the total recommended dose for<br />
prophylaxis of gout flares should be 0.3 mg given twice a week with close<br />
monitoring. For treatment of gout flares, the total recommended dose<br />
should be reduced to 0.6 mg (1 tablet) x 1 dose and the treatment course<br />
should not be repeated more than once every two weeks. For FMF<br />
patients the starting dose should be 0.3 mg per day and dosing can be<br />
increased with close monitoring.<br />
• Pregnancy: Use only if the potential benefit justifies the potential risk to<br />
the fetus.<br />
• Nursing Mothers: Caution should be exercised when administered to a<br />
nursing woman.<br />
• Geriatric Use: The recommended dose of colchicine should be based on<br />
renal function.<br />
Manufactured for:<br />
AR SCIENTIFIC, INC. Philadelphia, PA 19124 USA<br />
by:<br />
MUTUAL PHARMACEUTICAL COMPANY, INC.<br />
Philadelphia, PA 19124 USA<br />
Rev 02, September 2009<br />
Distributed by AR Scientifi c, Inc.<br />
A URL Pharma company.<br />
Philadelphia, PA<br />
www.urlpharma.com<br />
COL-088 Nov 09
Colorectal Cancer<br />
Screening<br />
LIFESAVING GUIDELINES<br />
Routine examinations,<br />
beginning at age 50,<br />
are key to preventing<br />
this disease.<br />
Colorectal (colon) cancer is<br />
extremely common. Of all<br />
the cancers that affect both<br />
men and women, colorectal cancer is<br />
the second-leading cancer killer in<br />
the United States. 1 The disease manifests<br />
in the colon or rectum, with<br />
70% of colorectal cancer occurring<br />
specifically in the sigmoid colon and<br />
rectum. 2,3 While colorectal cancer<br />
affects men and women of all racial<br />
and ethnic groups, cancer of the<br />
colon is more common in women,<br />
whereas cancer of the rectum is more<br />
common in men. 2,3 The disease is<br />
most often found in adults aged 50<br />
years or older, with incidence beginning<br />
to rise at age 40 and peaking at<br />
age 60 to 75. 3 According to United<br />
States Cancer Statistics, in 2005 there<br />
were 141,405 people diagnosed with<br />
colorectal cancer in the U.S., and<br />
53,005 deaths were attributed to it. 1,4<br />
Remarkably, up to 60% of deaths<br />
from this condition could be prevented.<br />
2 Routine screening, beginning<br />
at age 50, is the key to preventing<br />
colorectal cancer. 5 Screening saves<br />
lives (TABLE 1). 3<br />
Mary Ann E. Zagaria, PharmD, MS, CGP<br />
Senior Care Consultant <strong>Pharmacist</strong> and<br />
President of MZ Associates, Inc.<br />
Norwich, New York<br />
www.mzassociatesinc.com<br />
Recipient of the Excellence in Geriatric Pharmacy<br />
Practice Award from the Commission for<br />
Certification in Geriatric Pharmacy<br />
Clinical Features and Metastasis<br />
Symptoms of colorectal cancer<br />
develop insidiously and often are<br />
present for months, even years,<br />
before diagnosis. 6 Symptoms include<br />
blood in the stool or a change in<br />
bowel habits. 3 Colorectal tumors<br />
spread into adjacent structures (i.e.,<br />
by direct extension) and metastasize<br />
through the lymphatics and blood<br />
vessels. 6 Sites of metastatic spread<br />
are, preferentially, the regional lymph<br />
nodes and the liver, lungs, and<br />
bones; many other sites may follow. 6<br />
Carcinomas of the anal region are<br />
locally invasive and involve metastasis<br />
to regional lymph nodes and distant<br />
sites. 6<br />
Staging, Prognosis,<br />
and Treatment<br />
The extent of the tumor at time of<br />
diagnosis is the most important<br />
prognostic indicator of colorectal<br />
cancer. 6 Staging designates the<br />
extent of the disease regarding tumor<br />
penetration, regional lymph node<br />
metastasis, and distant metastasis. 7<br />
Treatment for colorectal cancer is by<br />
surgical resection and chemotherapy<br />
(for lymph node involvement). 3 Typical<br />
chemotherapeutic agents utilized are<br />
5-fluorouracil and leucovorin; survival<br />
is improved by 10% to 30% when<br />
used in patients with colorectal cancer<br />
with positive lymph nodes. 3 Combined<br />
radiation and chemotherapy may be<br />
beneficial in patients with rectal cancer<br />
with one to four positive lymph<br />
nodes. 3 For improving the rate of<br />
resectability in rectal cancer or reducing<br />
lymph node metastasis, preoperative<br />
radiation and chemotherapy may be<br />
employed. 3<br />
Colorectal Cancer<br />
Screening Saves Lives<br />
The premise for the utility of cancer<br />
screening, in general, is that early<br />
diagnosis may reduce cancer mortality,<br />
result in less radical therapy, and<br />
decrease costs. 3 Colorectal cancer<br />
screening, in particular, is capable of<br />
detecting precancerous polyps in the<br />
colon or rectum for removal and can<br />
detect early-stage cancer so that<br />
treatment may be initiated when it is<br />
more effective, often leading to a<br />
cure. 4,8 It is predicted that if all<br />
individuals aged 50 or older had<br />
regular colorectal screening tests<br />
resulting in the removal of all precancerous<br />
polyps, up to 90% of<br />
deaths from colorectal cancer could<br />
be prevented. 4<br />
Screening for colorectal cancer<br />
begins soon after an individual turns<br />
50 years of age, then continues at<br />
regular intervals (TABLE 1). 8,9 People<br />
at higher risk for colorectal cancer<br />
should be tested at a younger age<br />
and/or more frequently, including<br />
individuals who 1) have a personal<br />
or close family history of colorectal<br />
polyps or colorectal cancer; 2) have<br />
inflammatory bowel disease; 3) have<br />
genetic syndromes such as familial<br />
adenomatous polyposis (FAP) or<br />
hereditary nonpolyposis colorectal<br />
cancer. 8,10 Patients should be encouraged<br />
to speak to their health care<br />
provider to ascertain when they<br />
should begin screening and how<br />
often they should be tested. 8<br />
Screening Tests and Guidelines<br />
There are several screening tests<br />
that can be used to detect polyps<br />
or colorectal cancer; while each can<br />
29<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
COLORECTAL CANCER<br />
Table 1<br />
Routine Colorectal Cancer–Screening<br />
Schedule in Average-Risk Adults<br />
Recommendation ACS/USMSTF/ACR USPSTF<br />
Age to commence Commence at age 50 and Commence screening at<br />
and cease cease screening at point age 50. Routine screening<br />
screening in in time where curative between ages 76-85 and<br />
average-risk therapy would not be screening after age 85 is<br />
adults offered secondary to not recommended<br />
life-limiting comorbidity<br />
Stool testing Annual screening with Annual screening with<br />
(gFOBT) high-sensitivity guaiac- high-sensitivity guaiacbased<br />
tests<br />
based tests<br />
Flexible Screening every 5 years. Screening every 5 years,<br />
sigmoidoscopy Screening every 5 years, with gFOBT every 3 years<br />
with annual gFOBT or<br />
FIT optional<br />
Colonoscopy Screening every 10 years Screening every 10 years<br />
ACS/USMSTF/ACR: American Cancer Society, the U.S. Multi-Society Task Force on<br />
Colorectal Cancer, and the American College of Radiology; FIT: fecal immunochemical test;<br />
gFOBT: guaiac-based fecal occult blood test; USPSTF: U.S. Preventive Services Task Force.<br />
Source: References 13-15.<br />
be used alone, they are sometimes<br />
employed in combination. 11 The<br />
U.S. Preventive Services Task Force<br />
(USPSTF) recommends colorectal<br />
cancer screening in average-risk<br />
men and women aged 50 to 75<br />
years using high-sensitivity fecal<br />
occult blood testing, sigmoidoscopy,<br />
or colonoscopy (TABLE 1). 11<br />
A high-sensitivity fecal occult<br />
blood test (FOBT) checks for<br />
occult blood in three consecutive<br />
stool samples. 10,12 There are two<br />
types of FOBT: 1) guaiac based<br />
and 2) fecal immunochemical<br />
using antibodies. A test kit for<br />
home use can be provided by a<br />
health care practitioner. The<br />
patient employs a stick or brush to<br />
obtain a small amount of stool to<br />
be checked for an abnormality by<br />
the doctor or a laboratory. 11 Routine<br />
schedule: annually. 10,12<br />
A flexible sigmoidoscopy is a<br />
procedure in which a physician<br />
uses a short, thin, flexible, lighted<br />
tube (sigmoidoscope) to visually<br />
inspect the interior walls of the<br />
rectum and only a portion of the<br />
colon; Routine schedule: every 5<br />
years. 10,12<br />
A colonoscopy involves a flexible,<br />
lighted tube (colonoscope)<br />
with which the physician visually<br />
inspects the interior walls of the<br />
rectum and the entire colon; samples<br />
of tissue may be collected<br />
during the test for closer examination,<br />
and polyps may be removed<br />
as well. The colonoscopy is also<br />
used as a follow-up test if any previous<br />
result from one of the other<br />
screening tests is unusual. 10-12 Routine<br />
schedule: every 10 years. 10,12<br />
Other screening tests not recommended<br />
by the USPSTF may be<br />
used in some settings, may be recommended<br />
by other groups, or are<br />
being studied. 11 Health insurance<br />
plans usually do not cover these<br />
tests; additionally, if any unusual<br />
findings are noted, a follow-up<br />
colonoscopy is required. 11 Examples<br />
include a double-contrast barium<br />
enema, consisting of a liquid barium<br />
enema followed by an air enema,<br />
which allows for a visual outline of<br />
the colon on an x-ray; a virtual colonoscopy,<br />
creating images of the entire<br />
colon on a computer screen through<br />
the use of x-rays and computer technology<br />
(while no sedation is necessary,<br />
bowel preparation is still<br />
required; lesions cannot be biopsied<br />
during this diagnostic procedure as<br />
in the optical colonoscopy); and a<br />
stool DNA test, requiring the collection<br />
of an entire bowel movement to<br />
be sent to a laboratory to test for<br />
cancer cells. 7,11<br />
A consensus guideline for<br />
colorectal cancer screening was<br />
released in March 2008 by the<br />
American Cancer Society, the U.S.<br />
Multi-Society Task Force on<br />
Colorectal Cancer, and the American<br />
College of Radiology (ACS/<br />
USMSTF/ACR), while the USPSTF<br />
updated its screening recommendations<br />
in October 2008. 13-15 A concise<br />
and summarized version of the<br />
most current recommendations is<br />
available in TABLE 1; for complete<br />
and detailed coverage of the recommendations,<br />
refer to Reference 13<br />
online. Ongoing studies drive the<br />
constantly evolving recommended<br />
screening schedules. 3 The involved<br />
organizations promote a message<br />
for adults: Choose a test and get<br />
screened if you are 50 or older. 13<br />
The CDC indicates that the<br />
decision to be screened after age<br />
75 should be made on an individual<br />
basis; patients older than 75<br />
Resources<br />
Colorectal Cancer<br />
Screening Basic Fact Sheet<br />
www.cdc.gov/cancer/Colorectal<br />
Colorectal Cancer<br />
Activities Across the Nation<br />
States, tribes, and territories that have<br />
screening programs or laws related to<br />
colorectal cancer.<br />
www.cdc.gov/cancer/Colorectal<br />
(800) 4-CANCER<br />
or (800) ACS-2345<br />
Learn about screening options in<br />
your community.<br />
Colorectal Cancer Fact Sheet<br />
Learn how to reduce colon cancer risk<br />
by following screening guidelines,<br />
increasing activity levels, and eating a<br />
low-fat, healthy diet.<br />
www.cancer.org/docroot/PRO/content/<br />
PRO_1_1_2002_Fact_Sheets.asp?<br />
30<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
COLORECTAL CANCER<br />
are instructed to consult their<br />
physician as to whether they<br />
should be screened. 11 The USP-<br />
STF suggests that routine screening<br />
between ages 76 and 85 years<br />
is not recommended; screening<br />
after age 85 is also not recommended.<br />
13 According to the ACS/<br />
USMSTF/ACR consensus guideline<br />
for colorectal cancer screening,<br />
screening should end at a<br />
point where curative therapy<br />
would not be offered due to lifelimiting<br />
comorbidity. 13<br />
Demonstration Project<br />
Partnerships have been built by<br />
the CDC to encourage screening,<br />
REFERENCES<br />
1. Centers for Disease Control and Prevention. Colorectal<br />
(colon) cancer. www.cdc.gov/cancer/Colorectal. Accessed<br />
November 16, 2009.<br />
2. Centers for Disease Control and Prevention.<br />
Basic information about colorectal (colon) cancer.<br />
www.cdc.gov/cancer/colorectal/basic_info/index.htm.<br />
Accessed November 16, 2009.<br />
3. Beers MH, Porter RS, Jones TV, et al. The Merck<br />
Manual of Diagnosis and Therapy. 18th ed. Whitehouse<br />
Station, NJ: Merck Research Laboratories; 2006:89-<br />
94,173-178,1147-1150.<br />
4. Centers for Disease Control and Prevention. Colorectal<br />
Cancer Control Program. www.cdc.gov/cancer/crccp.<br />
Accessed November 16, 2009.<br />
5. U.S. Preventive Services Task Force. Screening for Colorectal<br />
Cancer: U.S. Preventive Services Task Force Recommendation<br />
Statement. Rockville, MD: Agency for Healthcare<br />
Research and Quality; October 2008. AHRQ publication<br />
08-05124-EF-3.<br />
support education and training,<br />
and conduct surveillance and<br />
research. 4 One particular program<br />
developed by the CDC is the<br />
Colorectal Cancer Control Program,<br />
which provides funding to<br />
26 states and tribes across the<br />
U.S. 4 It provides colorectal cancer–screening<br />
services to lowincome<br />
men and women aged 50<br />
to 64 years who do not have<br />
insurance or are underinsured for<br />
screening when no other insurance<br />
options are available. States and<br />
tribes in the CDC’s Colorectal<br />
Cancer Control Program can be<br />
found in the map provided in<br />
Reference 4 online.<br />
6. Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of<br />
Disease. 6th ed. Philadelphia, PA: WB Saunders Company;<br />
1999:834-835.<br />
7. The Merck Manuals Online Library. Colorectal cancer.<br />
Table 2. Staging colorectal cancer. Revised December 2007.<br />
www.merck.com/mmpe/sec02/ch021/ch021h.html. Accessed<br />
November 17, 2009.<br />
8. Centers for Disease Control and Prevention. Colorectal<br />
cancer screening. www.cdc.gov/cancer/colorectal/basic_info/<br />
screening. Accessed November 16, 2009.<br />
9. Comparison of 2008 ACS/USMSTF/ACR guidelines<br />
with those of the USPSTF. www.cancer.org/docroot/PRO/<br />
content/PRO_4_1x_ColonMD_Comparison_Guidelines.<br />
asp. Accessed November 16, 2009.<br />
10. Centers for Disease Control and Prevention. Colorectal<br />
cancer screening guidelines. www.cdc.gov/cancer/<br />
colorectal/basic_info/screening/guidelines.htm. Accessed<br />
November 16, 2009.<br />
11. Centers for Disease Control and Prevention. Colorectal<br />
cancer screening tests. www.cdc.gov/cancer/colorectal/basic_<br />
Conclusion<br />
Symptoms of colorectal cancer<br />
develop insidiously and often are<br />
present for months, and maybe<br />
years, before they are diagnosed.<br />
While screening for colorectal cancer<br />
saves lives, the disease remains<br />
extremely common. <strong>Pharmacist</strong>s,<br />
in the name of health promotion,<br />
disease prevention, and patient<br />
advocacy, should encourage individuals<br />
who are aged 50 or older<br />
or who think they may be at<br />
higher-than-average risk for<br />
colorectal cancer to speak to their<br />
doctor about getting screened.<br />
Routine screening is the key to<br />
preventing colorectal cancer.<br />
info/screening/tests.htm. Accessed November 16, 2009.<br />
12. U.S. Preventive Services Task Force. Guide to Clinical<br />
Preventive Services: Recommendations of the U.S. Preventive<br />
Services Task Force. Rockville, MD: Agency for Healthcare<br />
Research and Quality; September 2008. AHRQ publication<br />
08-05122.<br />
13. Comparison of 2008 ACS/USMSTF/ACR guidelines<br />
with those of the USPSTF. www.cancer.org/docroot/PRO/<br />
content/PRO_4_1x_ColonMD_Comparison_Guidelines.<br />
asp. Accessed November 16, 2009.<br />
14. Levin B, Lieberman D, McFarland B, et al. Screening<br />
and surveillance for the early detection of colorectal cancer<br />
and adenomatous polyps, 2008: a joint guideline from the<br />
American Cancer Society, the US Multi-Society Task Force<br />
on Colorectal Cancer, and the American College of Radiology.<br />
CA Cancer J Clin. 2008;58:130-160.<br />
15. U.S. Preventive Services Task Force. Screening for<br />
colorectal cancer: U.S. Preventive Services Task Force<br />
recommendation statement. Ann Intern Med.<br />
2008;149:627-637.<br />
Season’s Greetings<br />
Wishing you and your<br />
loved ones a joyous<br />
holiday season and a<br />
happy and healthy new year.<br />
From the staff of<br />
31<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Overview of<br />
Hepatitis B and C Management<br />
Hepatitis is an inflammation of the liver that is<br />
often caused by one of five hepatitis viruses:<br />
A, B, C, D, or E. Hepatitis A and E are commonly<br />
contracted by ingestion of contaminated food<br />
or water, while transmission of hepatitis B and C occurs<br />
by parenteral contact with infected body fluids. No<br />
specific drug therapy is available for the treatment of<br />
hepatitis A or E. Hepatitis B and C infections are<br />
worldwide concerns because they often lead to chronic<br />
liver disease and even death. Much effort has been<br />
dedicated to global eradication of these diseases through<br />
education and vaccination. Still, viral hepatitis is a major<br />
public health concern. While both hepatitis B and C<br />
are associated with significant morbidity and mortality,<br />
the therapeutic approach to treatment varies by virus<br />
type, and each will be discussed separately.<br />
Hepatitis B<br />
In the United States, only 4,519 new acute hepatitis B<br />
(HBV) cases were reported to the Centers for Disease<br />
Control in 2007. 1 This represents a significant decrease<br />
from the early 1980s, when the number of reported<br />
cases of HBV each year was generally greater than<br />
25,000. A national immunization strategy instituted in<br />
the early 1990s was largely responsible for the sharp<br />
decline in new HBV cases. The incidence of HBV in<br />
the U.S. is now 1.5 cases per 100,000 persons, which<br />
is an all-time low. 1 Still, HBV remains an important<br />
worldwide public health concern, with an estimated 1<br />
million deaths each year due to HBV sequelae.<br />
HBV is a DNA virus transmitted by percutaneous<br />
or mucosal contact with infectious blood or body fluids.<br />
Accordingly, intravenous drug users and those who<br />
practice unprotected sex are at increased risk of HBV<br />
infection. Infants born to infected mothers are also at<br />
greater risk of becoming infected with HBV. Morbidity<br />
and mortality associated with chronic HBV infection<br />
are connected to the development of<br />
cirrhosis or hepatocellular carcinoma<br />
(HCC). Worldwide, approximately<br />
75% of HCC cases are due to chronic<br />
HBV infection. 2<br />
Justin Hooper, PharmD, BCPS<br />
Pharmacy Clinical Manager, CompleteRx<br />
Trinity Mother Frances Hospital<br />
Tyler, Texas<br />
Amy Martin, PharmD, BCPS<br />
Clinical Staff <strong>Pharmacist</strong>, CompleteRx<br />
Trinity Mother Frances Hospital<br />
Tyler, Texas<br />
Clinical Characteristics and Diagnosis:<br />
HBV infection is often characterized<br />
by acute hepatitis, with approximately 5% of<br />
these infections progressing to chronic disease. The<br />
presence of serum hepatitis B surface antigen (HBsAg)<br />
indicates infection with HBV, and antibodies against<br />
HBsAg indicate recovery. Hepatitis B e antigen (HBeAg)<br />
is elevated during periods of active viral replication, but<br />
may be absent in chronic hepatitis due to a DNA mutation<br />
of the virus responsible for hepatitis B. In fact,<br />
HBeAg-negative chronic HBV is generally linked to<br />
more serious liver disease and a limited sustained response<br />
to antiviral therapy. The presence of anti-HBc (core<br />
antibody) indicates HBV infection at some point in<br />
time as opposed to positivity for HBV surface antibody,<br />
which may indicate humoral immunity in response to<br />
HBV vaccination. 3 Signs and symptoms of infection<br />
depend on the age of the patient, and many patients<br />
may be asymptomatic initially. Symptoms may be<br />
nonspecific and do not aid in differentiating HBV from<br />
other forms of acute hepatitis. Patients may complain<br />
of fever, fatigue, and abdominal pain. Other findings<br />
may include anorexia, nausea, vomiting, dark urine,<br />
clay-colored stools, joint pain, and jaundice.<br />
Management: The goals of treating chronic HBV are<br />
to achieve sustained suppression of viral replication and<br />
prevent progression of liver disease. 4 Response to treatment<br />
can be measured using biochemical (normalization<br />
of alanine aminotransferase [ALT]), virologic (clearance<br />
of HBV DNA), serologic (loss of HBeAg, HBeAg<br />
seroconversion), or histologic markers. All available<br />
treatment options have advantages and disadvantages,<br />
and drug therapy selection should take into account<br />
cost, efficacy, safety, risk of drug resistance, and method<br />
of administration.<br />
Antiviral Treatment: For the minority of patients who<br />
develop chronic HBV infection, there are currently<br />
eight drugs approved by the FDA<br />
for the treatment of chronic hepatitis<br />
B: conventional interferon (IFN)<br />
alpha-2b, lamivudine, adefovir dipivoxil,<br />
pegylated interferon (pegIFN)<br />
alpha-2a, entecavir, telbivudine, and<br />
tenofovir disoproxil fumarate. The<br />
prototype antiviral used for the treat-<br />
32<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
© KEITH KASNOT 2009<br />
www.kazstudios.com<br />
OVERVIEW OF HEPATITIS B AND C MANAGEMENT<br />
Though prevalence is declining, infection with the hepatitis B or C virus is a major<br />
health concern because it often leads to chronic liver failure and even death.<br />
ment of HBV is IFN. IFN is effective at inducing a<br />
virologic, histologic, and biochemical response at a dose<br />
of 10 million international units (IU) three times weekly<br />
or 5 million IU daily. Adverse reactions classified as<br />
severe were reported in 21% to 44% of patients, the<br />
most common being fever, fatigue, bone marrow suppression,<br />
and alopecia. 5 As a result, pegIFN has largely<br />
replaced IFN alpha-2b due to its longer half-life and<br />
improved tolerability. IFN alpha-2b is administered as<br />
a once-weekly subcutaneous injection for a duration of<br />
48 weeks.<br />
While treatment with IFN yields a highly durable<br />
viral response, nucleoside/nucleotide analogues have<br />
become the primary treatment modality for chronic<br />
HBV due to their ease of use and tolerability. Lamivudine<br />
(LAM) is a convenient oral therapy for treatment<br />
of chronic HBV with modest efficacy and minimal side<br />
effects. Unfortunately, LAM has been associated with a<br />
high rate of resistance (up to 70% after 5 years) and<br />
virologic breakthrough, thus limiting its usefulness as a<br />
first-line agent for chronic HBV. 6 Conversely, LAM is<br />
well tolerated and may be used in select circumstances<br />
such as HIV coinfection. For patients in whom LAM<br />
resistance is suspected or who have received therapy for<br />
more than 2 years, alternative therapies such as entecavir<br />
(ETV) and tenofovir disoproxil fumarate (TDF)<br />
have proven effective. 7<br />
Adefovir dipivoxil (ADV) is another<br />
well-tolerated oral therapy for treatment<br />
of chronic HBV with slightly less viral<br />
resistance than LAM. Primary nonresponse<br />
to ADV occurs at a rate of 20% to 50%,<br />
presumably due to the low dosage used<br />
in chronic HBV treatment. 8 ADV may<br />
cause nephrotoxicity at higher doses, thus<br />
limiting its utility as a first-line agent. It<br />
should be avoided in combination with<br />
TDF due to the additive risk of nephrotoxicity.<br />
Monitoring of serum creatinine<br />
every 3 months is recommended for<br />
patients with medical conditions that<br />
may lead to renal dysfunction and for<br />
patients receiving treatment with ADV<br />
for more than 1 year. 6<br />
ETV is a nucleoside analogue with<br />
excellent potency that is associated with<br />
minimal viral resistance in untreated<br />
patients. ETV has been used successfully<br />
in patients with LAM-resistant disease,<br />
though efficacy is reduced when compared<br />
to treatment of nucleoside analogue-naïve<br />
patients for whom a higher dosing strategy<br />
is used. 9 Like other nucleoside/<br />
nucleotide analogues, ETV must be dose<br />
adjusted in renal dysfunction.<br />
Telbivudine (LdT) is more potent than<br />
LAM at HBV suppression, but it has a<br />
high level of cross-resistance with LAM. Additionally,<br />
resistance to LdT develops rapidly, especially with treatment<br />
duration beyond 1 year. 6 Though this drug is<br />
generally well tolerated, myopathy and peripheral neuropathy<br />
have also been associated with its use. These<br />
safety and viral resistance concerns have caused LdT to<br />
have an uncertain role in contemporary management<br />
of HBV.<br />
The most recently approved therapy for treatment<br />
of chronic HBV is TDF. When compared to ADV,<br />
treatment with TDF yielded a significantly greater<br />
histologic response and normalization of ALT. 7 TDF is<br />
useful for treatment of LAM-resistant HBV. Renal<br />
dysfunction and decreases in bone mineral density have<br />
been reported infrequently. 7<br />
Hepatitis C<br />
Viral hepatitis C (HCV) affects approximately 4 million<br />
persons in the U.S. alone, with a worldwide disease<br />
burden estimated at 180 million. 10 Of those infected<br />
in the U.S., the vast majority have active disease. While<br />
some individuals may clear the disease, 75% develop<br />
chronic infection. Infection with HCV is often insidious,<br />
and affected individuals are often asymptomatic<br />
during much of the course of the disease. Significant<br />
morbidity is related to the development of cirrhosis,<br />
33<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
OVERVIEW OF HEPATITIS B AND C MANAGEMENT<br />
which currently affects over 600,000 individuals. HCVrelated<br />
mortality is attributed to complications of<br />
end-stage liver disease as well as death from development<br />
of HCC. The rate of newly diagnosed HCV<br />
infection has fortunately declined to about 17,000<br />
cases annually, mainly due to improved screening for<br />
HCV in blood products, which began around 1992.<br />
Additionally, heightened awareness of the risks of<br />
needle-sharing among injection drug users has reduced<br />
the transmission of HCV; still, acquisition of new<br />
HCV continues to occur primarily in injection drug<br />
abusers. 11 Despite the decline in new cases, HCVassociated<br />
mortality continues to rise due to clinical<br />
progression of HCV.<br />
Clinical Characteristics and Diagnosis: Acute HCV<br />
infection usually goes undetected, as symptoms are<br />
nonspecific in nature and may include anorexia, abdominal<br />
discomfort, and nausea and vomiting, along with<br />
elevated hepatic transaminases and, less commonly,<br />
jaundice. 11,12 For this reason, diagnosis cannot be made<br />
based on risk factors and clinical presentation. Specific<br />
serologic testing for the presence of anti-HCV antibodies<br />
is indicated in any at-risk individual (TABLE 1) and<br />
establishes exposure to the disease. 13 Virologic testing<br />
for the presence of HCV-ribonucleic acid (HCV-RNA)<br />
along with viral genotyping is also indicated in all<br />
patients who test positive for HCV, particularly in those<br />
patients being considered for antiviral therapy. 13<br />
Management of Patients With HCV: Determining a<br />
patient’s specific HCV genotype is mandatory because<br />
it aids in predicting the likelihood of response to drug<br />
therapy and determines optimal treatment duration as<br />
well. 12,13 There are a total of six distinct, numbered<br />
HCV genotypes. Genotype 1 accounts for about 70%<br />
of the disease in the U.S., followed by genotypes 2 and<br />
3. Genotype 1 is generally more refractory to antiviral<br />
drug therapy, and comparative studies have demonstrated<br />
substantially lower treatment response rates when compared<br />
to rates among those infected with genotypes 2<br />
or 3. 11,13 Genotyping is therefore valuable in evaluating<br />
the risk-to-benefit ratio of antiviral therapy. Because<br />
anti-HCV medications put patients at risk for significant<br />
treatment toxicities, a thorough assessment of a patient’s<br />
overall medical and mental health is necessary to determine<br />
if contraindications to treatment are present.<br />
Contraindications to combination HCV treatment<br />
Table 1<br />
Antiviral Therapies for Treatment-Naïve Patients With HBeAg-Positive Chronic HBV<br />
Pegylated<br />
Interferon Alpha-2a Lamivudine a Adefovir a Entecavir a Telbivudine a Tenofovir a<br />
Brand name Pegasys Epivir Hepsera Baraclude Tyzeka Viread<br />
Manufacturer Roche GlaxoSmithKline Gilead Bristol-Myers Squibb Novartis Gilead<br />
Dosage 180 mcg/wk 100 mg/day 10 mg/day 0.5 mg/day 600 mg/day 300 mg/day<br />
Route of SC PO PO PO PO PO<br />
administration<br />
Adverse Flulike symptoms, Minimal Minimal, Minimal Minimal Minimal,<br />
effects bone marrow but suggest but suggest<br />
suppression, monitoring monitoring<br />
depression, creatinine creatinine<br />
anxiety, autoimmune<br />
disorders<br />
Duration of 48 >48 >48 >48 >52 >48<br />
therapy (wk)<br />
Viral resistance None 15%-30% None None 6% None<br />
(1 y)<br />
Histologic 38% at Wk 72 49%-62% 53%-68% 72% 65% 74%<br />
improvement<br />
ALT normalization 39% 41%-75% 48%-61% 68% 60% 77%<br />
at end of Y 1<br />
a<br />
Requires dosage adjustment for renal dysfunction.<br />
ALT: alanine aminotransferase; HBeAg: hepatitis B e antigen; HBV: viral hepatitis B.<br />
Source: Adapted from Reference 8.<br />
34<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
OVERVIEW OF HEPATITIS B AND C MANAGEMENT<br />
Eligible patient<br />
HCV-antibody positive<br />
Genotype 1<br />
Obtain quantitative<br />
HCV-RNA and genotype<br />
Genotype 2,3<br />
Liver biopsy<br />
Liver biopsy<br />
(optional)<br />
No fibrosis =<br />
no treatment<br />
Fibrosis<br />
= treat<br />
Begin pegIFN plus ribavirin<br />
1,000 mg/day if 75 kg<br />
Check HCV-RNA at Week 12<br />
Treat with pegIFN<br />
plus ribarivin 800 mg/day<br />
× 24 weeks<br />
Check HCV-RNA level<br />
to establish end-oftreatment<br />
response<br />
Complete<br />
early response<br />
(no HCV-<br />
RNA)?<br />
Continue<br />
treatment for<br />
total of 48<br />
weeks<br />
Partial response<br />
(HCV-RNA ↓ >2<br />
log)? Continue<br />
treatment and<br />
repeat HCV-RNA<br />
at 24 weeks<br />
HCV-RNA<br />
negative?<br />
No early<br />
response<br />
(HCV-RNA<br />
↓ >2 log)<br />
Stop treatment<br />
HCV-RNA<br />
positive?<br />
HCV-RNA<br />
positive<br />
Treatment<br />
failed<br />
HCV-RNA<br />
negative<br />
Repeat<br />
HCV-RNA<br />
at Week 48<br />
to establish<br />
SVR<br />
Source: Adapted from Reference 13.<br />
Figure 1. HCV management strategy. HCV: viral hepatitis C; HCV-RNA: viral hepatitis C-ribonucleic acid; pegIFN: pegylated interferon;<br />
SVA: sustained virologic response.<br />
include decompensated liver disease; pregnancy; uncontrolled<br />
depression or neuropsychiatric illness; history<br />
of autoimmune hepatitis; severe uncontrolled comorbid<br />
illnesses such as seizure disorders, thyroid disorders,<br />
diabetes, and active coronary disease; age less than 2<br />
years; anemia; post solid-organ transplantation; or<br />
unwillingness to use adequate contraception. 13<br />
In general, patients who are considered candidates<br />
for combined anti-HCV therapy include adult patients<br />
with chronic HCV infection (≥6 months) who have<br />
evidence of chronic hepatitis based on liver biopsy<br />
with compensated liver disease and acceptable laboratory<br />
values on serum chemistry. In addition, due to<br />
high rates of neuropsychiatric side effects of combination<br />
ribavirin-INF (i.e., depression, and anxiety in up<br />
to one-thid of patients), it is advisable to screen for<br />
any occult psychiatric illness prior to therapy. Patients<br />
must also be willing and able to adhere to treatment.<br />
Antiviral Treatment: Subcutaneous pegIFN alpha<br />
combined with oral ribavirin is the mainstay of treatment<br />
of HCV virus infection with no clear evidence<br />
that one product is superior to the other (see FIGURE<br />
1). While monotherapy with IFN may be used in<br />
individualized cases where ribavirin is contraindicated,<br />
ribavirin should never be used as monotherapy. Goals<br />
of treatment include early virologic response (EVR;<br />
undetectable HCV-RNA after 12 weeks of treatment),<br />
end-of-treatment response (ETR), and a sustained<br />
virologic response (SVR), defined as undetectable HCV-<br />
RNA 24 weeks after cessation of antiviral therapy. 13<br />
Additional goals are to minimize treatment-related<br />
37<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Day 1<br />
Day 2 Day 3 Day 4 Day 5<br />
TAKE Z-PAK ® FOR 5 DAYS 1 OR...<br />
(azithromycin) 250 mg<br />
TAKE AZITHROMYCIN TO<br />
1 DAY. 1 DOSE.2<br />
Please see accompanying Zmax brief summary.<br />
Zmax is indicated for mild to moderate acute bacterial<br />
sinusitis in adults due to Haemophilus influenzae, Moraxella<br />
catarrhalis, or Streptococcus pneumoniae and is also indicated<br />
for community-acquired pneumonia due to Chlamydophila<br />
pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,or<br />
or Streptococcus pneumoniae in adult and pediatric patients<br />
aged 6 months and over, deemed appropriate for oral therapy.<br />
Zmax and Zithromax are contraindicated in patients with<br />
known hypersensitivity to azithromycin, erythromycin, or any<br />
macrolide or ketolide antibiotic. If an allergic reaction occurs,<br />
appropriate therapy should be instituted. Physicians should be<br />
aware that reappearance of the allergic symptoms may occur<br />
when symptomatic therapy is discontinued.<br />
There have been rare reports of serious allergic reactions including<br />
angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic<br />
epidermal necrolysis in patients on other formulations of<br />
azithromycin therapy. Rarely, fatalities have been reported.<br />
Clostridium difficile associated diarrhea (CDAD) has been<br />
reported with use of nearly all antibacterial agents, including<br />
azithromycin, and may range in severity from mild diarrhea<br />
to fatal colitis. CDAD must be considered in all patients who<br />
present with diarrhea following antibiotic use. Careful<br />
medical history is necessary since CDAD has been reported to<br />
occur over two months after the administration of<br />
antibacterial agents. If CDAD is suspected or confirmed,<br />
ongoing antibiotic use not directed against C. difficile may need<br />
to be discontinued, and appropriate management and treatment<br />
of C. difficile should be instituted as clinically indicated.<br />
As with all macrolides, including Zmax, exacerbations of<br />
myasthenia gravis have been reported.
Zmax: 1 product — indicated for both<br />
adult and pediatric patients 2<br />
Pediatric<br />
patients<br />
Adult<br />
patients<br />
A higher incidence of gastrointestinal adverse events (8 of 19<br />
subjects) was observed when Zmax was administered to a<br />
limited number of subjects with GFR
Zmax ® (azithromycin extended release) for oral suspension<br />
Brief Summary of Prescribing Information<br />
INDICATIONS AND USAGE<br />
Zmax is indicated for the treatment with mild to moderate infections caused by susceptible isolates<br />
of the designated microorganisms in the specific conditions listed below.<br />
Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or<br />
Streptococcus pneumoniae.<br />
Community-acquired pneumonia in adults and pediatric patients six months of age or older due to<br />
Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus<br />
pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on<br />
extrapolation of adult efficacy.<br />
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other<br />
antibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspected<br />
to be caused by susceptible bacteria. When culture and susceptibility information are available, they<br />
should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local<br />
epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.<br />
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative<br />
organism and its susceptibility to Zmax.Therapy with Zmax may be initiated before results of these tests are<br />
known; once the results become available, antimicrobial therapy should be adjusted accordingly.<br />
CONTRAINDICATIONS<br />
Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any<br />
macrolide or ketolide antibiotic.<br />
WARNINGS AND PRECAUTIONS<br />
Allergic and skin reactions<br />
Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic<br />
epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other<br />
formulations. Although rare, fatalities have been reported. Despite initially successful symptomatic<br />
treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms<br />
recurred soon thereafter in some patients without further azithromycin exposure.These patients<br />
required prolonged periods of observation and symptomatic treatment. The relationship of these<br />
episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has<br />
not been determined.<br />
If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware<br />
that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.<br />
Clostridium difficile-associated diarrhea<br />
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial<br />
agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with<br />
antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.<br />
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing<br />
strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to<br />
antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present<br />
with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been<br />
reported to occur over two months after the administration of antibacterial agents.<br />
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need<br />
to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic<br />
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.<br />
Exacerbation of myasthenia gravis<br />
Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been<br />
reported in patients receiving azithromycin therapy.<br />
Gastrointestinal Disturbances<br />
A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax<br />
was administered to a limited number of subjects with GFR
OVERVIEW OF HEPATITIS B AND C MANAGEMENT<br />
toxicities, which may emerge on therapy while maintaining<br />
efficacy.<br />
Both pegIFN products approved for use in the U.S.,<br />
pegINF alpha-2b and pegINF alpha-2a, have demonstrated<br />
superior efficacy to standard interferon plus<br />
ribavirin. 13 These products are similar in that both<br />
drugs have added various polyethylene glycol side<br />
chains to the parent molecule to increase the duration<br />
of pharmacologic activity. It is important to note that<br />
there are differences with respect to dosing, frequency,<br />
and how each product is combined with ribavirin.<br />
PegINF alpha-2b is given, in combination with ribavirin,<br />
as a weight-based dose of 1.5 mcg/kg, while a<br />
fixed dose of 180 mcg is used with pegINF alpha-2a.<br />
Both are given as weekly subcutaneous injections.<br />
Standard INF alphacon-1 is also approved for treatment<br />
in HCV in a fixed dosage given subcutaneously<br />
three times weekly alone or in combination with<br />
ribavirin. Adverse reactions to INF products are common<br />
and may lead to patient intolerance as well as<br />
reduced efficacy due to the need for dose reductions.<br />
Commonly experienced side effects attributable to<br />
INF include flulike symptoms, myelosuppression<br />
(anemia, neutropenia, and/or thrombocytopenia),<br />
psychiatric adverse effects, injection-site reactions,<br />
alopecia, anorexia, and sleep abnormalities. 14 Toxicities<br />
generally associated with ribavirin include hemolytic<br />
anemia, fatigue, dermatologic reactions, and precipitation<br />
of gout. Ribavirin is also an abortifacient and<br />
is carcinogenic and teratogenic. As a result, adequate<br />
contraception must be present with female patients as<br />
well as female partners of male patients who are of<br />
childbearing age and should be continued for 6 months<br />
following treatment cessation. 15<br />
Monitoring and Follow-up: Duration of therapy<br />
and disease monitoring are dependent on HCV<br />
genotype, with genotype 1 generally requiring a<br />
longer course of therapy. In genotype 1–infected<br />
patients started on pegIFN/ribavirin, quantitative<br />
HCV-RNA is measured at baseline and at 12 weeks<br />
after treatment (see FIGURE 1). Patients with an EVR<br />
should continue treatment for a total of 48 weeks<br />
and then be assessed for an ETR. HCV-RNA testing<br />
is repeated 24 weeks following treatment cessation<br />
to determine presence of an SVR. If partial EVR is<br />
attained at Week 12 (HCV-RNA reduction of ≥2<br />
log), treatment should be continued for an additional<br />
12 weeks. A negative HCV-RNA test at 24 weeks<br />
means treatment should be continued for a total of<br />
48 weeks. If no response is seen after 12 or 24 weeks,<br />
then treatment should be discontinued as the benefit<br />
is unlikely. In genotype 2 or 3 patients, HCV-<br />
RNA is not assessed until 24 weeks of therapy are<br />
complete. 13 If HCV-RNA is not detected, then assessment<br />
for SVR is performed at 48 weeks. If HCV is<br />
still detectable, treatment failure has occurred. Efficacy<br />
defined by attainment of SVR is roughly 75%<br />
for genotypes 2 and 3 and 50% for genotype 1. 13<br />
Ongoing monitoring for both INF and ribavirin<br />
toxicity is indicated during treatment. Baseline CBC,<br />
serum creatinine, transaminases, thryoid-stimulating<br />
hormone (TSH), and pregnancy testing should be assessed<br />
at baseline. TSH should be monitored every 12 weeks<br />
on therapy, while other chemistries may be assessed<br />
monthly for the first 12 weeks, then every 2 months<br />
until the end of treatment unless specific toxicity issues<br />
warrant more frequent visits. Specific dosage reductions<br />
or treatment cessation for ribavirin is necessary with the<br />
development of anemia and or severe renal failure. 15<br />
Dosage reductions of pegIFN may also be necessary<br />
with elevated liver enzymes or renal insufficiency.<br />
Patient Counseling<br />
<strong>Pharmacist</strong>s play an important role in the care of patients<br />
infected with viral hepatitis. The pharmacist may provide<br />
medication counseling and follow-up to ensure<br />
adherence or identify problems (e.g., drug toxicities)<br />
that emerge during therapy. All patients should be<br />
counseled to abstain from alcohol and avoid OTC drugs<br />
or supplements that may be hepatotoxic (e.g., high<br />
doses of acetaminophen). Counseling should include<br />
strategies to minimize disease prevention, such as use<br />
of barrier contraceptive methods or avoidance of highrisk<br />
behaviors. Immunization against HBV also plays<br />
a key role in primary prevention of HBV infection, and<br />
hepatitis B vaccination may be provided directly by<br />
pharmacists in many states.<br />
REFERENCES<br />
1. Centers for Disease Control and Prevention. Hepatitis B: FAQs for health professionals.<br />
www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview. Accessed October<br />
2, 2009.<br />
2. Marcellin P. Hepatitis B and hepatitis C in 2009. Liver Int. 2009;29(supp1):1-8.<br />
3. Liaw YF. Natural history of chronic hepatitis B virus infection and long-term<br />
outcome under treatment. Liver Int. 2009;29(supp1):100-107.<br />
4. Corey RL. Update on pharmacotherapy of chronic Hepatitis B and C. In:<br />
Richardson M, Chant C, Cheng JW, et al, eds. Pharmacotherapy Self-Assessment<br />
Program. 6th ed. Gastroenterology and Nutrition. Lenexa, KS: American College<br />
of Clinical Pharmacy; 2009:1-20.<br />
5. Intron A [package insert]. Kenilworth, NJ: Schering-Plough; 2008.<br />
6. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology.<br />
2009;50(3):661-662.<br />
7. Jenh AM, Thio CL, Pham PA. Tenofovir for the treatment of hepatitis B virus.<br />
Pharmacother. 2009;29(10):1212-1227.<br />
8. Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359:1486-1500.<br />
9. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management<br />
of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2(3):263-283.<br />
10. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C<br />
virus infection in the United States, 1999 through 2002. Ann Intern Med.<br />
2006;144:705-714.<br />
11. Centers for Disease Control and Prevention. Hepatitis C: FAQs for health<br />
professionals. www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section1. Accessed September<br />
7, 2009.<br />
12. Kowdley KV. Hepatitis C. In: Floch MH, Floch NR, Kowdley KV, et al, eds.<br />
Netter’s Gastroenterology. Carlstadt, NJ: Icon Learning Systems; 2005.<br />
13. Ghany MG, Strader DB, Thomas D, et al. AASLD practice guideline: diagnosis,<br />
management, and treatment of hepatitis C: an update. Hepatology.<br />
2009;49:1335-1373.<br />
14. Peg-intron [package insert]. Kenilworth, NJ: Schering-Plough; 2009.<br />
15. Copegus [package insert]. Nutley, NJ: Roche Laboratories; 2009.<br />
41<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Probiotic foods have recently become popular in the<br />
United States, although such products have been<br />
marketed for decades in Europe and Asia. 1 Probiotics<br />
are defined as living organisms that, when administered<br />
in sufficient numbers, are beneficial to the host. One<br />
probiotic food is Activia. It is a line of yogurt containing<br />
Lactobacillus, Streptococcus thermophilus, and Bifidobacterium<br />
animalis bacteria, and it is advertised to aid regularity.<br />
While new to the U.S., Activia has been sold in Europe<br />
since 1987. 1 Most probiotic products can be found in the<br />
dairy case of supermarkets or as dietary supplements. There<br />
are probiotic frozen yogurts and dairy-based drinks such<br />
as DanActive, a probiotic yogurt drink that contains<br />
Lactobacillus casei immunitas cultures. Its manufacturer<br />
(Dannon) indicates that the product is clinically proven<br />
to “help strengthen your body’s defenses.” 2 Products sold<br />
in the pharmacy include, among others, Culturelle (Lactobacillus<br />
GG), Florastor (Saccharomyces boulardii) and<br />
Lactinex (Lactobacillus acidophilus, Lactobacillus bulgaricus),<br />
which are indicated to reduce the chance of developing<br />
diarrhea due to antibiotics. 3 The FDA takes a neutral<br />
position on probiotics, policing food packages to ensure<br />
that companies do not try to equate probiotic products<br />
with disease-curing drugs.<br />
The growth of probiotics comes as many scientists are<br />
now focused on the role of beneficial bacteria to aid digestion,<br />
boost natural defenses, and fight off bacteria that<br />
could cause health problems. Intestinal bacteria can benefit<br />
health by breaking down toxins, synthesizing vitamins,<br />
and defending against infection. They may also play a role<br />
in preventing such diseases as peptic ulcers, colorectal<br />
cancer, and inflammatory bowel disease. 4 This article will<br />
describe the genesis and evolution of our indigenous microbial<br />
community, the size and makeup of its inhabitants, its<br />
effects, its benefits, and new research.<br />
Genesis and Evolution<br />
Most of us are aware that bacteria are a part of a healthy<br />
human ecosystem (i.e., an assembly of species and the<br />
organic and inorganic constituents characterizing a particular<br />
site). According to one author, the armies of bacteria<br />
that sneak into our bodies the moment we are born<br />
are the “primal illegal immigrants.” 5 Most are industrious<br />
and friendly, minding their own business in tight-knit,<br />
long-lived communities, doing the grunt biochemical work<br />
we all rely on to stay alive. 5 The ecosystem forms at birth,<br />
but the human-microbe alliance begins months before.<br />
Midway through pregnancy, a hormonal shift directs the<br />
cells lining the vagina to begin stockpiling sugary glycogen,<br />
the favorite food of sausage-shaped bacteria called lactobacilli.<br />
By fermenting the sugar into lactic acid, these<br />
bacteria lower the pH of the vagina to levels that discourage<br />
the growth of potentially dangerous invaders. 6<br />
Max Sherman, RPh<br />
President, Sherman Consulting Services, Inc.<br />
Warsaw, Indiana<br />
Probiotics<br />
and<br />
Microflora<br />
The infant mouth’s first inoculation<br />
of bacteria includes a generous sampling<br />
of the lactobacilli present in the mother’s<br />
birth canal. With the first gulp of breast milk, these<br />
lactobacilli are joined by millions of bifidobacteria, a related<br />
group of acid-producing microbes. 6 The source of these<br />
bacteria is the mother’s nipples, where the bacteria appear<br />
during the eighth month of pregnancy. Bifidobacteria secrete<br />
acids and antibiotic chemicals that repel potentially dangerous<br />
organisms, including Staphylococcus aureus. Bifidobacteria<br />
and lactobacilli are soon joined by acid-tolerant Streptococcus<br />
salivarius bacteria, which appear on a baby’s tongue<br />
during the first day of life. Bifidobacteria are anaerobic,<br />
pleomorphic rods that break down dietary carbohydrate<br />
and synthesize and excrete water-soluble vitamins. 7 Their<br />
name is derived from the observation that they often exist<br />
in a Y-shaped, or bifid, form. 8 These organisms predominate<br />
in the colons of breastfed babies, account for up to 95%<br />
of all culturable bacteria, and protect against infection. 9<br />
Strangely, they do not occur in such high numbers in<br />
adults. 8 Several other streptococci, along with one or more<br />
kinds of Neisseria bacteria, settle in during the first week.<br />
The vast majority emanate from the mother’s mouth, which<br />
is always within reach of a nursing baby’s fingers. 10<br />
As the baby begins nursing or drinking formula, the<br />
bacterial population inside the mouth increases. These<br />
bacteria consume enough oxygen to create a zone where<br />
anaerobic bacteria can thrive. By the time the baby is 2<br />
months old, a microscopic close-up of the gums will reveal<br />
clusters and chains of bacteria and fungi. Another wave of<br />
bacteria arrive when the first teeth appear. The first is<br />
Streptococcus sanguis, followed by Streptococcus mutans. By<br />
middle childhood, the diversity inside the mouth surpasses<br />
a hundred species, and their total number is greater than<br />
10 billion. 6 Bacteria also settle in the nasal cavities, which<br />
are connected to the mouth via the upper respiratory tract.<br />
The bacteria eventually lodge in the intestinal tract. In the<br />
small intestine, incoming microbes engage the infant’s<br />
dormant immune system. Pits on the surface of the Peyer’s<br />
patches (aggregated lymphoid tissue in the ileum) capture<br />
passing bacteria, where they are ushered<br />
into the underlying lymph tissue. Interaction<br />
on the Peyer’s patches triggers<br />
© JUPITERIMAGES<br />
42<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
the production of an abundance of immunoglobulin A<br />
(IgA) antibodies. Instead of marking the bacteria for destruction,<br />
IgA clusters across the bacterial surface, preventing<br />
the bacteria from attaching to the intestinal wall. This<br />
action also leads to the proliferation of T and B cells that<br />
will marshal an attack against these same bacteria should<br />
they turn up in the blood or other forbidden areas. 6 The<br />
small intestine must provide a platform for nutrient absorption,<br />
but at the same time the epithelium and its associated<br />
immune cells must keep out pathogens that escape the<br />
inhospitable environment of the stomach. To satisfy these<br />
responsibilities, small intestinal epithelial cells divide at a<br />
rate of 13 to 16 cells every hour. 6<br />
When the child reaches adulthood, his or her intestine<br />
becomes home to an almost inconceivable number of<br />
microorganisms. The size of the population—up to 100<br />
trillion—far exceeds all other microbial communities associated<br />
with the body’s surfaces and is more than 10 times<br />
greater than the total number of our somatic and germ<br />
cells combined. 11 (There is a significant variation in both<br />
the total number of bacteria and the composition of the<br />
bacterial flora in different body regions. 12 ) Since humans<br />
depend on their microbial inhabitants (microbiome) for<br />
various essential services, a person should really be considered<br />
a superorganism, consisting of his or her own cells<br />
and those of all the commensal bacteria.<br />
Humans are not inherently endowed with a healthy<br />
immune or digestive system. Fortunately, the microbiome<br />
in our intestinal tract provides us with genetic and metabolic<br />
attributes we have not been required to evolve on our own,<br />
including the ability to harvest otherwise inaccessible<br />
nutrients and to modify host immune reactivity. 11<br />
Inhabitants<br />
The adult human gastrointestinal (GI) tract contains all<br />
three domains of life—bacteria, archaea, and eukaryotes. 11<br />
Archaea are a group of prokaryotic and single-celled microorganisms,<br />
and while similar to bacteria, have evolved<br />
differently. Archaea were originally described in extreme<br />
environments but have since been found in all habitats<br />
including the digestive tracts of animals such as ruminants,<br />
termites, and humans. 13 Eukaryotes are organisms whose<br />
cells contain a limiting membrane around the nuclear<br />
material (the nucleus). Bacteria living in the human gut<br />
achieve the highest cell densities recorded for any ecosystem.<br />
14 The vast majority belong to two divisions, the<br />
Bacteroidetes (48%) and the Firmicutes (51%). Bacteroidetes<br />
include a number of Bacteroides genera, which have yet<br />
to be encountered in any environment other than animal<br />
GI tracts. Firmicutes include the genera Clostridium, Lactobacillus,<br />
Eubacterium, Ruminococcus, and several others.<br />
In the first comprehensive molecular survey of the gut<br />
microbiota (normal microflora), 395 bacterial and one<br />
archaeal phylotype (bacteria defined by their ribosomal<br />
RNA gene sequence) were identified. 14 Thus, the gut<br />
microbiota is a tremendously diverse bioreactor. Eight<br />
PROBIOTICS AND MICROFLORA<br />
divisions with divergent lineages are represented. This<br />
diversity is desirable for ecosystem stability. There appears<br />
to be a strong host selection for specific bacteria whose<br />
behavior is beneficial to the host. Cooperative activity by<br />
bacteria is required to break down nutrients and provide<br />
the host with energy. Populations of bacteria are remarkably<br />
stable within the human gut, which implies that mechanisms<br />
exist to suppress undesirable bacteria and promote the<br />
abundance of those that are needed. 11<br />
Bacteroides thetaiotaomicron is the prominent and remarkable<br />
bacterial species in the distal intestinal tract of adult<br />
humans. It is a very successful anaerobic glycophile (“sugarloving”<br />
microbe) whose prodigious capacity for digesting<br />
otherwise indigestible dietary polysaccharides is reflected<br />
in its genome. It encodes 241 glycoside hydrolases and<br />
polysaccharide lyases. This means that the organism has<br />
the ability to break down xylan-, pectin- and arabinosecontaining<br />
polysaccharides that are common components<br />
of dietary fiber. 15 When dietary polysaccharides are scarce,<br />
B thetaiotaomicron turns to host mucus by deploying a<br />
different set of polysaccharide-binding proteins and glycoside<br />
hydrolases. Other Bacteroides species include B<br />
vulgatus, B distasonis, and B fragilis. All play a role in the<br />
digestive process.<br />
New Research<br />
Microbiologists from Louis Pasteur (1822-1895) and Ilya<br />
Mechnikov (1845-1916) to present-day scientists have<br />
emphasized the importance of understanding the contributions<br />
of our microbiota to human health and disease.<br />
Mechnikov, who won the Nobel Prize for Physiology and<br />
Medicine in 1908, was one of the first researchers to study<br />
the flora of the human intestine. 16 He developed a theory<br />
that senility is due to poisoning of the body by the products<br />
of these bacteria. To prevent them from multiplying, he<br />
suggested a diet containing milk fermented by bacilli, which<br />
produce large quantities of lactic acid. 16<br />
Today, science is on the verge of understanding how<br />
the body maintains a state of equilibrium with its incredibly<br />
complex enteric microflora. 17 Appropriate immune<br />
recognition is also essential to host-bacteria symbiosis (i.e.,<br />
the biological association of two individuals or populations<br />
of different species). It has recently been shown that the<br />
recognition of commensal bacteria by epithelial cells protects<br />
against intestinal injury. 17 Other research indicates<br />
that use of antibiotics reduces the capacity of intestinal<br />
microflora to metabolize phytochemicals into compounds<br />
that may protect against cancer. 18 However, antibiotic use<br />
also disrupts the intestinal microflora metabolism of<br />
estrogens, which results in lower levels that might decrease<br />
the risk of some hormonal cancers. Use of antibiotics may<br />
be associated with cancer risk through effects on immune<br />
function and inflammation, although little is known about<br />
these mechanisms. 19,20<br />
Intestinal bacteria release chemical signals recognized<br />
by specific receptors—called toll-like receptors (TLRs)—of<br />
43<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
the innate immune system. The<br />
interaction helps to maintain the<br />
architectural integrity of the intestinal<br />
surface and enhance the ability<br />
of the epithelial surface to<br />
withstand injury. A deficiency in<br />
any of the numerous signaling<br />
molecules can induce intestinal<br />
inflammation, which may be a<br />
precursor of inflammatory bowel<br />
disease. Research is now ongoing<br />
to understand various types of TLR<br />
activation to ascertain how this<br />
information can be used to treat<br />
irritable bowel syndrome, Crohn’s<br />
disease, and other types of intestinal<br />
inflammatory conditions. 21<br />
A group of medical researchers<br />
in Ireland recently identified five<br />
probiotic bacteria than can prevent Salmonella infection<br />
in pigs and, if translatable to humans, could potentially<br />
reduce Salmonella-induced foodborne illnesses, which cause<br />
between 500 and 1,000 deaths every year in the U.S. 4<br />
This same group is also investigating the human microbiome<br />
for antimicrobials against pathogens. They have<br />
isolated a compound called lacticin 3147 from the harmless<br />
bacterium Lactococcus lactis, which is used to make<br />
cheese. Recently, lacticin 3147 has demonstrated antimicrobial<br />
activity against a range of genetically distinct<br />
Clostridium difficile strains isolated from the human gut.<br />
This indicates that lacticin 3147 may offer a new treatment<br />
for C difficile–associated diarrhea, a serious condition that<br />
affects 3 million people per year in the U.S. and is a major<br />
problem in hospitals. 4<br />
There is evidence confirming the effects of Lactobacillus<br />
GG in preventing diarrhea and atopy in children. 22,23 These<br />
organisms are thought to occupy binding sites in the gut<br />
mucosa that prevent pathogenic bacteria from adhering.<br />
Lactobacilli also produce bacteriocins that act as local<br />
antibiotics. Diarrhea associated with antibiotics may result<br />
PROBIOTICS AND MICROFLORA<br />
Table 1<br />
Strain-Specific Organisms<br />
Researched in the<br />
Prevention and Treatment of<br />
Antibiotic-Associated Diarrhea<br />
Bifidobacterium<br />
Lactobacillus GG (LGG) a<br />
Lactobacillus casei<br />
Lactobacillus plantarum 299v<br />
Enterococcus faecium (SF68)<br />
Saccharomyces boulardii a<br />
Saccharomyces cerevisiae<br />
Bacillus clausii<br />
Clostridium butyricum<br />
Lactobacillus acidophilus<br />
a<br />
S boulardii and LGG are the most promising.<br />
Source: Reference 24.<br />
when the antibiotics disrupt the<br />
normal flora in the gut of a healthy<br />
person. Such disruptions cause<br />
dysfunction of the gut’s ecosystem<br />
and allow pathogens to colonize<br />
the gut and gain access to the<br />
mucosa. A number of organisms<br />
have been studied as probiotics to<br />
prevent antibiotic- and C difficile–<br />
associated diarrhea (TABLE 1). 24<br />
Whether probiotic supplements<br />
stop this process by reducing the<br />
disruption or by acting as substitutes<br />
for healthy flora is unclear.<br />
Final Thoughts<br />
Recent evidence has shown that<br />
microbes and their genes play<br />
important roles in the development<br />
of our immune systems, in the production of fatty acids<br />
that enhance healthy intestinal cell growth, in elaborating<br />
molecules that inhibit the growth and virulence of enteric<br />
bacterial pathogens, and in the detoxification of ingested<br />
substances that could otherwise lead to cancerous cell<br />
growth or alter our ability to metabolize medicines. 25,26<br />
<strong>Pharmacist</strong>s will thus become more involved in counseling<br />
patients interested in taking probiotics. In Europe, probiotics<br />
are regarded as medicines and prescribed along with<br />
antibiotics. 27 In the U.S., pharmacists can advise patients<br />
to take such probiotic products as Culturelle, Florastor,<br />
or Lactinex while on antibiotics and for 3 to 7 days thereafter.<br />
3 The same products can be taken to help prevent<br />
traveler’s diarrhea. They should be taken a few days before<br />
the trip and continued through its duration. Instruct<br />
patients to separate any probiotic and antibiotic doses by<br />
2 hours to prevent the antibiotic from destroying the<br />
probiotic organisms. 3 Immunocompromised patients should<br />
be advised not to use probiotics because of the potential<br />
for systemic infections. Other side effects can include GI<br />
upset (e.g., flatulence, discomfort).<br />
REFERENCES<br />
1. Martin A. In live bacteria, food makers see a bonanza. NY Times.<br />
January 22, 2007. www.nytimes.com/2007/01/22/business/<br />
22yogurt.html. Accessed September 2, 2009.<br />
2. DanActive. Dannon. www.danactive.com. Accessed<br />
September 10, 2009.<br />
3. Probiotics for digestive health. <strong>Pharmacist</strong>’s Letter.<br />
2006;7(22):220704.<br />
4. Friedrich MJ. Benefits of gut microflora under study. JAMA.<br />
2008;299:162.<br />
5. Zuger A. Separating friend from foe among the body’s invaders.<br />
NY Times. November 27, 2007. www.nytimes.com/2007/11/27/<br />
health/27book.html. Accessed September 2, 2009.<br />
6. Sacks JS. Good Germs, Bad Germs. New York, NY: Hill &<br />
Wang; 2007.<br />
7. Macfarlane GT, Cummings JH. Probiotics and prebiotics: can<br />
regulating the activities of intestinal bacteria benefit health? BMJ.<br />
1999;318:999-1003.<br />
8. Intestinal flora. http://tuberose.com/Intestinal_Flora.html.<br />
Accessed September 2, 2009.<br />
9. Bullen CL, Willis AT. Resistance of the breast-fed infant to<br />
gastroenteritis. BMJ. 1971;3:338-343.<br />
10. Berkowitz RJ, Turner J, Green P. Maternal salivary levels of<br />
Streptococcus mutans and primary oral infection of infants.<br />
Arch Oral Biol. 1981;26:147-149.<br />
11. Backhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism<br />
in the human intestine. Science. 2005;307:1915-1920.<br />
12. Leyden JJ, McGinley KJ, Nordstrom KM, Webster GF. Skin<br />
microflora. J Invest Dermatol. 1987;88(suppl 3):65s-72s.<br />
13. Introduction to the archaea. University of California Museum of<br />
Paleontology. www.ucmp.berkeley.edu/archaea/archaea.html.<br />
Accessed September 2, 2009.<br />
14. Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the<br />
unseen majority. Proc Natl Acad Sci USA. 1998;95:6578-6583.<br />
15. Gordon JI, Ley RE, Wilson R, et al. Extending our view of self:<br />
the human gut microbiome initiative. Center for Genome Sciences.<br />
www.genome.gov/Pages/Research/Sequencing/SeqProposals/<br />
HGMISeq.pdf. Accessed September 2, 2009.<br />
16. Ilya Mechnikov. The Nobel Prize in Physiology or Medicine<br />
1908. Biography. http://nobelprize.org/nobel_prizes/medicine/<br />
laureates/1908/mechnikov-bio.html. Accessed September 2, 2009.<br />
17. Fiocchi C. One commensal bacterial molecule—all we need for<br />
health? N Eng J Med. 2005;353:2078-2080.<br />
18. Velicer CM, Heckbert SR, Lampe JW, et al. Antibiotic use in<br />
relation to the risk of breast cancer. JAMA. 2004;291:827-835.<br />
19. Velicer CM, Lampe JW, Heckbert SR, et al. Hypothesis: is antibiotic<br />
use associated with breast cancer? Cancer Causes Control.<br />
2003;14:739-747.<br />
20. Reed MJ, Purohit A. Aromatase regulation and breast cancer.<br />
Clin Endocrinol. 2001;54:563-571.<br />
21. Madara J. Building an intestine—architectural contributions of<br />
commensal bacteria. N Eng J Med. 2004;351:1685-1686.<br />
22. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and<br />
prevention of acute infectious diarrhea in infants and children: a systematic<br />
review of published, randomized, double-blind placebo-controlled<br />
trials. J Pediatr Gastroenterol Nutr. 2001;33(suppl):S17-S25.<br />
23. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in<br />
primary prevention of atopic disease: a randomized placebo-controlled<br />
trial. Lancet. 2001;357:1076-1079.<br />
24. Rohde CL, Bartolini V, Jones N. The use of probiotics in the<br />
prevention and treatment of antibiotic-associated diarrhea with special<br />
interest in Clostridium difficile-associated diarrhea. Nutr Clin<br />
Pract. 2009;24:33-40.<br />
25. Mindell DP. Evolution in the everyday world. Sci Am.<br />
2009;300:82-89.<br />
26. Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms<br />
of action of probiotics. Nutr Clin Pract. 2009;24:10-14.<br />
27. Berger A. Science commentary: probiotics. BMJ.<br />
2002;324:1364.<br />
44<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Annual Index 2009<br />
Title, Month:page<br />
Consult Your <strong>Pharmacist</strong><br />
Appropriate Use of<br />
Nonprescription<br />
Hydrocortisone, 4:12<br />
Automated External<br />
Defibrillators in the<br />
Community Setting,<br />
2:12<br />
Fatigue and Drowsiness:<br />
Everyday Exhaustion<br />
and Beyond, 11:12<br />
Getting to the Bottom of<br />
Common Foot<br />
Problems, 10:11<br />
Minor Eye Problems in the<br />
Elderly, 6:12<br />
Patients With Headaches:<br />
The <strong>Pharmacist</strong>’s Role,<br />
1:12<br />
Pediatric Otitis Media:<br />
Managing Ear Infections<br />
in Children, 3:12<br />
Recent Developments in<br />
Birth Control and STD<br />
Prevention for Men,<br />
8:12<br />
Recommending Analgesics<br />
for Common<br />
Conditions, 5:12<br />
Strategies for the Relief of<br />
Bloating and Gas,<br />
12:16<br />
Treating Common<br />
Problems in the<br />
Pregnant Patient, 9:12<br />
Why Patients Need<br />
Protection From the<br />
Sun, 7:14<br />
Contemporary<br />
Compounding<br />
Buprenorphine 2 mg/mL<br />
Sublingual Drops, 2:40<br />
Coal Tar 0.4% Alcohol<br />
Gel, 1:40<br />
Dexamethasone 0.2%<br />
With Tetracycline 2.4%<br />
or Metronidazole 10%<br />
Periodontal Gel, 3:42<br />
Gentamicin, Polymyxin,<br />
Neomycin, and<br />
Hydrocortisone in 50%<br />
Alcohol Otic Drops,<br />
8:70<br />
Ketamine Hydrochloride<br />
10-mg Troches, 11:58<br />
Ketoprofen 2% Oral Gel,<br />
10:48<br />
Metronidazole 2%,<br />
Misoprostol 0.0024%,<br />
and Phenytoin 5%<br />
Topical Gel, 6:50<br />
Myristyl Nicotinate 5%<br />
Topical Cream, 7:42<br />
Naproxen Sodium 100-<br />
mg/mL Injection, 5:48<br />
Ondansetron<br />
Hydrochloride 0.8 mg/<br />
mL Oral Liquid, 4:38<br />
Tamiflu Oral Suspension,<br />
12:54<br />
Vitamin E 200-IU<br />
Suppositories, 9:56<br />
Continuing Education<br />
An Update on the Current<br />
Treatment of HIV,<br />
8:76*<br />
Drug Information<br />
Resources for the<br />
Community<br />
<strong>Pharmacist</strong>, 2:45*<br />
Emergency Contraception:<br />
An Update of Clinical<br />
and Regulatory<br />
Changes, 11:70*<br />
Herpes Zoster (Shingles)<br />
and Postherpetic<br />
Neuralgia Management,<br />
5:53*<br />
Ovarian Cancer: One of<br />
the Common<br />
Gynecologic<br />
Malignancies, 10:61*<br />
Pediatric and Adolescent<br />
Sports-Related Injuries<br />
and Ailments, 3:44*<br />
Perimenopause:<br />
Management of<br />
Common Symptoms<br />
During the Menopausal<br />
Transition, 9:73*<br />
Prescription Drug Abuse:<br />
Strategies to Reduce<br />
Diversion, 12:61*<br />
Tetrabenazine for the<br />
Treatment of Huntington’s<br />
Chorea, 1:47*<br />
The Prevention and<br />
Treatment of Pressure<br />
Ulcers, 4:44*<br />
Treatment Options in<br />
Acute Lung Injury and<br />
Acute Respiratory<br />
Distress Syndrome,<br />
7:52*<br />
Urinalysis: A Guide for<br />
<strong>Pharmacist</strong>s, 6:52*<br />
Diagnostic Spotlight<br />
At-Home Test for Tobacco-Product<br />
Use, 7:36<br />
Malaria Test Kit, 8:46<br />
Novel Device for<br />
Medication<br />
Management, 6:Epub<br />
Features<br />
Alcohol-Induced<br />
Pancreatitis, 8:26<br />
Assisting Seniors With<br />
Insomnia: A<br />
Comprehensive<br />
Approach, 6:38<br />
Cardiovascular Risk: What<br />
Should We Measure?,<br />
2:25<br />
Evaluating the Link<br />
Between Diet and<br />
Acne, 4:26<br />
Food and Lifestyle<br />
Interactions With<br />
Warfarin: A Review,<br />
2:28<br />
Gestational Diabetes<br />
Mellitus, 9:43<br />
High Cholesterol in<br />
Childhood, 3:27<br />
IBS Treatment Guidelines,<br />
12:Epub<br />
Influenza Update: Seasonal<br />
and H1N1 Vaccines,<br />
10:Epub<br />
Managing Chronic<br />
Diabetic Peripheral<br />
Neuropathy in the<br />
Elderly, 1:30<br />
Massage Therapy:<br />
Implications for<br />
Pharmaceutical Care,<br />
5:Epub<br />
Medications Used in<br />
Opioid Maintenance<br />
Treatment, 11:40<br />
New Drug Review 2009,<br />
10:37<br />
Osteoporosis: A<br />
Preventable Part of<br />
Aging, 6:27<br />
Overview of Hepatitis B<br />
and C Management,<br />
12:32<br />
Pediatric OTC Cough and<br />
Cold Product Safety,<br />
6:39<br />
<strong>Pharmacist</strong>s’ Role in<br />
Preventing Vaccine-<br />
Preventable Diseases,<br />
8:39<br />
Pharmacologic Management<br />
of Alcohol<br />
Dependence, 11:60<br />
Pharmacotherapy of<br />
Diabetes in the Elderly,<br />
7:44<br />
Pharmacy Students<br />
Providing Patient<br />
Medication Discharge<br />
Counseling in<br />
Pennsylvania, 8:49<br />
Probiotics and Microflora,<br />
12:42<br />
Psychotropic Medication<br />
During Pregnancy, 9:58<br />
Recent Advances in the<br />
Treatment of Pain<br />
Associated With<br />
Fibromyalgia, 9:49<br />
Recommendations for the<br />
Use of OTC Cough<br />
50<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Annual Index 2009<br />
and Cold Medications<br />
in Children, 3:33<br />
Restless Legs Syndrome:<br />
A Common,<br />
Underdiagnosed<br />
Disorder, 1:24<br />
Solutions to Male<br />
Infertility, 8:58<br />
So Many Options, So<br />
Little Difference in<br />
Efficacy: What Is the<br />
Appropriate<br />
Antidepressant?, 11:26<br />
The Diagnosis and Treatment<br />
of Gout, 5:40<br />
The Relationship Between<br />
GERD and Asthma,<br />
7:30<br />
The Use of<br />
Antidepressants for<br />
Chronic Pain, 5:26<br />
The Use of OTC<br />
Medications in Older<br />
Adults, 6:44<br />
Understanding<br />
Breastfeeding: Beyond<br />
Medication, 9:25<br />
Updates in<br />
Nonprescription<br />
Therapy for Heartburn<br />
and GERD, 10:52<br />
ISMP: Medication<br />
Safety<br />
A Warning About Warning<br />
Labels, 2:Epub<br />
Health Literacy—<br />
¿Comprende? Not<br />
Necessarily, 6:11<br />
Transdermal Patches and<br />
Burns, 4:43<br />
Patient Teaching Aids<br />
Bipolar Disorder, 11:17<br />
Fibromyalgia, 5:17<br />
Insomnia, 1:17<br />
Knee Replacement<br />
Surgery, 6:19<br />
Melanoma, 4:17<br />
Meningitis, 10:29<br />
Pancreatitis, 12:25<br />
Prostatitis, 8:17<br />
Smoking Cessation, 7:21<br />
Sudden Infant Death<br />
Syndrome, 3:17<br />
Tubal Ligation, 9:17<br />
Ventricular Tachycardia,<br />
2:17<br />
Pharmacy Law<br />
Criminalization of<br />
Medication Errors,<br />
11:66<br />
Disposal of Controlled<br />
Substances, 3:38<br />
Federal Preemption of<br />
States’ Drug Product<br />
Liability Laws DOA,<br />
5:50<br />
Gender Discrimination<br />
and Its Consequences,<br />
12:56<br />
HIPAA Breach<br />
Notification Rule,<br />
10:56<br />
<strong>Pharmacist</strong>s Beware: Data<br />
Mining Unlawful, 6:48<br />
Pharmacy Robberies,<br />
7:49<br />
Recusal of Judges, 4:40<br />
Right of Conscience:<br />
Federal Developments,<br />
2:43<br />
Rogue Internet<br />
Pharmacies, 1:42<br />
The Price of Living: Endof-Life<br />
Costs, 8:72<br />
Unraveling Plan B’s Legal<br />
Status, 9:69<br />
Senior Care<br />
Amyloidosis: Interference<br />
With Organ Structure<br />
and Function, 8:21<br />
Assessing Pain in the<br />
Cognitively Impaired,<br />
5:21<br />
Caring for the Aging: Key<br />
Health Care<br />
Legislation, 6:22<br />
Colorectal Cancer<br />
Screening, 12:29<br />
Dermatologic Signs of<br />
Rheumatoid Arthritis,<br />
4:22<br />
Obesity: Reality and<br />
Relevance to Health,<br />
9:20<br />
Progressive Supranuclear<br />
Palsy, 11:20<br />
Raising Awareness About<br />
Pulmonary Embolism,<br />
7:24<br />
The Dying Patient:<br />
Choices, Control, and<br />
Communication, 10:32<br />
Venous Thrombosis:<br />
Pathogenesis and<br />
Potential for Embolism,<br />
2:22<br />
Vitamin D Deficiency and<br />
Bone Pain, 3:22<br />
Wrist and Thumb Pain in<br />
Seniors: Focus on De<br />
Quervain’s<br />
Tenosynovitis, 1:20<br />
TrendWatch<br />
Acute Negative Feelings<br />
Among Adults, 11:10<br />
Cancer Trends in Women,<br />
9:10<br />
Dietary Behaviors and<br />
Weight-Control<br />
Practices Among<br />
Youths, 3:11<br />
Disparities in Respiratory<br />
Diseases, 7:13<br />
Drugs Used for Pain<br />
Relief, 5:10<br />
FDA Postmarketing<br />
Surveillance, 10:10<br />
Health Status and Health<br />
Care of Elderly<br />
Americans, 6:Epub<br />
Incidence and Prevalence<br />
of Prostate Cancer, 8:10<br />
Neurologic Visits to<br />
Ambulatory-Care<br />
Settings, 1:Epub<br />
Prevalence of Selected<br />
Cardiovascular Diseases,<br />
2:8<br />
The Burden of Digestive<br />
Diseases, 12:12<br />
Trends in the Practice of<br />
Dermatology, 4:10<br />
Supplements<br />
Diabetes &<br />
Pharmaceutical Care,<br />
May<br />
CE Article: Addressing<br />
Patient Challenges to<br />
Diabetes Treatment<br />
Through the Use of<br />
Incretin-Based<br />
Therapies*<br />
Glucose Sensors: The New<br />
Frontier of Diabetes<br />
Technology<br />
Hypertriglyceridemia<br />
Management in<br />
Patients with Diabetes<br />
Osteoporosis: An Understated<br />
Complication of<br />
Diabetes<br />
Generic Drug Review,<br />
June<br />
Follow-On Biologics: The<br />
Controversy Continues<br />
Generic Drug Use: Survey<br />
Results<br />
Generic Drugs: History,<br />
Approval Process, and<br />
Current Challenges<br />
Generic Substitution of<br />
Narrow Therapeutic<br />
Index Drugs<br />
How Is the Quality of a<br />
Generic Drug<br />
Evaluated?<br />
Q&A With GPhA<br />
President and CEO<br />
Kathleen Jaeger<br />
Oncology/Hematology<br />
Breast Cancer Pathology<br />
Report: What<br />
52<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Annual Index 2009<br />
<strong>Pharmacist</strong>s Need to<br />
Know, May<br />
Concepts in Cancer Pain<br />
Management,<br />
November<br />
Drug Interactions With<br />
Newer Oral<br />
Chemotherapy Agents,<br />
July<br />
Management of<br />
Chemotherapy<br />
Extravasations,<br />
September<br />
Mantle Cell Lymphoma,<br />
September<br />
Pharmacological<br />
Management of Colon<br />
Cancer, March<br />
Oral Mucositis: Update on<br />
Prevention and<br />
Management Strategies,<br />
January<br />
Sickle Cell Disease and<br />
Stroke Prevention in<br />
Children, January<br />
The Expanded Role of<br />
Bisphosphonates in<br />
Survivors of Breast<br />
Cancer, March<br />
Treatment Options in the<br />
Management of<br />
Nonmuscle-Invasive<br />
Bladder Cancer, July<br />
OTC Trends, April<br />
OTCs & Seniors: Risks<br />
and Safeguards<br />
<strong>Pharmacist</strong> Consultation<br />
for Self-Care With<br />
NSAIDs<br />
Insomnia and Its<br />
Treatment With<br />
Nonprescription<br />
Products<br />
Sponsored Supplements<br />
CE Article: Initiating and<br />
Monitoring<br />
Pharmacotherapy in<br />
Patients with<br />
Parkinson’s Disease,<br />
February*<br />
CE Article: Optimizing<br />
Individualized<br />
Management of<br />
Osteoarthritis, June*<br />
CE Article: The Rx for<br />
Gout: The <strong>Pharmacist</strong>’s<br />
Role in Improving<br />
Clinical Outcomes for<br />
Patients, April*<br />
Disease State Information<br />
Guide: Irritable Bowel<br />
Syndrome: Overview of<br />
Diagnosis and Management<br />
of IBS: Focus on<br />
Probiotics, May<br />
Generic Pharmaceuticals<br />
2009: The Road Ahead,<br />
January<br />
Patient Counseling Aid:<br />
Contact Lens Care, July<br />
Product Information<br />
Guide: AMITIZA<br />
(lubiprostone) 8 mcg<br />
Twice Daily in the<br />
Management of<br />
Irritable Bowel<br />
Syndrome with<br />
Constipation in<br />
Women 18 Years of Age<br />
and Older, April<br />
Product Information<br />
Guide: The Future of<br />
Hazardous IV Drug<br />
Preparation Is Here,<br />
May<br />
Product Information<br />
Guide: Update on<br />
Respiratory Syncytial<br />
Virus Infection in<br />
Children With<br />
Emphasis on<br />
Immunoprophylaxis,<br />
February<br />
Product Information<br />
Guide: What<br />
<strong>Pharmacist</strong>s Should<br />
Know About Caring for<br />
Contact Lenses, May<br />
Health Systems<br />
<strong>Edition</strong> Features<br />
Antiplatelet Therapy for<br />
the Secondary<br />
Prevention of Acute<br />
Coronary Syndrome,<br />
2:HS-1<br />
A Review of Testicular<br />
Cancer, 8:HS-3<br />
Diagnosis and Treatment<br />
of Acute Inflammatory<br />
Dermatoses, 4:HS-1<br />
Evidence-Based Medicine<br />
in Pharmacy Practice,<br />
10:HS-14<br />
Hypothyroidism, 9:HS-3<br />
Immunizations in the<br />
Older Population,<br />
6:HS-1<br />
Management of<br />
Hypertensive Crises,<br />
5:HS-8<br />
Management Strategies in<br />
Stable COPD, 1:HS-10<br />
Managing Acute<br />
Exacerbations of<br />
COPD, 7:HS-11<br />
Metabolic Syndrome and<br />
Cardiovascular Risk<br />
Factors, 2:HS-12<br />
Methicillin-Resistant<br />
Staphylococcus aureus<br />
Skin and Soft Tissue<br />
Infections, 4:HS-8<br />
Multiple Sclerosis: A<br />
Therapeutic Overview,<br />
1:HS-3<br />
Newly Approved mTOR<br />
Inhibitors for the<br />
Treatment of Metastatic<br />
Renal Cell Carcinoma,<br />
11:HS-20<br />
Optimal Management of<br />
Hyperglycemia in<br />
Hospitalized Patients,<br />
5:HS-14<br />
Polymyalgia Rheumatica,<br />
6:HS-7<br />
Prophylactic Therapies in<br />
Traumatic Brain Injury<br />
Management,<br />
11:HS-10<br />
Prostate Cancer: Updates<br />
in Pharmacotherapy,<br />
8:HS-15<br />
Rapid Molecular Testing in<br />
Bloodstream Infections,<br />
9:HS-9<br />
Reducing Medication<br />
Errors Using<br />
Technological<br />
Innovations, 3:HS-15<br />
Refractory Epilepsy,<br />
3:HS-8<br />
Review of Selected NMEs<br />
2009, 10:HS-3<br />
Schizophrenia: A Review<br />
of Pharmacologic and<br />
Nonpharmacologic<br />
Treatments, 11:HS-2<br />
Surgical Procedures for<br />
Weight Loss, 12:HS-2<br />
The Management of<br />
Amyotrophic Lateral<br />
Sclerosis, 8:HS-10<br />
Topical Anesthesia Use in<br />
Children, 3:HS-4<br />
Treatment of Hypertension<br />
in the Elderly, 6:HS-12<br />
Tuberculosis: Insidious But<br />
Treatable, 7:HS-2<br />
Understanding the<br />
Pharmacologic Therapy<br />
for Patients Afflicted<br />
with Complex Regional<br />
Pain Syndrome,<br />
5:HS-3<br />
In-Service Primers<br />
Adaptogenic or Medicinal<br />
Mushrooms, 4:HS-16<br />
Capsaicin, 7:HS-17<br />
Gastrointestinal Bleeding,<br />
12:HS-12<br />
Nutrition and Clinical<br />
Depression, 11:HS-28<br />
Whey Protein, 9:HS-14<br />
*Available as online CEs.<br />
Visit www.uspharmacist.com.<br />
53<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Contemporary Compounding<br />
Tamiflu Oral Suspension<br />
A liquid version of this influenza medication may<br />
be easily prepared using the capsule formulation.<br />
●FORMULA<br />
Tamiflu Oral Suspension 1,2<br />
Rx: Ingredient 12 mg/mL 15 mg/mL<br />
Tamiflu (as 1.2 g 1.5 g<br />
75-mg capsules) (16 caps) (20 caps)<br />
Vehicle qs 100 mL qs 100 mL<br />
A preferred vehicle may be chosen from the following:<br />
Cherry syrup (Humco)<br />
Ora-Sweet SF<br />
If neither of the above is available, one of the following<br />
alternative vehicles may be used:<br />
PCCA-Plus<br />
Acacia syrup<br />
Methylcellulose 1% solution<br />
Other a<br />
a<br />
Other suitable vehicles are available commercially, or the following<br />
products from the USP <strong>Pharmacist</strong>s’ Pharmacopeia, 2nd edition,<br />
may be used: Vehicle for Oral Solution, Sugar Free USP or Vehicle<br />
for Oral Suspension. These products are compounded vehicles using<br />
routine compounding ingredients.<br />
Method of Preparation:<br />
Calculate the quantity of<br />
each ingredient for the<br />
amount to be prepared.<br />
Accurately weigh or measure<br />
each ingredient.<br />
Carefully separate the<br />
capsule body and cap<br />
and transfer the contents<br />
of the required number<br />
of Tamiflu 75-mg capsules<br />
into a clean mortar.<br />
Triturate the granules to<br />
a fine powder. Add about<br />
one-third of the specified<br />
amount of vehicle to the<br />
Loyd V. Allen, Jr, PhD<br />
Professor Emeritus, College of<br />
Pharmacy, University of Oklahoma,<br />
Oklahoma City<br />
mortar, and triturate the<br />
powder until a uniform<br />
suspension is achieved.<br />
Transfer the suspension<br />
to an amber glass or<br />
polyethylene terephthalate<br />
bottle that has been<br />
properly calibrated for<br />
the final volume. Add<br />
another one-third<br />
(approximate) of the<br />
vehicle to the mortar,<br />
rinse the pestle and mortar,<br />
and transfer the contents<br />
to the bottle.<br />
Repeat the rinsing with<br />
the sufficient vehicle,<br />
adding it to final volume<br />
in the calibrated container.<br />
Place a child-resistant<br />
cap on the bottle.<br />
Shake well, then package<br />
and label.<br />
Use: Tamiflu oral suspension<br />
is indicated for prophylaxis<br />
and treatment<br />
of uncomplicated influenza<br />
infection in patients<br />
aged ≥1 year. 3<br />
Packaging: Package in<br />
tight, light-resistant<br />
containers.<br />
Labeling: Shake well<br />
before use. Keep out of<br />
the reach of children.<br />
Discard after ____ [time<br />
period].<br />
Stability: Cherry syrup<br />
(Humco) and Ora-Sweet<br />
SF formulations—Refrigeration:<br />
stable for 5<br />
weeks (35 days) when<br />
stored in a refrigerator at<br />
2°C to 8°C (36°F to<br />
46°F). Room temperature:<br />
cherry syrup stable<br />
for 5 days when stored at<br />
room temperature of<br />
25°C (77°F); Ora-Sweet<br />
SF stable for 35 days<br />
when stored at room<br />
temperature.<br />
PCCA-Plus, acacia<br />
syrup, and methylcellulose<br />
1% solution formulations—Refrigeration:<br />
stable<br />
for 90 days when<br />
stored in a refrigerator at<br />
2°C to 8°C (36°F to<br />
46°F). Room temperature:<br />
stable for 90 days<br />
when stored at room<br />
temperature of 25°C<br />
(77°F).<br />
Note: The time periods<br />
listed above are recommended<br />
by Ford et<br />
al. 2 Shorter dating is suggested,<br />
however, as this<br />
preparation is intended<br />
for short-term storage<br />
and use.<br />
Other vehicles—Stability<br />
information is not<br />
available for other vehicles.<br />
Therefore, the USP<br />
General Chapter <br />
standard would be to<br />
assign a beyond-use date<br />
of 14 days for the preparation<br />
when stored in a<br />
refrigerator at 2°C to<br />
8°C (36°F to 46°F).<br />
Quality Control: Quality-control<br />
assessment<br />
can include weight/volume,<br />
pH, specific gravity,<br />
active drug assay,<br />
color, rheologic properties/pourability,<br />
physical<br />
observation, and physical<br />
stability (discoloration,<br />
foreign materials, gas formation,<br />
mold growth). 4<br />
Discussion: It has been<br />
announced that Tamiflu<br />
54<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Contemporary Compounding<br />
capsules will be manufactured<br />
to meet current<br />
demands and that pharmacists<br />
will compound<br />
the oral suspension for<br />
consumers. The manufacturer<br />
can mass-produce<br />
many more capsules<br />
than the oral<br />
suspension formulation<br />
in a given time period.<br />
The labeling for Tamiflu<br />
includes instructions on<br />
how to prepare an oral<br />
suspension using two<br />
different vehicles, as presented<br />
above. 1<br />
Different vehicles<br />
may be used and different<br />
concentrations may<br />
be compounded, according<br />
to the needs of the<br />
physician or patient and<br />
the availability of vehicles.<br />
The stability implications<br />
must be considered<br />
in the event that<br />
other concentrations are<br />
compounded.<br />
Oseltamivir phosphate<br />
(C 16<br />
H 28<br />
N 2<br />
O 4<br />
.<br />
H 3<br />
PO 4<br />
, MW 420.40) is<br />
an ethyl ester prodrug<br />
available as a capsule<br />
containing 75 mg oseltamivir<br />
for oral use as<br />
an antiviral (influenza).<br />
It is manufactured as a<br />
capsule and as a powder<br />
for oral suspension. The<br />
suspension, when reconstituted<br />
according to<br />
labeling instructions,<br />
contains 12 mg/mL<br />
oseltamivir. Oseltamivir<br />
phosphate occurs as a<br />
white crystalline solid.<br />
The capsules also contain<br />
pregelatinized<br />
starch, talc, povidone<br />
K30, croscarmellose<br />
sodium, and sodium<br />
stearyl fumarate; the<br />
capsule shells contain<br />
gelatin and coloring<br />
agents.<br />
REFERENCES<br />
1. Tamiflu.com. Dosing,<br />
administration and storage:<br />
extemporaneous preparation.<br />
www.tamiflu.com/hcp/dosing/<br />
extprep.aspx. Accessed November<br />
13, 2009.<br />
2. Ford SM, Kloesel LG,<br />
Grabenstein JD. Stability of<br />
oseltamivir in various extemporaneous<br />
liquid preparations. IJPC.<br />
2007;11:162-174.<br />
3. Physicians’ Desk Reference. 63rd<br />
ed. Montvale, NJ: Thomson<br />
Reuters; 2009:2649-2654.<br />
4. Allen LV Jr. Standard operating<br />
procedure for performing physical<br />
quality assessment of oral and<br />
topical liquids. IJPC. 1999;3:<br />
146-147.<br />
Report Six of Six in a series<br />
Problem:<br />
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gluten, casein, dye, sugar, or flavorings.<br />
Solution.<br />
All products in the SyrSpend SF line are<br />
gluten-free, casein-free, dye-free, and sugarfree.<br />
Unflavored versions of SyrSpend SF<br />
contain no flavoring. Call or e-mail us now<br />
for your free sample. Mention code UPh-6.<br />
1.800.423.6967 www.gallipot.com<br />
GALLIPOT ®<br />
The Art Of Compounding ®
Gender Discrimination<br />
and Its Consequences<br />
There is no reason<br />
to differentiate<br />
compensation or<br />
enforcement of<br />
policies based on<br />
gender alone, as a<br />
female pharmacist<br />
and a large pharmacy<br />
chain have learned.<br />
Legislation to apply the principle<br />
of equal pay for equal work without<br />
discrimination because of sex is<br />
a matter of simple justice.<br />
President Dwight D. Eisenhower, 1956 1<br />
A<br />
recent case from the<br />
Supreme Judicial Court of<br />
Massachusetts affirmed a<br />
jury verdict in favor of a female<br />
pharmacist who claimed she was<br />
paid less than her male counterparts.<br />
2 With interests, costs, and<br />
attorney fees, the recovery from the<br />
defendant chain store corporation<br />
will be well over $3.5 million. 3,4<br />
Facts of the Case<br />
Cynthia Haddad worked as a pharmacist<br />
for Wal-Mart for 10 years, 7<br />
of those years in the Pittsfield, Massachusetts,<br />
store. For the majority of<br />
this time, she worked as a staff pharmacist<br />
and consistently had excellent<br />
evaluations. In March 2003, the<br />
Jesse C. Vivian, RPh, JD<br />
Professor, Department of Pharmacy Practice<br />
College of Pharmacy and Health Sciences<br />
Wayne State University<br />
Detroit, Michigan<br />
plaintiff accepted the position of<br />
pharmacy manager. From that point<br />
until her involuntary termination 13<br />
months later, she was paid at an<br />
hourly rate considerably lower than<br />
any male pharmacy manager in the<br />
geographic region. Although she was<br />
told that she would receive the additional<br />
hourly pay that was paid to all<br />
pharmacy managers, she did not<br />
receive this differential. After numerous<br />
complaints, on April 9, 2004,<br />
she finally received a check for the<br />
pharmacy manager bonus that others<br />
received in February, but she<br />
never received the 13 months’ worth<br />
of differential hourly pay.<br />
On April 14, 2004, a district<br />
manager, who was not a pharmacist,<br />
and two other supervisors met with<br />
Ms. Haddad. They questioned her<br />
about two prescriptions that had<br />
been fraudulently written and filled<br />
by a pharmacy technician. One of<br />
the prescriptions, for Prevacid (lansoprazole),<br />
had been written in<br />
October 2002, while the female<br />
pharmacist was on duty (well before<br />
she had been promoted to manager),<br />
and one was written on March 20,<br />
2004, while a male pharmacist was<br />
working. The pharmacy technician<br />
on duty immediately admitted that<br />
she had falsified the October 2002<br />
prescription. The female pharmacist<br />
denied any knowledge of the fraudulent<br />
prescriptions, but told the district<br />
manager that it could have been<br />
written when she briefly left the<br />
pharmacy area to purchase a soda at<br />
a nearby counter, when she was in<br />
the restroom, when she was in the<br />
front of the pharmacy talking to customers,<br />
or when she was in the back<br />
of the pharmacy eating lunch or<br />
counting narcotics. There was no<br />
written policy prohibiting a pharmacist<br />
from leaving the pharmacy for<br />
short periods of time while the pharmacist<br />
remained inside the store.<br />
Ms. Haddad’s employment was<br />
terminated that day. She was told<br />
that the reason for her dismissal was<br />
based on her statement during the<br />
interview that she failed to secure<br />
the pharmacy, in violation of an<br />
unspecified policy, and that she had<br />
briefly left the pharmacy area unsecured<br />
while a technician was unattended<br />
in the pharmacy area. A written<br />
form filled out by the district<br />
manager indicated she was terminated<br />
for “gross misconduct, misappropriation.”<br />
The technician was<br />
also fired the same day.<br />
The other fraudulent prescription<br />
contained the male pharmacist’s initials.<br />
Neither he, who was on duty<br />
when the second fraudulent prescription<br />
was written, nor any other<br />
pharmacist was questioned about it<br />
or disciplined for it. Employees testified<br />
that the pharmacy did not further<br />
investigate the second fraudulent<br />
prescription because the<br />
technician did not admit to having<br />
forged it. Ironically, the same male<br />
pharmacist was appointed to be<br />
pharmacy manager on the day that<br />
the female pharmacist was fired. The<br />
male pharmacist testified at trial that<br />
he commonly left the pharmacy area<br />
unsecured to talk to a customer in<br />
the OTC area, to go to the restroom,<br />
or to get a snack. He also<br />
stated that he was unaware of any<br />
policy prohibiting this practice and<br />
was never disciplined for doing so.<br />
56<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
GENDER DISCRIMINATION AND ITS CONSEQUENCES<br />
He also admitted that within 3<br />
months of assuming the manager<br />
position, he was earning substantially<br />
more per hour than the female<br />
pharmacist had ever earned during<br />
the 13 months that she held the<br />
position.<br />
At the time of the female pharmacist’s<br />
termination, in the geographic<br />
district containing the store<br />
she worked at, 20 of the 21 managers<br />
above the pharmacy manager<br />
level were male, and all of the pharmacy<br />
technicians were female. Only<br />
two of the pharmacy managers were<br />
females.<br />
Law and Evidence<br />
Under Massachusetts law, every<br />
pharmacy must have a pharmacist<br />
“manager of record,” who is responsible<br />
for complying with state and<br />
federal reporting requirements and<br />
supervising the pharmacy staff, and a<br />
registered pharmacist must be on<br />
duty during a pharmacy’s hours of<br />
operation. 5 During the period at<br />
issue, the pharmacy employed one<br />
pharmacist at its Pittsfield store who<br />
was designated the pharmacy manager<br />
to serve as the manager of<br />
record. A staff pharmacist generally<br />
worked under the pharmacy manager,<br />
and several pharmacy technicians<br />
assisted the staff pharmacist. At<br />
most times, only one pharmacist<br />
would be on duty.<br />
On appeal, Wal-Mart argued that<br />
there was no evidence to support the<br />
jury’s finding that it discriminated<br />
against the female pharmacist on the<br />
basis of her gender. In its defense,<br />
the pharmacy offered several facially<br />
valid reasons for the plaintiff’s termination.<br />
According to this court,<br />
however, there was ample evidence<br />
from which a jury could have<br />
inferred that the pharmacy’s stated<br />
reasons were pretexts, and consequently<br />
that it acted with discriminatory<br />
intent. A pretext in law is the<br />
reason assigned to justify an act,<br />
which only has the appearance of<br />
truth but is without foundation. 6<br />
The court concluded that the jury<br />
could have justifiably decided that<br />
all of the pharmacy’s proffered reasons<br />
for terminating the plaintiff’s<br />
employment were false.<br />
The district manager had previously<br />
given a variety of conflicting<br />
reasons for the termination. He testified<br />
that the female pharmacist was<br />
terminated because she failed to<br />
secure the pharmacy area and that<br />
she disclosed her computer sign-on<br />
code to a technician. This statement<br />
could be construed as false for several<br />
reasons. The pharmacist testified<br />
that she had never disclosed her<br />
password to anyone, and the sign-on<br />
code was known by everyone to be<br />
the pharmacist on duty’s first, middle,<br />
and last initials. A number of<br />
pharmacy employees testified that it<br />
was routine practice for pharmacists<br />
to log on to the computer in the<br />
morning and to stay logged on all<br />
day, so that a technician could easily<br />
use the pharmacist’s computer<br />
account. In addition, there was substantial<br />
evidence that similarly situated<br />
male pharmacists were treated<br />
differently than the female pharmacist<br />
for similar infractions of pharmacy<br />
policies. There was evidence<br />
that male pharmacists routinely left<br />
the pharmacy area unsecured in<br />
order to purchase snacks or drinks,<br />
and that no other pharmacist had<br />
been terminated for such a reason.<br />
There was also evidence that the<br />
policy on lunch breaks did not mandate<br />
that a pharmacist secure the<br />
pharmacy before leaving the pharmacy<br />
area. The policy stated that a<br />
pharmacist may close and lock the<br />
pharmacy if only one pharmacist<br />
was on duty and was going on a<br />
meal break, and that the pharmacist<br />
may leave the pharmacy area, but<br />
should not leave the building. Additionally,<br />
evidence showed that the<br />
incident had occurred 18 months<br />
prior to the termination. There was<br />
testimony that male pharmacists<br />
routinely left the pharmacy to purchase<br />
food or beverages in the store<br />
or to assist customers. The reason<br />
initially checked on the exit interview<br />
form—“gross misconduct, misappropriation”—could<br />
have been<br />
erroneous because there was no evidence<br />
or even any allegation that the<br />
plaintiff misappropriated assets.<br />
In circumstances virtually identical<br />
to the purported incident for<br />
which the female pharmacist was<br />
terminated, a male pharmacist was<br />
neither questioned about nor disciplined<br />
for the second fraudulent prescription<br />
filled by the technician,<br />
even though his initials were on the<br />
prescription, he was on duty at the<br />
time it was filled, the prescription<br />
appeared suspicious on its face, and<br />
the incident had occurred only a few<br />
weeks, rather than 18 months,<br />
before the plaintiff’s termination.<br />
The evidence indicated that the<br />
store’s investigation of the second<br />
fraudulent prescription was limited<br />
to questioning the plaintiff about it<br />
and thereafter asking the technician<br />
whether she had written it.<br />
The pharmacy claimed that its<br />
decision to investigate only the<br />
plaintiff and none of the male pharmacists<br />
regarding the fraudulent prescriptions<br />
is “legally irrelevant, and<br />
cannot support an inference of discrimination.”<br />
The pharmacy asserted<br />
that it did not investigate or discipline<br />
the male pharmacist on duty<br />
when the tech wrote the second<br />
fraudulent prescription because it<br />
had no reason to suspect the male<br />
pharmacist had engaged in wrongdoing.<br />
This argument was considered<br />
meritless because the evidence<br />
showed that the pharmacy questioned<br />
the female pharmacist about<br />
both the prescription the technician<br />
wrote when the female pharmacist<br />
was on duty and the one written<br />
when the male pharmacist was on<br />
duty, but did not question the male<br />
pharmacist about either prescription.<br />
Given the evidence of the fraudulent<br />
prescription with the male pharmacist’s<br />
initials, the pharmacy should<br />
have had as much reason to suspect<br />
that the male pharmacist was<br />
engaged in wrongdoing as it did to<br />
suspect the female pharmacist.<br />
57<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
GENDER DISCRIMINATION AND ITS CONSEQUENCES<br />
Notwithstanding the proffered<br />
reason that the female pharmacist<br />
was terminated for leaving the pharmacy<br />
area unattended in October<br />
2002, at that time she was a staff<br />
pharmacist and not the pharmacy<br />
manager legally responsible for seeing<br />
that the pharmacy was secure.<br />
Moreover, terminating her employment<br />
for a single policy infraction<br />
did not comport with the corporation’s<br />
stated policy of progressive discipline,<br />
with employees first<br />
“coached” about proper procedures,<br />
then suspended, and then, in<br />
extreme circumstances, terminated<br />
from employment.<br />
Perhaps even more telling, there<br />
was evidence that Ms. Haddad’s termination<br />
had been planned in<br />
advance. Her termination notice was<br />
originally dated on the day before<br />
the interview, and the district supervisor<br />
testified that he told the<br />
regional manager the day before that<br />
he intended to interview and then<br />
terminate the pharmacist on the following<br />
day. In addition, without the<br />
female pharmacist’s prior knowledge,<br />
the male pharmacist was registered<br />
with the Board of Pharmacy to<br />
become the manager of record 3<br />
days prior to her termination.<br />
There was also evidence of other<br />
incidents in which male pharmacists<br />
were not disciplined for far more<br />
serious infractions of pharmacy policies,<br />
or even for actions that violated<br />
state and federal law. For instance, a<br />
videotape from a surveillance camera<br />
showed the technician placing drugs<br />
in her purse while a male pharmacist<br />
on duty was standing near her. The<br />
store policy prohibited bringing<br />
purses into the pharmacy area. That<br />
male pharmacist, who remained<br />
employed by the pharmacy at the<br />
time of trial, testified that he was<br />
not questioned or disciplined about<br />
the incident. In August 2003, the<br />
pharmacy discovered that another<br />
male pharmacist had been writing<br />
prescriptions for himself for a Schedule<br />
II narcotic. A district manager<br />
instructed that pharmacist to have a<br />
prescription written by his physician,<br />
and no disciplinary action was taken<br />
against him for these forged prescriptions.<br />
That pharmacist was also<br />
later observed taking drugs from the<br />
pharmacy. His employment was not<br />
terminated for this conduct.<br />
Most difficult for the pharmacy<br />
to justify, the undisputed evidence<br />
showed that the female pharmacist’s<br />
base pay was significantly less per<br />
hour than all the male pharmacy<br />
managers in the region. In addition,<br />
despite her repeated requests for the<br />
additional hourly pay and bonus<br />
that the male pharmacy managers<br />
received, the pharmacy failed to pay<br />
her the bonus until just before her<br />
termination.<br />
Damages<br />
The jury awarded $17,700 in special<br />
damages, $125,000 in emotional<br />
distress damages, back pay of<br />
$95,000, and front pay of $733,307<br />
based on an estimated 19 years of<br />
continued employment if not for the<br />
wrongful termination. On appeal,<br />
the pharmacy contested only the<br />
front pay award. It argued that a)<br />
the front pay award is excessive and<br />
speculative; b) the judge failed to<br />
consider evidence of the pharmacist’s<br />
future earning ability; and c) a<br />
19-year award is too long. The jury<br />
also awarded $1 million in punitive<br />
damages. However, the trial court<br />
judge reversed the punitive damages<br />
award and entered a verdict for the<br />
compensatory amount. The pharmacist<br />
appealed for reinstatement of<br />
this award.<br />
Front pay is intended to compensate<br />
a plaintiff for the loss of<br />
future earnings caused by the defendant’s<br />
discriminatory conduct. The<br />
judge properly instructed the jury<br />
that front pay damages must be<br />
“proven with reasonable certainty;”<br />
that in awarding such damages they<br />
should consider the “amount of<br />
future earnings, including salary,<br />
bonuses and benefits that the plaintiff<br />
would have received but for the<br />
defendant’s unlawful discrimination;”<br />
that they should not overcompensate<br />
the plaintiff; and that<br />
the plaintiff had a duty to mitigate<br />
her damages by reasonable efforts to<br />
secure other employment. The<br />
judge also correctly instructed the<br />
jury to consider and weigh five factors<br />
in determining the amount of<br />
any front pay award: 1) the amount<br />
of earnings, including salary and<br />
benefits, that the plaintiff would<br />
have received between the time of<br />
trial and the plaintiff’s projected<br />
retirement date; 2) the plaintiff’s<br />
probable retirement date; 3) the<br />
amount of earnings that the plaintiff<br />
would probably have received from<br />
another employer until her retirement,<br />
which would reduce any<br />
front pay award; 4) the availability<br />
of other employment opportunities;<br />
and 5) the possibility of future wage<br />
increases and inflation. The judge<br />
further instructed that any award of<br />
front pay damages must be based on<br />
the present discounted value of the<br />
income stream, and he provided an<br />
explanation of how that value was<br />
to be calculated. Notably, the female<br />
pharmacist hired a PhD economist<br />
as an expert to testify about front<br />
pay damages, and the pharmacy did<br />
not offer any contradictory testimony<br />
or evidence.<br />
Ms. Haddad testified to her difficulty<br />
in obtaining a new job. After<br />
more than 6 months of seeking<br />
employment, she eventually secured<br />
a position at a small pharmacy that<br />
was owned by a relative of her inlaws<br />
with less advancement potential,<br />
significantly fewer benefits, and<br />
fewer available hours. She remained<br />
in that position at the time of trial;<br />
the evidence suggested that the<br />
plaintiff intended to stay in the<br />
Pittsfield area and to continue working<br />
at her present type of job as a<br />
pharmacist. Her tendency to job<br />
stability was supported by evidence<br />
that she had worked at the defendant<br />
pharmacy for 10 years. While<br />
the pharmacy emphasizes that the<br />
pharmacist’s hourly pay in the new<br />
job is higher, it ignores the fact that<br />
58<br />
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GENDER DISCRIMINATION AND ITS CONSEQUENCES<br />
the pharmacist earns less money<br />
than she did before termination of<br />
her employment because fewer<br />
hours are available in her new position<br />
than had been available to her<br />
during her employment with the<br />
defendant.<br />
The pharmacy contends that a<br />
19-year award is excessive. However,<br />
the award of lost income of 19 years<br />
is consistent with the pharmacist’s<br />
anticipated retirement age of 65<br />
years. Based on her 10-year employment<br />
history with the pharmacy,<br />
her testimony that she had planned<br />
to continue working there for the<br />
remainder of her career, and with<br />
the limited number of pharmacies<br />
in the area around Pittsfield, the<br />
jury permissibly could have concluded<br />
that an award of 19 years<br />
was appropriate.<br />
As to the punitive damages, the<br />
pharmacy claimed there was insufficient<br />
evidence to justify the award.<br />
Concluding that the pharmacy had<br />
presented no evidence that it knowingly<br />
or intentionally violated the<br />
antidiscrimination statute, 7 and that<br />
there was no evidence that its conduct<br />
was otherwise outrageous, evil<br />
in motive, or could be viewed as<br />
exhibiting a reckless indifference for<br />
the pharmacist’s rights, the judge<br />
reversed the jury’s finding on the<br />
punitive damages award.<br />
Under existing Massachusetts law,<br />
punitive damages may be awarded<br />
for conduct that is outrageous,<br />
because of the defendant’s evil<br />
motive or his reckless indifference to<br />
the rights of others. These cases have<br />
held that if a defendant knows that<br />
it has acted unlawfully by interfering<br />
with the legally protected rights of<br />
the plaintiff, such “reckless indifference”<br />
to the rights of others constituted<br />
conduct warranting “condemnation<br />
and deterrence,” sufficient to<br />
support an award of punitive damages.<br />
That the defendant acted with<br />
the knowledge that it was interfering<br />
with the plaintiff’s right to be free of<br />
unlawful discrimination, however,<br />
has been only one circumstance warranting<br />
an award of punitive damages.<br />
If the defendant’s act was otherwise<br />
outrageous, egregious, evil in<br />
motive, or undertaken with reckless<br />
indifference to the rights of others,<br />
an award of punitive damages has<br />
been allowed.<br />
There was evidence that the pharmacy<br />
had policies prohibiting harassment,<br />
from which a jury could infer<br />
that the pharmacy was aware that<br />
gender discrimination was not<br />
legally permitted. In addition, there<br />
was sufficient evidence of reprehensible<br />
or recklessly indifferent conduct<br />
to support an award of punitive<br />
damages. The pharmacy maintained<br />
policies prohibiting harassment and<br />
“inappropriate conduct.” The pharmacy<br />
training manuals provided for<br />
“coaching” on “harassment/inappropriate<br />
conduct.” The pharmacy considered<br />
“serious harassment/inappropriate<br />
conduct” to be “gross<br />
misconduct” justifying immediate<br />
termination without the possibility<br />
of future rehire.<br />
The pharmacy contended that<br />
the award of $1 million in punitive<br />
damages was excessive. In considering<br />
whether an award of punitive<br />
damages is excessive in a gender discrimination<br />
case, Massachusetts law<br />
requires consideration of three factors:<br />
1) the degree of reprehensibility<br />
of the defendant’s conduct; 2)<br />
the ratio of the punitive damage<br />
award to the actual harm inflicted<br />
on the plaintiff; and 3) a comparison<br />
of the punitive damages award<br />
and the civil or criminal penalties<br />
that could be imposed for comparable<br />
misconduct. An award of punitive<br />
damages also requires a heightened<br />
finding beyond mere liability<br />
and also beyond a knowing violation<br />
of the statute. Punitive damages<br />
may be awarded where the defendant’s<br />
conduct is outrageous or egregious.<br />
Punitive damages are warranted<br />
where the conduct is so<br />
offensive that it justifies punishment<br />
and not merely compensation. In<br />
making an award of punitive damages,<br />
the jury must find that the<br />
award is needed to deter such<br />
behavior toward the class of which<br />
the plaintiff is a member, or that the<br />
defendant’s behavior is so egregious<br />
that it warrants public condemnation<br />
and punishment. According to<br />
this court, the jury was justified in<br />
concluding that the pharmacy’s pattern<br />
of unequal treatment of male<br />
and female pharmacists was outrageous<br />
and reprehensible. For these<br />
reasons, the punitive damage award<br />
for Ms. Haddad was reinstated.<br />
Conclusion<br />
In this day and age, there is no reason<br />
to differentiate compensation or<br />
enforcement of policies based on<br />
gender alone. As the court found, the<br />
facts of this case were so egregious as<br />
to be without any reasonable explanation.<br />
This conduct not only justified<br />
compensatory damages due the<br />
female pharmacist for her disparate<br />
treatment but punitive damages to<br />
deter such discrimination in the<br />
future. It took a long time against<br />
formidable odds for this pharmacist<br />
to be vindicated. In the end, maybe<br />
this case will make pharmacy a better<br />
profession for all its practitioners,<br />
male and female alike.<br />
Author’s Note: At the time this article was<br />
submitted for publication, the defendant corporation<br />
had not paid the judgment. According<br />
to the plaintiff’s attorney, Richard E.<br />
Fradette, RPh, JD, the company was haggling<br />
over the payment of pre- and postjudgment<br />
interest and attorney fees. According to<br />
his estimate, those fees are accumulating at<br />
approximately $900 per day that the judgment<br />
remains unpaid. This is just further<br />
evidence of how difficult it is to bring and<br />
prevail in cases like this one.<br />
REFERENCES<br />
1. Eisenhower DD. Quotations Book. http://quotationsbook.com/<br />
quote/45318/. Accessed November 5, 2009.<br />
2. Haddad v. Wal-Mart, Slip Op No SJC-10261 (October 5, 2009),<br />
2009 Mass Lexis 654.<br />
3. The trial was discussed in an earlier column. Vivian JC.<br />
David victorious over Goliath. US Pharm. 2007;32(10):58-60.<br />
www.uspharmacist.com/content/d/pharmacy_law/c/10228/.<br />
Accessed October 13, 2009.<br />
4. The final judgment estimate was provided by Richard E.<br />
Fradette, RPh, JD, counsel for the plaintiff, in an e-mail to the<br />
author dated October 29, 2009.<br />
5. GL c 112, §§ 24, 39; 247 Code Mass Regs §§ 6.01, 6.02, 6.07.<br />
6. Pretext. Law Dictionary. www.law-dictionary.org/PRETEXT.<br />
asp?q=PRETEXT. Accessed October 13, 2009.<br />
7. GL c 151B.<br />
60<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
2 CE Credits<br />
Prescription Drug Abuse<br />
Strategies to Reduce Diversion<br />
Law CE<br />
Imagine a cocktail of<br />
morphine, Demerol<br />
(meperidine), codeine,<br />
chlorpheniramine, Placidyl<br />
(ethchlorvynol), and Valium<br />
(diazepam). These and other<br />
drugs were found in “significant<br />
quantities” in the<br />
tissues of Elvis Presley upon<br />
his death in 1977 from a<br />
suspected drug overdose. 1<br />
More than 30 years later,<br />
the actor Heath Ledger, who<br />
was found dead from a drug<br />
overdose, had Vicodin<br />
(hydrocodone), OxyContin<br />
(oxycodone), diazepam, and<br />
alprazolam in his bloodstream. 2 What is especially noteworthy<br />
in these two high-profile cases was that none of<br />
these substances are illegal drugs, but rather medications<br />
that can be readily obtained by almost anyone through<br />
normal, legal channels with a prescription. Although the<br />
abuse of legal prescription drugs may garner headlines when<br />
well-known celebrities like these are involved, most of the<br />
lay public and many health professionals equate drug abuse<br />
with illegal street drugs. However, the problem of prescription<br />
drug abuse has become increasingly prevalent.<br />
A number of reports have shown that the abuse of<br />
prescription drugs, especially opiates, stimulants, and<br />
sedatives, has reached alarming proportions, particularly<br />
among teenagers. 3 In fact, prescription drugs have become<br />
the second most abused drug, behind only marijuana,<br />
among young people aged 12 to 17 years, and the gap is<br />
shrinking. 3 Teen abuse of prescription drugs has become<br />
so pervasive that the Partnership for a Drug-Free America<br />
has introduced the term “Generation Rx” to refer to these<br />
adolescents. 4 Helping to fuel the rise in this trend of drug<br />
abuse is the perception among young people and their<br />
parents that legal prescription drugs provide a safer high<br />
than street drugs. Health professionals, especially pharmacists,<br />
need to be aware of the potential<br />
for prescription drug abuse and to<br />
recognize their responsibility to limit<br />
the diversion of legitimate, beneficial<br />
U.S. <strong>Pharmacist</strong> Continuing Education<br />
GOAL: To provide pharmacists with an understanding of the<br />
diversion and abuse of prescription drugs and the legal issues<br />
designed to limit diversion.<br />
OBJECTIVES: After completing this activity, participants<br />
should be able to:<br />
1. Describe the demographics of prescription drug abuse.*<br />
2. Identify the dangers associated with the nonmedical use of<br />
prescription drugs.*<br />
3. Recognize the patient characteristics and techniques that<br />
may suggest the possibility of diversion.*<br />
4. Discuss the legal risks and responsibilities that arise from<br />
the diversion of drugs.*<br />
5. Implement strategies to reduce diversion.<br />
* Also applies to pharmacy technicians.<br />
Gerald Gianutsos, PhD, JD<br />
Associate Professor of Pharmacology<br />
University of Connecticut School of Pharmacy<br />
Storrs, Connecticut<br />
medications to those who<br />
would misuse them.<br />
This review will examine<br />
the problem of prescription<br />
drug abuse and what<br />
the pharmacist can do to<br />
recognize and minimize<br />
the problem of drug diversion.<br />
<strong>Pharmacist</strong>s should<br />
also be aware that abuse<br />
of legal drugs does not end<br />
with prescription medications;<br />
OTC drugs are also<br />
widely prone to abuse,<br />
especially by adolescents,<br />
and the interested pharmacist<br />
is directed to other<br />
resources for further information. 5<br />
Patterns of Prescription Drug Abuse<br />
Demographics: It is undeniable that the abuse of prescription<br />
medications is on the rise. Recent surveys report that<br />
the number of Americans abusing prescription drugs is<br />
approaching 7 million. From 2000 to 2006, there was an<br />
80% increase in prescription drug abuse, and it has now<br />
become more common than the number of individuals<br />
who are abusing street drugs like cocaine, heroin, hallucinogens,<br />
Ecstasy, and inhalants combined. 6 The use of<br />
illegal drugs has generally tended to show a gradual decline<br />
over the past decade, but the misuse of prescription drugs,<br />
especially sedatives, opiates, and stimulants, has grown<br />
over the same period. 7<br />
The age group most likely to abuse prescription drugs<br />
is individuals between 18 and 25 years of age, although<br />
younger groups and even the elderly are not immune. 8<br />
Among adolescents, opiates are the most popular prescription<br />
drugs. 9 OxyContin use increased for all grades from<br />
2002 to 2007. The annual prevalence of use in 2007 was<br />
1.8%, 3.9%, and 5.2% in grades 8, 10, and 12, respectively.<br />
Vicodin abuse occurred at higher levels but remained fairly<br />
constant over the same time period,<br />
with prevalence rates of 2.7%, 7.2%,<br />
and 9.6% in grades 8, 10, and 12,<br />
respectively. 9 High rates of use of pre-<br />
61<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
scription drugs are also noted in college students and young<br />
adults. 10 Other classes of prescription drugs frequently<br />
diverted by adolescents include tranquilizers and stimulants.<br />
10,11 Among teens, 10% have abused Adderall (amphetamine<br />
and dextroamphetamine) or Ritalin (methylphenidate)<br />
compared with 9% having tried crack cocaine. 11<br />
While white males are the most common demographic<br />
among prescription abusers overall, in the younger 12-<br />
to 17-year-old age group, girls are more likely to abuse<br />
prescription drugs than boys, with stimulants and<br />
sedatives being the most popular among adolescent<br />
girls. 8,9 Across all age groups, women are more likely<br />
to abuse prescription drugs than illegal drugs. 12 Data<br />
suggest that prescription abuse is highest in small metropolitan<br />
areas compared with larger metropolitan or<br />
rural areas, which may be related to the availability,<br />
purity, and cost of heroin in a local region. 13<br />
A significant factor in the growth of prescription<br />
drug abuse is the ease with which these drugs can be<br />
obtained. Young people are readily able to secure prescription<br />
drugs; 40% of 12th-graders reported that painkillers<br />
are “fairly” or “very” easy to get, and more than half<br />
say the same thing for stimulants. 14 The majority of teens<br />
indicate that prescription drugs are easier to obtain than<br />
illicit dugs, and more than half say they abuse prescription<br />
painkillers because they are not illegal. Teens also<br />
believe that there is less shame attached to using these<br />
drugs (33%) and that their parents would not be as<br />
concerned if they got caught (21%). This mirrors the<br />
perception among parents that prescription drug abuse<br />
is a safer alternative to street drug use.<br />
Nearly two-thirds (64%) of teenagers who have abused<br />
prescription drugs reported receiving, buying, or stealing<br />
them from friends or relatives; almost half (46%) say they<br />
got prescription pain relievers for free from a relative or<br />
friend. 14 Thus, in many cases, the procuring of prescription<br />
drugs does not entail the same risks and consequences<br />
associated with traditional drug dealing. Another 9% said<br />
they bought pain relievers from a friend or relative, while<br />
5% took the drugs without asking. Only 4% had to resort<br />
to buying them from a drug dealer. 14<br />
Relationship to Increased Use of Prescription Drugs:<br />
<strong>Pharmacist</strong>s are well aware that total prescription volume<br />
is on the rise. Could the escalating abuse of prescription<br />
drugs be a reflection of the increased prescribing of drugs<br />
in the population generally and not an unusual phenomenon?<br />
Data fail to support this view. Between 1992 and<br />
2002, the increase in the number of prescriptions written<br />
for scheduled drugs outpaced the rate of increase in nonscheduled<br />
drugs and the growth in the population by 3-<br />
and 12-fold, respectively. 13<br />
Overall, opiates represent three-fourths of the volume<br />
of prescription drugs that are abused. 8 The number of<br />
people using analgesics for nonmedical reasons increased<br />
four-fold from 1980 to 1998 and shows little sign of abating.<br />
8 Retail sales of methadone increased almost 10-fold<br />
between 1997 and 2005, 11 while the number of prescriptions<br />
for hydrocodone and oxycodone increased 376% and<br />
380%, respectively, from 1992 to 2002. 15 This compares<br />
with an overall increase in prescription volume of 61% and<br />
a population growth of 12% over the same time frame. 15<br />
It is clear that the prescribing of scheduled drugs in general,<br />
and opiates in particular, has far outpaced the increase in<br />
use of most other drug classes. Part of this growth is related<br />
to an appropriate increased emphasis on and recognition<br />
of pain management, and reflects a legitimate expansion<br />
of prescription use. However, the disproportionate increase<br />
in the availability of opiate drugs in the supply chain can<br />
also lead to increased diversion into the hands of abusers.<br />
Dangers of Prescription Drug Abuse<br />
The increased misuse of prescription drugs has coincided<br />
with increased risks and mortality. Death from drugs is<br />
the second leading cause of accidental death in the U.S.,<br />
exceeded only by motor vehicle accidents. 16 According to<br />
the CDC, unintentional drug overdose deaths increased<br />
68% between 1999 and 2004. 17 In a recent study from<br />
West Virginia, 63% of deaths due to unintentional overdose<br />
of prescription drugs were associated with diversion<br />
of the drug (i.e., there was no documented prescription<br />
for the deceased person), while another 21% involved<br />
persons who had obtained prescriptions for controlled<br />
substances from five or more physicians (representing<br />
probable “doctor shopping”). 18 These data indicate that<br />
the primary cause of overdose death from prescription<br />
drugs results from their nonmedical use. Prescription drug<br />
overdose associated with diversion most closely resembles<br />
the profile of traditional abusers of street drugs, being<br />
highest in unmarried men and in the 18- to 24-year-old<br />
group. 17 This group was also more likely to have a history<br />
of other substance abuse and to combine prescription<br />
drugs with illicit drugs. In contrast, overdose linked to<br />
doctor shopping was highest in the group aged 35 to 44<br />
years and was more likely to involve women. 18<br />
Nationally, the number of opioid analgesic poisonings<br />
listed on death certificates increased 91% between 1999<br />
and 2002, while poisonings due to heroin and cocaine<br />
increased by much smaller percentages (12.4% and 22.8%,<br />
respectively). 11 Emergency room admissions for prescription<br />
opioid use increased 74% from 2002 to 2006, and<br />
the misuse of opioid analgesics now results in more drug<br />
overdose deaths than cocaine and heroin combined. 16<br />
Overall, the nonmedical use of controlled prescription<br />
drugs is estimated to cost the health care system more<br />
than $72 billion annually. 16<br />
Nearly one-third of new drug abusers report that their<br />
first experience involved a prescription drug, with 19%<br />
citing opioids. 16 These data highlight the risks associated<br />
with the intentional misuse of prescription drugs and are<br />
contrary to the belief among adolescents and their parents<br />
that prescription drug abuse represents a safer alternative<br />
62<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
Table 1<br />
Methods Used to Obtain Prescription<br />
Drugs for Purposes of Abuse<br />
• “Doctor shopping” (i.e., seeing more than one<br />
physician for the same prescription)<br />
• Traditional drug dealing<br />
• Theft from pharmacies or homes, including family<br />
members taking someone else’s drugs from a<br />
medicine cabinet<br />
• Acquiring prescription drugs via the Internet without<br />
a physician visit<br />
• Receiving drugs from friends or relatives<br />
• Buying drugs from patients leaving clinics<br />
• Feigning legitimate illness (e.g., sports injuries,<br />
anxiety) to obtain a prescription<br />
Source: References 6, 20.<br />
to street drug use. Criminal activity, including thefts and<br />
robberies from pharmacies, is an additional risk. 19<br />
Methods of Prescription Drug Diversion<br />
Surveys by the National Center on Addiction and Substance<br />
Abuse (CASA) at Columbia University asked health care<br />
professionals and the public what they perceive to be<br />
responsible for diversion of prescription drugs from legitimate<br />
uses. 20 Individuals who may inappropriately acquire<br />
prescription drugs employ a variety of different means to<br />
obtain them (TABLE 1). 6,20<br />
Physicians: Among physicians, the main reason cited for<br />
diversion (96%) is doctor shopping, followed by patient<br />
manipulation or deception of the physician, and forged<br />
or altered prescriptions. 20 Clearly, physicians place the<br />
primary blame for diversion on patients who, they believe,<br />
either seek drugs from multiple sources, mislead the physician<br />
into making an inappropriate medical decision, or<br />
commit outright theft. Increased access to medical information<br />
on the Internet has facilitated the faking of apparently<br />
appropriate physical symptoms that can deceive the<br />
busy physician into issuing a prescription when it is not<br />
necessary to treat the patient. Nearly half the surveyed<br />
physicians, especially younger physicians, admitted that<br />
patients try to pressure them into prescribing a controlled<br />
drug. However, not all patients receiving prescriptions use<br />
the drugs themselves; some individuals may collect thousands<br />
of pills each year and sell them on the street, and<br />
there are also reports of patients supplementing Social<br />
Security income by selling all or part of their prescriptions. 9<br />
Physicians also admit to gaps in their medical school<br />
training that complicate their ability to detect misuse.<br />
Only 40% were trained in identifying prescription abuse<br />
and addiction. 20 Almost half of primary care physicians<br />
report that they find it difficult to discuss prescription<br />
drug abuse with patients for whom they prescribe the<br />
medications; fewer than half of the surveyed physicians<br />
asked about prescription drug abuse when taking a patient<br />
history, and one-third do not regularly call or obtain records<br />
from other treating physicians before prescribing controlled<br />
drugs on a long-term basis. 20<br />
<strong>Pharmacist</strong>s: Almost half (46%) of the pharmacists in<br />
one survey viewed diversion and abuse of prescription<br />
opioid analgesics as a problem in their community, and<br />
10% of these considered the problem as serious. 21<br />
<strong>Pharmacist</strong>s surveyed by CASA agreed with physicians<br />
on the three most common methods of diversion, but the<br />
order was slightly different. 20 <strong>Pharmacist</strong>s also felt that<br />
doctor shopping is the most common mechanism, followed<br />
by forged or altered prescriptions and patient manipulation<br />
of physicians. Less common methods were believed to be<br />
theft of prescription pads from physicians and deliberate<br />
diversion by physicians. In all, more than 60% of pharmacists<br />
believed that physicians bear the primary responsibility<br />
for preventing prescription abuse and addiction.<br />
Only half of the surveyed pharmacists agreed that they<br />
had received training in identifying prescription drug abuse<br />
and addiction, and less than half had received instruction<br />
in preventing diversion. 20 However, more than 25% of<br />
the pharmacists admitted that when a patient presents a<br />
prescription for a controlled drug, they “somewhat” or<br />
“very often” think it is for purposes of abuse or diversion.<br />
More than three-fourths of pharmacists said that they<br />
become somewhat or very concerned about abuse and<br />
diversion if a patient asks for a controlled drug by its brand<br />
name, believing that a brand name would have a higher<br />
resale value on the black market. Other circumstances that<br />
raise suspicions among pharmacists include a prescription<br />
with apparent irregularities; the patient’s lack of familiarity<br />
with the prescribing physician; a patient and/or prescribing<br />
physician from out of town; the patient’s demeanor<br />
(overly friendly, nervous, or aberrant); or the patient trying<br />
to pay in cash instead of using insurance. Some pharmacists<br />
admit to relying on their “gut instinct.”<br />
Although pharmacists may believe that physicians bear<br />
the primary responsibility for preventing prescription abuse,<br />
pharmacists are reminded that they share the responsibility<br />
for preventing diversion. The Controlled Substance Act<br />
(CSA) mandates that only prescription orders for controlled<br />
substances that are for a “legitimate medical purpose” and<br />
issued in the “usual course of professional practice” may<br />
be dispensed by a pharmacist. 22 The Drug Enforcement<br />
Agency (DEA) reminds pharmacists that while the primary<br />
responsibility for proper prescribing rests with the physician,<br />
the pharmacist who dispenses the prescription has a corresponding<br />
responsibility. A pharmacist who “knowingly”<br />
fills a prescription that is not issued in the usual course of<br />
professional treatment is subject to the penalties of the<br />
CSA. 22 The pharmacist is required to exercise sound professional<br />
judgment when determining the legitimacy of a<br />
prescription for a controlled substance. The pharmacist<br />
63<br />
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PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
who “looks the other way” and fills a prescription for a<br />
controlled substance that he or she knew or should have<br />
known was not for a legitimate purpose may be prosecuted.<br />
Merely contacting the physician for verification that the<br />
prescription was written by that prescriber may not be<br />
sufficient to fulfill the pharmacist’s duty, and the pharmacist<br />
should refuse to fill the prescription if there is reasonable<br />
suspicion that it is not valid. The DEA has established<br />
criteria that can serve as guidelines for a pharmacist to<br />
potential prescribing for illegitimate purposes or prescriptions<br />
that are not legitimate (TABLE 2). Of course, these are<br />
guidelines, and nothing can substitute for the pharmacist’s<br />
own experience and knowledge of the community. Recently,<br />
a major national pharmacy chain was fined $5 million by<br />
the DEA for CSA violations. 23<br />
<strong>Pharmacist</strong>s are also reminded that under federal and<br />
state laws, a controlled-substance prescription issued to an<br />
addict or habitual user for the purpose of keeping him or<br />
her comfortable (i.e., avoiding withdrawal) is not considered<br />
to be a valid prescription, since this is outside of the<br />
scope of legitimate medical purpose (except for patients<br />
enrolled in a licensed treatment program). 22<br />
Studies suggest that many pharmacists do not know<br />
what constitutes legitimate dispensing practices for controlled<br />
substances under federal or state policy in emergencies<br />
or for patients with terminal illnesses, especially<br />
for noncancer patients. 21 Only 29% of pharmacists<br />
“strongly agreed” that their knowledge of relevant controlled-substance<br />
regulation was adequate. 21 <strong>Pharmacist</strong>s,<br />
like physicians, also believe that there are gaps in their<br />
Table 2<br />
DEA Criteria That Indicate a<br />
Prescription May Not Be for a<br />
Legitimate Medical Purpose<br />
• A prescriber’s prescription pattern is different<br />
from that of other prescribers in the area (e.g.,<br />
more prescriptions for controlled substances or<br />
prescriptions for larger quantities of controlled drugs)<br />
• Prescriber writes for antagonistic drugs (e.g.,<br />
stimulant and depressant at the same time)<br />
• Patient returns to the pharmacy more frequently than<br />
expected (e.g., prescription quantities do not last as<br />
long as expected)<br />
• Patient presents multiple prescriptions for the same<br />
drug written for different people<br />
• A number of people appear within a short time period<br />
for the same controlled drug from the same physician,<br />
or a large number of previously unknown patrons<br />
show up with prescriptions from the same physician<br />
• The patron presents a prescription that shows<br />
evidence of possible forgery (e.g., unusual directions<br />
or quantities, no abbreviations, apparent erasures,<br />
unusual legibility, evidence of photocopying)<br />
DEA: Drug Enforcement Agency. Source: Reference 22.<br />
education with respect to drug abuse. More than twothirds<br />
of pharmacists reported that they received 2 hours<br />
or less of addiction and substance abuse education in<br />
pharmacy school, and almost 30% received no addiction<br />
education. 24 Many pharmacists are also unaware of the<br />
important distinctions among addiction, physical dependence,<br />
and tolerance. Significantly, more than half of the<br />
pharmacists said that they had never referred a patient<br />
to a drug treatment program.<br />
<strong>Pharmacist</strong>s also need to be on the lookout for fraudulent<br />
prescriptions. Patients may alter a legitimate prescription,<br />
steal prescription pads, copy prescriptions (or<br />
scan and print legitimate prescriptions), or create authentic-looking<br />
prescription blanks with a real physician’s<br />
name but a fake phone number, which would be answered<br />
if the pharmacist called to verify. 22 Modern technology<br />
has made these fraudulent prescriptions even more difficult<br />
to detect.<br />
When pharmacists were asked what they would do if<br />
they suspected a patient of abusing or diverting a controlled<br />
prescription drug, the most common responses<br />
were to call the prescribing physician (93%) or refuse to<br />
dispense the prescription (76.6%). 20 Less than half would<br />
call the police. Only 1.7% said they would take no action,<br />
justifying their inaction as due to fear of reprisal by the<br />
patient or their employer. 20<br />
Patients may not obtain their drugs from a pharmacy<br />
by fraudulent means but may resort to theft. The CASA<br />
survey revealed that 29% of pharmacists had experienced<br />
a theft or robbery of prescription drugs in the preceding<br />
5 years, most commonly involving OxyContin. 20 Moreover,<br />
21% of pharmacies would not stock certain controlled<br />
drugs, including OxyContin, Percocet, and Percodan, in<br />
an effort to reduce diversion. 20<br />
Data from the DEA reveal that in the period from<br />
2000 through 2003, nearly 28 million dosage units of<br />
controlled substances were diverted by theft or loss from<br />
lawful channels, including pharmacies, of which 24%<br />
were opioid analgesics (primarily hydrocodone, oxycodone,<br />
morphine, methadone, meperidine, hydromorphone,<br />
and fentanyl); these figures are believed to represent<br />
underreporting of the true incident rate. 25 These data<br />
provide evidence that a considerable volume of drug<br />
diversion occurs through criminal actions even before<br />
being prescribed. 12,25<br />
Approximately 6,500 pharmacy thefts occur annually<br />
in the U.S. 25 Among retail pharmacies, about half the<br />
thefts are attributed to employees, with the remainder<br />
being attributed to individuals who break into pharmacies<br />
or clinics or commit armed robberies to acquire the drugs.<br />
Individuals also steal pharmaceuticals from friends or<br />
relatives who possess legitimate prescriptions. 19<br />
Role of the Internet<br />
The Internet has brought many changes to the practice<br />
of pharmacy and medicine. Among them is the strongly<br />
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PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
held belief that it is a source of diversion for prescription<br />
drugs, especially for Schedule III and IV drugs. 26 A report<br />
from CASA states that “drugs continue to be as easy to<br />
buy over the Internet as candy.” 27 According to the report,<br />
89% of sites selling controlled drugs have no prescription<br />
requirement; and of the 11% that do require a prescription,<br />
70% only require a faxed copy that can be easily<br />
forged. Many Internet sites dispense drugs after a patient<br />
completes an online questionnaire, which may or may not<br />
have been reviewed by a physician. The most commonly<br />
sold drugs on these sites are anxiolytics like diazepam and<br />
lorazepam, followed closely by OxyContin and Vicodin. 27<br />
Of the total sites identified in 2006, slightly less than half<br />
were portal sites (acting as a conduit to a retailer) and the<br />
rest were anchor sites (which sell the drug to and receive<br />
payment from the consumer). The anchor site may or<br />
may not operate the pharmacy where the prescription is<br />
actually filled and may not even be located in the same<br />
geographic area as the dispensing pharmacy. Indeed, many<br />
sites operate beyond the borders of the U.S.<br />
Many of the illegitimate Internet sites are run by non-<br />
DEA registrants without medical or pharmacy training. 26<br />
These sites typically work with physicians who approve<br />
the prescription, frequently targeting young graduates with<br />
significant debt or retired practitioners looking for additional<br />
sources of income. In many cases, the prescriber<br />
reviews an online questionnaire, bypassing the accepted<br />
patient-prescriber relationship and contrary to the accepted<br />
standard of medical care. In one documented case, a Texas<br />
physician authorized over 20,000 prescriptions without<br />
ever meeting a single patient or verifying any medical<br />
information. 12 Some of the rogue Internet pharmacy sites<br />
claim that a physician may contact the patient via telephone<br />
or e-mail while others attempt to distance themselves from<br />
the requirement for consultation by claiming that they are<br />
merely providing a referral service. 27 The DEA also noted<br />
an absence of protection against minors obtaining potentially<br />
dangerous drugs through this process, citing an<br />
example of a 13-year-old who obtained methylphenidate<br />
after accurately filling out the form with his correct height,<br />
weight, and age. 26<br />
The Internet facilitators also recruit pharmacies, often<br />
targeting small, struggling independents. 26,27 The facilitator<br />
will tell the pharmacist that all he or she has to do<br />
is prepare and ship prescriptions to customers, and provide<br />
reassurance to the pharmacist that the prescriptions<br />
are only for Schedule III or Schedule IV substances and<br />
have been “approved” by a physician. In addition to<br />
paying the pharmacy for the cost of the drug, the Internet<br />
facilitator will pay the pharmacy an agreed-upon<br />
amount that may total into the millions of dollars. The<br />
DEA has seen pharmacies close their doors completely<br />
to walk-in patients and convert their entire business to<br />
filling Internet orders. The DEA estimates that controlled<br />
substances represent 11% of prescription volume at a<br />
typical brick-and-mortar pharmacy, but may constitute<br />
Table 3<br />
Behavioral Traits That Might<br />
Trigger Suspicion of Drug Abuse<br />
• Depression<br />
• Loss of interest in personal appearance or activities<br />
that used to bring enjoyment<br />
• Low self-esteem<br />
• Feelings that the individual does not fit in or<br />
is not popular<br />
• Feeling sluggish or exhibiting sleep disturbances<br />
• An aggressive or rebellious attitude toward<br />
authority figures<br />
• Difficulty paying attention<br />
• A shift in pattern of attending social functions<br />
• Vague physical complaints that the subject indicates<br />
need to be treated by drugs or exaggeration of<br />
medical problems<br />
• A family history of substance or alcohol abuse<br />
• Seeing multiple physicians for prescriptions<br />
(“doctor shopping”)<br />
• Frequently borrowing money or having unexpected<br />
extra cash<br />
Source: References 6, 14, 20, 29.<br />
as much as 95% at rogue Internet pharmacies. 26 With a<br />
typically higher prescription volume, the DEA estimates<br />
that rogue Internet pharmacies may sell 20-fold more<br />
prescriptions for controlled substances each day than the<br />
normal brick-and-mortar pharmacy. 26 At least one study,<br />
however, suggests that the Internet is overestimated as a<br />
direct source for illicit drug procurement. 28<br />
Warning Signs<br />
What can a concerned parent, pharmacist, or other<br />
health professional do to prevent or stop prescription<br />
drug abuse? Individuals who are prone to abusing prescription<br />
drugs do not advertise the fact but often exhibit<br />
certain traits that can be signals to health professionals<br />
or loved ones that the person is at risk and may need<br />
monitoring or intervention. Some behavioral traits that<br />
experts believe might trigger suspicion of drug abuse are<br />
listed in TABLE 3. 6,14,20,29 Patients may also employ various<br />
deceptive practices when dealing with health professionals<br />
in order to procure prescriptions or products for<br />
illicit purposes (TABLE 4). 20<br />
Patients who are concerned about their own risk of<br />
abuse and are seeking guidance can be directed by the<br />
pharmacist to the CAGE questionnaire, first proposed<br />
more than 25 years ago as a screening mechanism to detect<br />
alcoholism. 30 The questionnaire has been adapted for<br />
prescription drug abuse, where patients ask themselves<br />
four questions (TABLE 5). 31 The patient who answers two<br />
or more questions affirmatively may be showing indications<br />
of a probable drug addiction. Even a single affirmative<br />
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PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
Table 4<br />
Deceptive Practices Used<br />
to Procure Prescriptions<br />
• The patient must be seen right away<br />
• The patient is visiting friends or relatives or is<br />
passing through town and cannot see his or her<br />
regular physician<br />
• The individual claims to be a patient of a practitioner<br />
who is unavailable, or will not name the practitioner<br />
• The individual requests only specific drug brand<br />
names and is reluctant to try an alternative or<br />
claims to be “allergic” or nonresponsive to<br />
nonopiate alternatives<br />
• The patient shows unusual knowledge of controlled<br />
substances<br />
• The patient claims that his or her prescription has<br />
been lost or stolen<br />
• The patient pressures the practitioner by eliciting<br />
sympathy or guilt or uses direct threats<br />
• The patient uses a surrogate, such as a child, when<br />
seeking methylphenidate, or an elderly person when<br />
seeking opiates<br />
Source: Reference 20.<br />
answer may deserve further evaluation and should be<br />
referred to a health care professional.<br />
Prescription Drug Monitoring Programs<br />
Regulators have taken several steps in an attempt to minimize<br />
the diversion of prescription products and the<br />
proliferation of prescription drug abuse. One measure that<br />
has grown over the past decade is the institution of national<br />
or local prescription monitoring programs that attempt<br />
to detect suspicious patterns of controlled-substance use.<br />
Federal Programs: Nationally, the National All Schedules<br />
Prescription Electronic Reporting (NASPER) Act was<br />
signed into law in August 2005. 32 The intent of NASPER<br />
was to establish a national electronic system that would<br />
monitor Schedule II, III, and IV controlled-substance<br />
prescriptions. It would be administered by the states and<br />
would enable health care providers to have timely and<br />
accurate access to prescription history information that<br />
could be used in the early identification of patients at risk<br />
for addiction or diversion and would encourage appropriate<br />
medical intervention. 32,33<br />
Under this law, each time a controlled substance was<br />
dispensed, the pharmacist would be required to report<br />
to Health and Human Services (HHS) specific information<br />
about the controlled substance, including: 1) identifying<br />
the patient; 2) name, date, and quantity of the<br />
drug dispensed; 3) number of refills ordered; 4) practitioner<br />
who signed the prescription; and 5) identity of<br />
the dispenser. Compilations of this information would<br />
be provided to practitioners (i.e., physicians, pharmacists,<br />
other licensed persons) who certify that they need this<br />
information to provide care to a current patient. HHS<br />
would also be permitted to provide compilations of this<br />
information to any local, state, or federal law enforcement,<br />
narcotics control, licensure, or disciplinary authority<br />
requesting the information as part of an ongoing drug<br />
diversion investigation. 32<br />
NASPER attempts to minimize doctor shopping,<br />
particularly by users who cross state lines, a limitation of<br />
individual state programs (discussed later). In order to<br />
receive funding under the Act, a state must collect data<br />
on Schedules II, III, and IV drugs and must meet standards<br />
that enable data sharing. 34 In this way, users who try to<br />
circumvent local monitoring by presenting prescriptions<br />
in multiple locations would be subject to detection; this<br />
would be more difficult to monitor when done on a stateby-state<br />
basis. In 2007, the first pilot project was initiated<br />
for sharing of information between states (Nevada and<br />
California). 34 The measure was also supported by the<br />
National Association of Chain Drug Stores (NACDS),<br />
which favored uniform standards that would apply in all<br />
states where a chain operates pharmacies. The Act authorized<br />
$60 million from 2006 to 2010 for grants to establish<br />
or improve state-run prescription drug monitoring<br />
programs; however, funding has yet to be committed. 34<br />
State Programs: Although the federal program has been<br />
slow to launch, as of November 2008, 38 states had enacted<br />
legislation that would require prescription drug monitoring<br />
programs (32 are currently in operation and 6 are in<br />
the start-up phase). 34 However, the state programs vary in<br />
their design and requirements. A current summary of state<br />
programs can be found on the DEA Web site. 34 All of the<br />
states track Schedule II drugs and most, but not all, also<br />
track Schedule III and IV; some also include Schedule V<br />
drugs. An additional 11 states are reportedly considering<br />
legislation; the only holdouts at this time are Wisconsin<br />
and the District of Columbia. Every state program contains<br />
safeguards to protect patient confidentiality. Only those<br />
Table 5<br />
CAGE Questionnaire for<br />
Prescription Drug Abuse<br />
1 Have you ever felt the need to Cut down on your use<br />
of prescription drugs?<br />
2. Have you ever felt Annoyed by remarks your friends or<br />
loved ones made about your use of prescription drugs?<br />
3. Have you ever felt Guilty or remorseful about your use<br />
of prescription drugs?<br />
4. Have you Ever used prescription drugs as a way to<br />
“get going” or to “calm down”?<br />
Source: Reference 31.<br />
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PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
individuals who are authorized by statute or regulation<br />
can access the controlled-substance prescription information.<br />
34 Some state programs proactively notify physicians<br />
when their patients are seeing multiple prescribers for the<br />
same class of drugs, which should assist health care professionals<br />
in managing patients.<br />
One of the advantages noted by the DEA in an electronic<br />
information system is that it would eliminate the<br />
need for investigators to visit each location to obtain<br />
prescription information. 34 Some of the expected benefits<br />
of these programs include deterrence and identification of<br />
illegal activity such as prescription forgery, indiscriminate<br />
prescribing, and doctor shopping; the agency believes that<br />
it has already been successful in thwarting diversion in a<br />
number of states.<br />
The first state program, which many other states have<br />
used as a model, is the KASPER (Kentucky All Schedule<br />
Prescription Electronic Reporting) program, established<br />
in 1998 in Kentucky. 31 KASPER is a reporting system<br />
designed to be both a source of information for practitioners<br />
and pharmacists and an investigative tool for law<br />
enforcement personnel. KASPER tracks controlledsubstance<br />
prescriptions dispensed within the state and<br />
shows all scheduled prescriptions for an individual over<br />
a specified time period, the prescriber, and the dispenser.<br />
KASPER specifically indicates that it is not intended to<br />
prevent people from obtaining needed drugs or to decrease<br />
the number of doses dispensed. The state also claims that<br />
access to KASPER reports are carefully controlled through<br />
identity and credential checks and secure Web access.<br />
KASPER reports are available only to prescribers and<br />
dispensers for medical treatment of a current or prospective<br />
patient; law enforcement officers for a bona fide<br />
drug-related investigation; licensure boards for an investigation<br />
of a licensee; Medicaid for utilization review on<br />
a recipient; a grand jury by subpoena; and a judge,<br />
probation, or parole officer administering a drug diversion<br />
or probation program.<br />
Some states have approached the diversion problem<br />
in a different way. For example, a few states mandate the<br />
use of state-issued multiple-part prescription forms for<br />
Schedule II drugs that can be monitored. 35 <strong>Pharmacist</strong>s<br />
are cautioned to stay up to date on their state’s current<br />
requirements.<br />
Effects on Legitimate Use for Pain<br />
Although the abuse of prescription drugs has become a<br />
serious problem, the response by law enforcement and<br />
other concerned agencies to limit diversion has also created<br />
a therapeutic dilemma. At stake is whether the concern<br />
over diversion and the possibility of addiction impacts the<br />
legitimate treatment of pain by making prescribers reluctant<br />
to provide analgesic drugs or stigmatizing patients<br />
who receive chronic pain medications. 8<br />
In general, attitudes towards opioids in pain management<br />
have undergone cyclical changes over the past few<br />
decades. In the middle of the 20th century, irrational fear<br />
of addiction resulted in the withholding of opioids from<br />
patients until they were close to death, a position even<br />
held by the president of the American Medical Association<br />
(AMA) in the 1940s. 36 In the latter part of the 20th<br />
century, the pendulum swung in the opposite direction<br />
with the emergence of the apparently erroneous belief that<br />
chronic pain patients were immune to the risks of aberrant<br />
drug-seeking behavior. 36 The dilemma between appropriate<br />
pain management and the concern over the risk of<br />
addiction and diversion continues to influence the prescribing<br />
of opioid drugs today.<br />
In 2007, the American Pain Foundation conducted a<br />
survey of health care practitioners including primary care<br />
physicians, pain specialists, nurse practitioners, and physician<br />
assistants. 37 It found that more than three-fourths of<br />
the respondents felt that moderate-to-severe noncancer<br />
pain is undertreated in the U.S. The reasons for any<br />
undertreatment include many factors. Nearly 75% of<br />
surveyed physicians refrained from prescribing controlled<br />
drugs because of concern over addiction, and physicians<br />
were especially wary about prescribing controlled drugs<br />
to a patient with a history of drug or alcohol abuse. 11,37<br />
Nevertheless, 77% said that current drug control laws and<br />
policies impact their opioid-prescribing practices, and most<br />
practitioners felt that many of their patients face prejudices<br />
while filling their prescriptions for opioids.<br />
In a survey of pharmacists, a large number of respondents<br />
did not view the chronic prescribing or dispensing<br />
of opioids for more than several months to patients with<br />
chronic pain of malignant or nonmalignant origin as a<br />
lawful and acceptable medical practice, especially when<br />
the patient had a history of opioid abuse. 21<br />
Federal and state law and policy can also influence<br />
prescribing practices. For example, DEA regulations<br />
require that all prescriptions for controlled substances<br />
“be dated as of, and signed on, the day when issued.” 38<br />
However, longstanding federal law and DEA regulations<br />
provide no express requirement that a prescription be<br />
filled within a certain time frame after it was issued. In<br />
2007, the DEA issued a revised rule allowing practitioners<br />
to provide individual patients with multiple prescriptions<br />
to be filled sequentially for the same Schedule II controlled<br />
substance, with such multiple prescriptions having the<br />
effect of allowing a patient to receive up to a 90-day<br />
supply of the controlled substance, a benefit for the<br />
terminally ill. 38<br />
Individual states, however, can have more restrictive<br />
policies, and pharmacists need to be aware of the policies<br />
in their state. Currently, 47 states and the District<br />
of Columbia have pain management policies (i.e., from<br />
a medical or pharmacy board), the exceptions being<br />
Alaska, Delaware, Illinois, and Indiana at the time this<br />
lesson was prepared. 39 For example, pain policies in<br />
eight states restrict the quantity of prescription medications<br />
that can be prescribed and dispensed at one time,<br />
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PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
stipulating either a maximum number of dosage units<br />
(100-120) or duration (30-day or 1-month supply)<br />
irrespective of patient need. 39 Similarly, the number of<br />
days within which a prescription for a controlled substance<br />
must be dispensed following its issuance is not<br />
regulated by federal law or the laws of most states.<br />
However, policies in some states restrict the length of<br />
time that a Schedule II prescription is valid to less than<br />
2 weeks; the state of Hawaii limits the period of validity<br />
to as little as 3 days. These policies are established<br />
in an apparent effort to prevent “uncashed,” although<br />
valid, prescriptions from being used as a possible source<br />
of diversion. 39<br />
Other policies that can affect pain management include<br />
statutes in 14 states and regulations in two states that<br />
classify physical dependence as synonymous with addiction,<br />
effectively making a prescription that is being used<br />
to reduce withdrawal in a terminally ill patient an invalid<br />
prescription. 39 Other state policies reserve opioids as a<br />
treatment of last resort, recommend drug holidays as a<br />
part of prescribing, or limit the off-label use of certain<br />
drugs. Other polices exist that impact pharmacy practice;<br />
for example, Michigan and Oregon have legislation<br />
mandating continuing education about pain management<br />
for pharmacists. 39<br />
Summary and Conclusions<br />
It is clear that many of the prescriptions dispensed by<br />
pharmacists each year are diverted for inappropriate<br />
use and that this problem is growing, particularly<br />
among adolescents. Patients may receive prescriptions<br />
from multiple physicians or deceive physicians into<br />
writing prescriptions for the wrong reasons. Other<br />
individuals receive or purchase unwanted drugs from<br />
family or friends, while some resort to outright theft<br />
from family or pharmacies.<br />
The pharmacist needs to be aware of the potential<br />
for drug diversion, recognize the warning signs of possible<br />
misuse, and acknowledge a legal obligation to<br />
minimize the use of prescription drugs for improper<br />
purposes. <strong>Pharmacist</strong>s also need to proactively disabuse<br />
the public of the notion that prescription drug abuse<br />
represents a safe alternative to street drugs, since statistics<br />
show that drug-induced morbidity and mortality<br />
continue to rise. In addition, pharmacists need to<br />
be aware of their state (and possible multistate or<br />
federal) prescription drug monitoring programs. By<br />
taking an active role in reducing the incidence of<br />
prescription drug abuse, the pharmacist makes a valuable<br />
contribution to society.<br />
References available online at www.uspharmacist.com.<br />
■ Disclosure Statements:<br />
Dr. Gianutsos has no actual or potential conflict of interest in relation to<br />
this activity.<br />
U.S. <strong>Pharmacist</strong> does not view the existence of relationships as an implication<br />
of bias or that the value of the material is decreased. The content of the activity<br />
was planned to be balanced, objective, and scientifically rigorous. Occasionally,<br />
authors may express opinions that represent their own viewpoint. Conclusions<br />
drawn by participants should be derived from objective analysis of<br />
scientific data.<br />
■ Disclaimer:<br />
Participants have an implied responsibility to use the newly acquired information<br />
to enhance patient outcomes and their own professional development. The information<br />
presented in this activity is not meant to serve as a guideline for patient<br />
management. Any procedures, medications, or other courses of diagnosis or treatment<br />
discussed or suggested in this activity should not be used by clinicians<br />
without evaluation of their patients’ conditions and possible contraindications or<br />
dangers in use, review of any applicable manufacturer’s product information,<br />
and comparison with recommendations of other authorities.<br />
EXAMINATION<br />
Select one correct answer for each question and record<br />
your responses on the examination answer sheet. Mail<br />
it to U.S. <strong>Pharmacist</strong>, address shown on the answer<br />
sheet (photocopies are acceptable). Please allow four<br />
weeks for processing. Alternatively, this exam can be<br />
taken online at www.uspharmacist.com. Please<br />
contact CE Customer Service at (800) 825-4696 or<br />
cecustomerservice@jobson.com with any questions.<br />
2 CE Credits<br />
Prescription Drug Abuse:<br />
Strategies to Reduce Diversion<br />
1. The abuse of prescription drugs by teenagers<br />
and young adults:<br />
A. Has become the second most common form of<br />
drug abuse<br />
B. Is common but less frequent than the abuse of<br />
cocaine or heroin<br />
C. Has gradually declined over the past decade<br />
D. Is less frequent than abuse in the 40- to 50-yearold<br />
age group<br />
2. The class of prescription drugs most commonly<br />
abused is:<br />
A. Stimulants C. Antianxiety drugs<br />
B. Opiates D. Steroids<br />
3. The percentage of teens who reported<br />
improperly receiving prescription pain relievers<br />
from friends and relatives for free is<br />
approximately:<br />
A. 10% C. Nearly half<br />
B. 25% D. Less than 1%<br />
4. The incidence of prescription drug abuse has<br />
increased:<br />
A. At the same rate as the growth of prescription<br />
volume<br />
B. Proportionally to the increase in the U.S. population<br />
68<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
PRESCRIPTION DRUG ABUSE: STRATEGIES TO REDUCE DIVERSION<br />
C. Much faster than both the increase in prescription<br />
volume and the population<br />
D. But has declined relative to population growth<br />
5. Death from drug overdose:<br />
A. Rarely occurs from accidental misuse<br />
B. Is the second leading cause of accidental death<br />
in the U.S.<br />
C. Occurs with either street drugs or prescription<br />
drugs, but is rarely seen as a combination<br />
of these<br />
D. Has declined in the past decade due to more<br />
available information on the dangers of drug use<br />
11. If a pharmacist has reason to believe that a<br />
prescription for a controlled substance has been<br />
written for a nonmedical purpose, he/she:<br />
A. May wish to take some action but is under no<br />
obligation to do so<br />
B. Fulfills his/her obligation if he/she contacts the<br />
physician and documents that the physician wrote<br />
the suspicious prescription<br />
C. Must fill the suspicious prescription if he/she can<br />
verify that it was written by a legitimate physician<br />
D. Should refuse to fill the prescription even if the<br />
physician verifies that he/she wrote the<br />
prescription<br />
6. Overdose from prescription drugs:<br />
A. Leads to more deaths than from heroin<br />
B. Is common, but trails far behind deaths attributed<br />
to heroin<br />
C. Is rare because the standardization of prescription<br />
drugs and dosing leads to greater safety<br />
D. Costs the U.S. health care system between<br />
$10 and $20 billion annually<br />
7. ______ of pharmacists surveyed considered<br />
prescription drug diversion a problem in their<br />
community.<br />
A. 10%<br />
B. 25%<br />
C. Nearly half<br />
D. More than 90%<br />
8. <strong>Pharmacist</strong>s believe that the biggest cause of<br />
prescription drug diversion is:<br />
A. Obtaining prescriptions for the same drug from<br />
different physicians<br />
B. Theft of prescription pads<br />
C. Theft from pharmacies<br />
D. Sale of illegitimate prescriptions by physicians<br />
9. When pharmacists were asked what<br />
they would do if they suspected a patient<br />
of abusing or diverting a controlled<br />
prescription drug, the most common<br />
answer was:<br />
A. Call the police or the DEA<br />
B. Refuse to fill the prescription<br />
C. Call the physician for verification<br />
D. Take no action<br />
10. The percentage of surveyed pharmacies<br />
experiencing thefts of prescription drugs over a<br />
5-year period is approximately:<br />
A. 5%<br />
B. 10%<br />
C. 30%<br />
D. 50%<br />
12. Which statement about Internet pharmacies<br />
is true?<br />
A. Internet pharmacies cannot supply Schedule II<br />
drugs<br />
B. Internet pharmacies using a patient<br />
questionnaire are complying with standard<br />
medical practice<br />
C. Many Internet pharmacies operate outside of the<br />
U.S. and are beyond the reach of the DEA<br />
D. The volume of controlled drug prescriptions from<br />
Internet pharmacies is roughly comparable to a<br />
traditional brick-and-mortar pharmacy<br />
13. Applying DEA guidelines, which of the<br />
following situations would not be a reason to<br />
question the legitimacy of a controlled drug<br />
prescription?<br />
A. A prescription is written too legibly<br />
B. A patient presents multiple prescriptions for the<br />
same drug for different people<br />
C. A patient is receiving large quantities of an opiate<br />
drug on a regular basis<br />
D. A patient presents prescriptions for an opiate and<br />
a stimulant at the same time<br />
14. “Doctor shopping” refers to:<br />
A. Seeking out a physician who will write a<br />
prescription for a controlled drug for a fee<br />
B. Obtaining prescriptions for the same controlled<br />
drug from multiple prescribers<br />
C. Paying other individuals to obtain a prescription<br />
for a controlled drug from a physician<br />
D. Buying prescriptions from unlicensed physicians<br />
operating on the Internet<br />
15. Which of the following situations has been<br />
cited as potentially raising a suspicion that a<br />
patient is misusing prescription drugs?<br />
A. The patient claims to be “allergic” to<br />
noncontrolled alternative medications<br />
B. The patient demands only a brand name of a<br />
controlled drug<br />
69<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
Examination Answer Sheet<br />
Credits: 2.0 hours (0.20 ceu)<br />
Expires: December 31, 2011<br />
This exam can be taken online at www.uspharmacist.com. Upon passing, you can<br />
print out your statement immediately and view your test history. Alternatively, you<br />
can mail this answer sheet to the address below. Please contact CE Customer<br />
Service at (800) 825-4696 or cecustomerservice@jobson.com with any questions.<br />
Prescription Drug Abuse:<br />
Strategies to Reduce Diversion<br />
Directions: Select one answer for each question in the exam and completely darken<br />
the appropriate circle. A minimum score of 70% is required to earn credit. An identifier<br />
is required to process your exam. This is used for internal processing purposes only.<br />
Mail to: U.S. <strong>Pharmacist</strong>–CE, PO Box 487, Canal Street Station, New York, NY 10013<br />
Check one:<br />
Payment:<br />
$6.50 per exam, fee enclosed<br />
Check is enclosed (payable to Jobson Medical Information LLC)<br />
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Signature:<br />
1. A B C D<br />
2. A B C D<br />
3. A B C D<br />
4. A B C D<br />
5. A B C D<br />
6. A B C D<br />
7. A B C D<br />
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14. A B C D<br />
15. A B C D<br />
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18. A B C D<br />
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20. A B C D<br />
* Also applies to pharmacy technicians.<br />
Please retain a copy for your records. Please print clearly.<br />
You must choose and complete ONE of the following three identifier types:<br />
1 SS # - -<br />
2 Last 4 digits of your SS # and date of birth -<br />
3 State Code and License #<br />
(Example: FL12345678)<br />
First Name<br />
Last Name<br />
E-Mail<br />
The following is your: Home Address Business Address<br />
Business<br />
Name<br />
Address<br />
City<br />
ZIP<br />
Telephone # - -<br />
Fax # - -<br />
State<br />
Profession: <strong>Pharmacist</strong> Pharmacy Technician Other<br />
By submitting this answer sheet, I certify that I have read the lesson in its entirety and<br />
completed the self-assessment exam personally based on the material presented.<br />
I have not obtained the answers to this exam by any fraudulent or improper means.<br />
Signature<br />
$45 for grading of<br />
12 lessons, fee enclosed*<br />
1 of 12 lessons,<br />
fee previously paid<br />
* Valid for 18 months<br />
from date of receipt<br />
1 = Excellent 2 = Very Good 3 = Good 4 = Fair 5 = Poor<br />
6 = N/A for Pharmacy Technicians<br />
Rate the effectiveness of how well the activity:<br />
21. Met objective 1:*<br />
22. Met objective 2:*<br />
23. Met objective 3:*<br />
24. Met objective 4:*<br />
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25. Met objective 5:<br />
26. Related to your educational needs:<br />
27. The active learning strategies<br />
(questions, cases, discussions) were<br />
appropriate and effective learning tools:<br />
28. Avoided commercial bias:<br />
29. How would you rate the overall<br />
usefulness of the material presented?<br />
1 2<br />
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30. How would you rate the quality of the faculty? 1 2 3 4 5<br />
31. How would you rate the appropriateness<br />
of the examination for this activity?<br />
32. Comments on this activity:<br />
1 2 3 4 5<br />
Date<br />
Postgraduate Healthcare Education, LLC is accredited by the<br />
Accreditation Council for Pharmacy Education as a provider<br />
of continuing pharmacy education.<br />
®<br />
0430-0000-09-030-H03-P<br />
Lesson 106448 Type of Activity: Knowledge 0430-0000-09-030-H03-T<br />
✁<br />
PRESCRIPTION DRUG ABUSE<br />
C. The patient, who has insurance, wants to pay cash<br />
for the drug<br />
D. All of the above<br />
16. State prescription drug monitoring programs:<br />
A. Have been established in all 50 states<br />
B. Are uniform in all states<br />
C. Monitor the prescribing of Schedule II–V drugs in<br />
all states that have programs<br />
D. Do not yet permit nationwide sharing of<br />
information between all states<br />
17. The KASPER prescription drug monitoring<br />
program in Kentucky:<br />
A. Is the first state program in the U.S.<br />
B. Permits physicians to access reports but not<br />
pharmacists<br />
C. Requests the name of the prescriber of each<br />
controlled-substance prescription on reports but<br />
does not identify where prescriptions were filled<br />
D. Is intended to decrease the number of dosages<br />
dispensed for opiates<br />
18. In a typical prescription drug monitoring<br />
program, a report of controlled substances<br />
dispensed is available to:<br />
A. State licensing boards during an investigation<br />
B. Medicaid<br />
C. A patient’s parole officer<br />
D. All of the above<br />
19. Physicians and pharmacists surveyed about<br />
prescription opiates:<br />
A. Are wary of prescribing or dispensing opiates<br />
to patients, especially if they have a history<br />
of abuse<br />
B. Feel that prescribing or dispensing chronic opiates<br />
to patients with nonmalignant pain is appropriate<br />
C. Do not feel that current regulations have an effect<br />
on prescribing opiates<br />
D. Do not believe that patients receiving opiates are<br />
stigmatized<br />
20. Which statement is false with respect to<br />
prescriptions for opioid drugs?<br />
A. The number of opioid doses that can be prescribed<br />
by a physician is limited to a 30-day supply by<br />
the DEA<br />
B. The number of opioid doses that can be dispensed<br />
by a pharmacist is limited by the laws and policies<br />
of some states<br />
C. Some states restrict the period that an unfilled<br />
prescription for a Schedule II drug is valid, and<br />
this can be as short as 3 days<br />
D. Some state policies equate addiction with<br />
physical dependence<br />
70<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
U.S. <strong>Pharmacist</strong> Classifieds<br />
CAREER OPPORTUNITIES<br />
We are currently hiring for the following positions:<br />
● Director of Pharmacy<br />
DE – Smyrna<br />
IA – Sheldon<br />
KY – Prestonburg<br />
● Assistant Director of Pharmacy<br />
NC – Wilmington<br />
● System Clinical Manager<br />
LA – Shreveport<br />
● Clinical Staff <strong>Pharmacist</strong><br />
TX - Odessa; San Antonio<br />
● Staff <strong>Pharmacist</strong><br />
AZ - Mesa<br />
CT – Sharon<br />
DE – Smyrna<br />
FL– Tampa (PRN)<br />
NV – N. Las Vegas (PRN)<br />
● Pharmacy Technicians<br />
AZ – Mesa; Phoenix<br />
DE – Smyrna<br />
LA – Shreveport (2)<br />
MD – Rockville<br />
RI – Westerly<br />
● Clinical Manager<br />
TX – Bryan<br />
PA – Waynesburg<br />
TX – Sulphur Springs (PRN);<br />
San Antonio (1) F/T,<br />
(1) PRN;<br />
TX – The Woodlands (PRN)<br />
TX – Bryan; Odessa<br />
UT – Layton<br />
WV – Princeton<br />
UT – Salt Lake City (PRN)<br />
WV – Bluefield (P/T)<br />
WY – Rocksprings<br />
● R x e-source SM (Staff <strong>Pharmacist</strong>s at Remote Centers, 7on/7 off Overnight)<br />
CA – Glendale NC – Cary MA – Marlborough<br />
● Senior Consultant, Clinical Operations<br />
IN – Indianapolis<br />
● Clinical Specialist, Critical Care<br />
NY – Valhalla<br />
VA – Newport News<br />
MI – Grand Rapids<br />
CAREER OPPORTUNITIES<br />
● Quality Training Manager<br />
TX – Houston<br />
FL – Port St. Lucie<br />
TX – The Woodlands<br />
Nome, Alaska<br />
Where else might you see musk oxen and sled dogs<br />
on your way to work and still pan for gold on the beach?<br />
Serve the people of northwest Alaska in a unique, comprehensive health system<br />
in a vast, stark and fiercely beautiful yet surprisingly livable Seward Peninsula.<br />
Director of Pharmacy: $140,000+ DOE, benefits, relocation allowance<br />
and potential for student loan repayment from the Indian Health Service.<br />
Norton Sound Health Corporation<br />
Steve Brock<br />
sbrock@nshcorp.org | 877-538-3142<br />
(NO Recruitment firms or agency reps)<br />
Who is Cardinal Health?<br />
• Leading, global provider of information, products, services<br />
and technologies for the health care industry<br />
• Ranked 18th in Fortune 500<br />
• 30,000 employees worldwide<br />
• $87 billion global company<br />
Who is Pharmacy Solutions?<br />
• We bring 40 years of expertise in helping hospitals and healthcare<br />
systems improve both the financial predictability of pharmacies<br />
and the quality of patient care.<br />
• 1,000 pharmacists employed, including 110 clinical specialists<br />
• Participate in more than 140 accreditation survey reviews each year<br />
• We process four million order lines remotely each year and identified<br />
20,000 patient safety events through our R x e-source SM centers<br />
in 2008<br />
• R x e-view TM solution is an automated medication order management<br />
and clinical intervention tracking tool<br />
• We also offer a customized portfolio of drug contracts<br />
For information or to apply,<br />
call 800-231-9807 ext. 1315<br />
or fax 281-749-2026<br />
CAREER OPPORTUNITIES<br />
To place a classified ad, call:<br />
Toll Free: (800) 983-7737<br />
Phone: (610) 854-3770<br />
Fax: (610) 854-3780<br />
PRODUCTS AND SERVICES<br />
FILL RXS FASTER- TIME IS LIFE phone or fax NOW:<br />
1-800-487-5024<br />
Improved...Shake & Roll speedy tab/cap counter.<br />
Durable, maintenance-free, over 20,000 sold.<br />
$129. 85 + frght, 30-day free trial. (eliminate Count-<br />
Fatigue forever - be happy).<br />
Chem-Pharm Corp<br />
Box 6246, West Palm Beach, FL 33405.
U.S. <strong>Pharmacist</strong> Classifieds<br />
CAREER OPPORTUNITIES<br />
To place a classified ad, call:<br />
Toll Free: (800) 983-7737<br />
Phone: (610) 854-3770<br />
Fax: (610) 854-3780<br />
A D<br />
I NDEX<br />
National<br />
Coca-Cola Co. . . . . . . . . . . . . . . . . . 5<br />
CorePharma LLC . . . . . . . . . . . CV4<br />
Eli Lilly and Company . . . . . . . . . . 18<br />
Falcon Pharmaceuticals . . . . . . . . 24<br />
Fougera . . . . . . . . . . . . . . . . . . . . . . 9<br />
Gallipot . . . . . . . . . . . . . . . . . . . . . 55<br />
Greenstone LLC . . . . . . . . . . . . . . 11<br />
King Pharmaceuticals, Inc. . . . . . . 45<br />
Mylan Pharmaceuticals Inc. . . . . . . 7<br />
Novartis Pharmaceuticals . . . . . . . 35<br />
Pfizer Inc. . . . . . . . . . . . . . . . . . . . 38<br />
Takeda Pharmaceuticals<br />
North America . . . . . . . . . . . CV2, 76<br />
Teva Pharmaceuticals . . . . . . . . . . 13<br />
URL Pharma . . . . . . . . . . . . . . . . . 27<br />
Health Systems<br />
Baxter Healthcare . . . . . . . . . . HS07<br />
Cubist Pharmaceuticals . . . . . . HS03<br />
Dr. Reddy's . . . . . . . . . . . . . . . HS09<br />
Eli Lilly and Company . . . . . . . HS13<br />
Medi-Dose Group . . . . . . . . . . 51-HS<br />
Pfizer Injectables . . . . . . HS01, HS15<br />
Teva Pharmaceuticals . . . . . . . .HS11<br />
New Products - National<br />
Authorized Generics /<br />
Greenstone LLC . . . . . . . . . . . . . . . . . 11<br />
Afinitor / Novartis Pharmaceuticals . .35<br />
Brimonidine Tartrate Ophthalmic Solution /<br />
Falcon Pharmaceuticals . . . . . . . . . .24<br />
Embeda / King Pharmaceuticals, Inc. . 45<br />
New Products - National<br />
Kapidex / Takeda Pharmaceuticals<br />
North America . . . . . . . . . . . . . . . . . . .76<br />
Methenamine Hippurate /<br />
CorePharma LLC . . . . . . . . . . . . . . CV4<br />
Uloric / Takeda Pharmaceuticals<br />
North America . . . . . . . . . . . . . . . . . CV2<br />
New Products - Health Systems<br />
Distinctive Labeling / Baxter<br />
Healthcare . . . . . . . . . . . . . . . . HS07<br />
Product Labeling /<br />
Teva Pharmaceuticals . . . . . . . .HS11<br />
Injectables /<br />
Pfizer Injectables . . . . . . HS01, HS15
Product News<br />
Mirixa Corporation<br />
Announces MirixaEdge<br />
Mirixa Corporation, a pharmacybased<br />
patient care service, has<br />
announced the launch of Mirixa-<br />
Edge. MirixaEdge enables pharmacists<br />
to design their own patient<br />
care programs for any of their<br />
patients, regardless of health plan,<br />
employer, or age. MirixaEdge<br />
helps set in motion the process of<br />
personalized program creation by<br />
providing pharmacists with predefined<br />
templates for conditions<br />
such as asthma, diabetes, and cardiovascular<br />
disease. Templates for<br />
medication therapy management<br />
also are available.<br />
Teva Introduces<br />
Extended-Release Tablets<br />
Teva Pharmaceuticals has<br />
announced the introduction and<br />
availability of fexofenadine hydrochloride<br />
(HCl) and pseudoephedrine<br />
HCl extended-release (ER)<br />
tablets. This product is the same<br />
as Allegra-D (sanofi-aventis U.S.)<br />
12 Hour (fexofenadine HCl 60<br />
mg/pseudoephedrine HCl 120<br />
mg) ER Tablets. Fexofenadine<br />
HCl and pseudoephedrine HCl<br />
ER tablets are available in<br />
60-mg/120-mg strength, in bottle<br />
sizes of 100 and 500.<br />
FDA Approves<br />
Pennsaid Topical Solution<br />
Covidien, a global health care<br />
products company, and Nuvo<br />
Research Inc., a Canadian drug<br />
development company, has<br />
announced FDA approval of<br />
Pennsaid Topical Solution (diclofenac<br />
sodium topical solution)<br />
1.5% w/w. Pennsaid Topical Solution<br />
is a nonsteroidal anti-inflammatory<br />
drug used for the treatment<br />
of the signs and symptoms<br />
of osteoarthritis of the knee.<br />
Sandoz Launches Authorized<br />
Generic Prevacid Capsules<br />
Sandoz, a division of Novartis, has<br />
introduced lansoprazole delayedrelease<br />
(DR) capsules, an authorized<br />
generic equivalent of<br />
Prevacid, in the U.S. Lansoprazole<br />
is a proton pump inhibitor indicated<br />
for the treatment of active<br />
duodenal and gastric ulcers and<br />
the common symptoms of gastroesophageal<br />
reflux disease, including<br />
heartburn and erosive esophagitis.<br />
Lansoprazole DR capsules<br />
offer the same efficacy and<br />
strength as Prevacid.<br />
Genzyme Launches Renvela<br />
Genzyme Corporation has<br />
announced the U.S. launch of<br />
Renvela (sevelamer carbonate) for<br />
oral suspension, a powder dosing<br />
option for the control of serum<br />
phosphorus in patients with<br />
chronic kidney disease who are on<br />
dialysis. Renvela is a next-generation<br />
version of Renagel (sevelamer<br />
HCl) and is the only phosphate<br />
binder available in both tablet and<br />
powder form.<br />
Prasco Partners With sanofiaventis<br />
to Market Generics<br />
Prasco Laboratories has entered<br />
into agreements with Winthrop<br />
U.S., a business of sanofi-aventis<br />
U.S., to provide sales support and<br />
distribution services to Winthrop<br />
U.S. for authorized generic versions<br />
of Allegra-D 12 Hour ER<br />
tablets and Drisdol (ergocalciferol)<br />
capsules in the U.S. under the<br />
Winthrop label.<br />
Medi-Dose Releases New<br />
Addition to Packaging Line<br />
To complement its existing products,<br />
Medi-Dose, Inc., has introduced<br />
new Deeper Oval Medi-Cup<br />
Blisters. The deeper capacity<br />
accommodates larger medications,<br />
including most<br />
fish oil tablets,<br />
AIDS medications,<br />
and veterinary medicines.<br />
Produced in green Nultraviolet<br />
plastic, the Deeper Oval Medi-Cup<br />
Blister provides the same tamper<br />
evidence, moisture resistance, and<br />
ultraviolet inhibitance as other<br />
Medi-Dose products.<br />
FDA Approves New Drug<br />
Treatment for Shingles<br />
NeurogesX, Inc., has announced<br />
FDA approval of Qutenza (capsaicin)<br />
8%, a medicated skin patch<br />
that relieves the pain of postherpetic<br />
neuralgia, a serious complication<br />
that can occur after an<br />
attack of shingles. Qutenza delivers<br />
a synthetic form of capsaicin<br />
through a topical delivery system,<br />
providing up to 12 weeks of<br />
reduced pain following a single<br />
1-hour application.<br />
73<br />
U.S. <strong>Pharmacist</strong> • December 2009 • www.uspharmacist.com
KAPIDEX WORKS A<br />
SECOND SHIFT<br />
TO HELP SHUT DOWN ACID PUMPS
KAPIDEX is the first and only PPI with a<br />
Dual Delayed Release (DDR) formulation,<br />
which provides a second release of drug<br />
1200<br />
Mean plasma concentration (in healthy subjects; day 5; ng/mL) 1<br />
1000<br />
800<br />
600<br />
400<br />
200<br />
KAPIDEX 60 mg<br />
KAPIDEX 30 mg<br />
0<br />
0 6 12 18 24<br />
Time (h)<br />
• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic<br />
non-erosive gastroesophageal reflux disease patients at week 4 1<br />
• KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates<br />
at week 8 1<br />
• KAPIDEX offers a safety and tolerability profile similar to lansoprazole 1<br />
• KAPIDEX can be taken without regard to food 1<br />
KAPIDEX should be swallowed whole. Alternatively, capsules can be opened,<br />
sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While<br />
KAPIDEX can be taken without regard to food, some patients may benefit from<br />
administering the dose prior to a meal if post-meal symptoms do not resolve<br />
under post-fed conditions.<br />
Conclusions of comparative efficacy cannot be drawn from this information.<br />
Indications<br />
KAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for<br />
up to 8 weeks, maintaining healing of EE for up to 6 months, and treating<br />
heartburn associated with symptomatic non-erosive gastroesophageal reflux<br />
disease (GERD) for 4 weeks.<br />
Important Safety Information<br />
KAPIDEX is contraindicated in patients with known hypersensitivity to any<br />
component of the formulation. Hypersensitivity and anaphylaxis have been reported<br />
with KAPIDEX use. Symptomatic response with KAPIDEX does not preclude the<br />
presence of gastric malignancy. Most commonly reported treatment-emergent<br />
adverse reactions (≥2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%),<br />
upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).<br />
Do not co-administer atazanavir with KAPIDEX because atazanavir systemic<br />
concentrations may be substantially decreased. KAPIDEX may interfere with<br />
absorption of drugs for which gastric pH is important for bioavailability (e.g.,<br />
ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant<br />
warfarin may require monitoring for increases in international normalized ratio<br />
(INR) and prothrombin time. Increases in INR and prothrombin time may lead to<br />
abnormal bleeding, which can lead to serious consequences. Concomitant<br />
tacrolimus use may increase tacrolimus whole blood concentrations.<br />
Please see adjacent brief summary of prescribing information for KAPIDEX.
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION<br />
KAPIDEX (dexlansoprazole) delayed release capsules<br />
INDICATIONS AND USAGE<br />
KAPIDEX is indicated for:<br />
<br />
<br />
<br />
<br />
CONTRAINDICATIONS<br />
<br />
<br />
[see Adverse Reactions]<br />
WARNINGS AND PRECAUTIONS<br />
Gastric Malignancy<br />
<br />
<br />
ADVERSE REACTIONS<br />
Clinical Trials Experience<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
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<br />
Table 2: Incidence of Treatment-Emergent Adverse<br />
Reactions in Controlled Studies<br />
Adverse Reaction<br />
Placebo<br />
(N=896)<br />
%<br />
KAPIDEX<br />
30 mg<br />
(N=455)<br />
%<br />
KAPIDEX<br />
60 mg<br />
(N=2218)<br />
%<br />
KAPIDEX<br />
Total<br />
(N=2621)<br />
%<br />
Lansoprazole<br />
30 mg<br />
(N=1363)<br />
%<br />
<br />
<br />
<br />
<br />
<br />
Tract Infection<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
Blood and Lymphatic System Disorders: Cardiac<br />
Disorders: <br />
Ear and Labyrinth Disorders: <br />
Endocrine Disorders: Eye Disorders: <br />
Gastrointestinal Disorders: <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
General Disorders and Administration Site Conditions: <br />
<br />
Hepatobiliary Disorders: <br />
Immune System Disorders: <br />
Infections and Infestations: <br />
<br />
Injury, Poisoning and Procedural Complications: <br />
Laboratory Investigations: ALP<br />
<br />
<br />
<br />
Metabolism and Nutrition<br />
Disorders: Musculoskeletal<br />
and Connective Tissue Disorders: <br />
Nervous System Disorders: <br />
<br />
Psychiatric Disorders:<br />
Renal and<br />
Urinary Disorders: Reproductive System and<br />
Breast Disorders: <br />
disorder; Respiratory, Thoracic and Mediastinal Disorders: <br />
<br />
Skin and Subcutaneous Tissue Disorders: <br />
Vascular Disorders:<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
DRUG INTERACTIONS<br />
Drugs with pH-Dependent Absorption Pharmacokinetics<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
Warfarin<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
Tacrolimus<br />
<br />
<br />
<br />
USE IN SPECIFIC POPULATIONS<br />
Pregnancy<br />
Teratogenic Effects<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
Nursing Mothers<br />
<br />
<br />
<br />
<br />
[see Carcinogenesis, Mutagenesis, Impairment of Fertility] <br />
<br />
<br />
Pediatric Use
Geriatric Use<br />
<br />
<br />
<br />
<br />
<br />
<br />
Renal Impairment<br />
<br />
<br />
<br />
<br />
<br />
Hepatic Impairment<br />
<br />
<br />
<br />
<br />
<br />
OVERDOSAGE<br />
<br />
<br />
<br />
<br />
<br />
CLINICAL PHARMACOLOGY<br />
Pharmacodynamics<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
[see Nonclinical Toxicology ]<br />
<br />
<br />
c <br />
<br />
<br />
c <br />
NONCLINICAL TOXICOLOGY<br />
Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
[see Clinical Pharmacology].<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
PATIENT COUNSELING INFORMATION<br />
[see FDA-Approved Patient Labeling in the full prescribing information]<br />
Information for Patients<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
Takeda Pharmaceuticals America, Inc.<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
KAPIDEX and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc.,<br />
and are used under license by Takeda Pharmaceuticals America, Inc.<br />
Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.<br />
©2009 Takeda Pharmaceuticals North America, Inc.<br />
LPD-00827 10/09 Printed in U.S.A.