New Drug Update 2009-2010 - LAFP

New Drug Update 2009-2010
C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS
Professor of Clinical Pharmacy and Outcome Sciences
South Carolina College of Pharmacy
Professor of Family Medicine
Medical University of South Carolina
Charleston, South Carolina
weartcw@musc.edu
1

NEW DRUG UPDATE 2009-2010
FDA Safety Alerts 3-17
Quadravalent HPV Vaccine – Gardasil by Merck 18-22
Bivalent HPV Vaccine - Cervarix by GSK 22
Saxagliptin – Onglyza by BMS/Astra Zeneca 23-30
Liraglutide – Victoza by Novo-Nordisk 31-39
ADA/EASD and AACE/ACE Type 2 DM Guidelines 2009 39-40
IV Zoledronic acid – Reclast by Novartis 41-47
Febuxostat – Uloric by TAP 48-51
Dexlansoprazole- Kapidex by TAP NOW Dexilant 52-58
Milnacipran - Savella by Forest/Cypress 59-69
Tapentadol – Nucynta by ProCara, Ortho-McNeil, Jansen 70-77
Asenapine – Saphris by Schering Plough 78-83
Iloperidone – Fanapt by Vanda/Novartis 84-93
Prasugrel – Effient by Sankyo/Lilly 94-99
Dronedarone – Multaq by Sanofi Aventis 100-108
Benzyl alcohol lotion 5% - Ulesfia by Sciele 109-113
Guanfacine extended release – Intuniv by Shire 114-120
Pitavastatin - Livalo by Kowa and Lilly 121-122
Sipuleucel – T - Provenge by Dendreon Corp 123
Estradiol valerate and estradiol valerate/dienogest) 124-126
- Natazia by Bayer
Ketorolac tromethamine Nasal Spray- Sprix 127-128
by Roxro Pharma
Denosumab – Prolia by Amgen 129-133
Faculty Disclaimer: I am on the speaker’s bureau for Novartis in the area of hypertension
and Pfizer in the areas of cardiovascular disease and pain. I am a consultant for Merck in
the area of outcomes research. I will disclose any off label or investigational information.
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FDA MedWatch Information
9/9/2006 Concomitant Use of Ibuprofen and Aspirin: Ibuprofen can interfere with the anti-platelet
effect of low dose aspirin. “Patients who use immediate release aspirin (NOT enteric coated) and take a
single dose of ibuprofen 400mg should dose the ibuprofen at least 30 minutes or longer after aspirin
ingestion, or more than 8 hours before aspirin ingestion to avoid attenuation of aspirin’s effect.” “Other
non-selective OTC NSAIDs should be viewed as having the potential to interfere with the anti-platelet
effect of low dose aspirin unless proven otherwise.”
The PRECISION trial, a large randomized comparison of celecoxib, naproxen, and ibuprofen in patients
at moderate cardiovascular risk or with CVD with and without aspirin, started in 2006 but results are not
expected until 2013..
2/16/2007 FDA Alerts consumers to unsafe, misrepresented drugs purchased over the internet:
The FDA has become aware that a number of Americans who have ordered prescription medications
over the internet (Ambien, Xanax, Lexapro and Ativan) have received a product that based upon
preliminary analysis contains haloperidol and antipsychotic that can cause muscle stiffness and spasms,
agitation and sedation. The origin of these products is unknown but the packages were postmarked in
Greece. The FDA is reissuing a warning to consumers about the possible dangers of buying prescription
drugs on-line. Before you buy any prescription drug on-line make sure that it is a licensed and legitimate
pharmacy with all of the built in safe guards.
The National Association of Boards of Pharmacy (NABP) is a professional association of the state boards
of pharmacy. It has a program to help find some of the pharmacies that are licensed to sell medicine
online. They have identified 5750 on-line pharmacies and only 4% are ligitamate the remainder havebeen
described as rougue by the NABP. Internet websites that display the seal of this program have been
checked to make sure they meet state and federal rules. For more on this program and a list of
pharmacies that display the Verified Internet Pharmacy Practice Sites Seal, (VIPPS ® Seal), go to
www.vipps.info
The Ryan Haight Online Pharmacy Consumer Protection Act, legislated and signed into federal law in
2008, is named for a teenager whose death resulted in part from the ease with which he acquired a
narcotic drug over the Internet without a valid prescription. Haight was able to sign onto an Internet site
posing as a legitimate pharmacy. He purchased a narcotic drug, which was delivered to his house, where
he consumed the drug and died.
The act implemented in April 2009 amended the Controlled Substances Act (part of 1970's
Comprehensive Drug Abuse Prevention and Control Act) to prohibit delivery, distribution, or dispensing of
controlled substances over the Internet without a valid prescription. The amendments included a definition
of "online pharmacy" as well as registration, reporting, and Web site disclosure requirements for online
pharmacies.
October 3, 2007 FDA Acts to Ensure Thyroid Drugs Don’t Lose Potency Before Expiration Date
The U.S. Food and Drug Administration is tightening the potency specifications for levothyroxine sodium,
used to treat underactive thyroid glands and other thyroid conditions, to ensure the drug retains its
potency over its entire shelf life. This action is being taken in response to concerns that the potency of the
drug may deteriorate prior to its expiration date. The change will help improve the quality of the product
so that consumers receive the level of medication needed to treat their thyroid disorders. Levothyroxine
sodium products are used by over 13 million patients.
FDA is mandating that levothyroxine sodium drug products tighten their potency specifications to meet a
95 percent to 105 percent potency specification until their expiration date. The shelf life is the length of
time a drug can be stored before it degrades to unacceptable levels. The 95 percent lower potency
specification will ensure the drugs do not degrade by more than 5 percent of the labeled claim before their
expiration date and the 105 percent upper specification is appropriate to address occasional analytical
testing variability. Traditionally these products were allowed a potency range of 90 to 110 percent.
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Trade Name Applicant Potency TE Code Appl No
Product
No
UNITHROID STEVENS J 0.025MG AB1 21210 001
LEVOTHYROXINE
SODIUM
MYLAN 0.025MG AB1 76187 001
LEVOXYL KING PHARMS 0.025MG AB1 21301 001
SYNTHROID ABBOTT 0.025MG AB1 21402 001
SYNTHROID ABBOTT 0.025MG AB2 21402 001
LEVOTHYROXINE
SODIUM
MYLAN 0.025MG AB2 76187 001
LEVO-T ALARA PHARM 0.025MG AB2 21342 001
UNITHROID STEVENS J 0.025MG AB2 21210 001
LEVOTHYROXINE
SODIUM
GENPHARM 0.025MG AB2 76752 001
LEVOXYL KING PHARMS 0.025MG AB3 21301 001
LEVO-T ALARA PHARM 0.025MG AB3 21342 001
UNITHROID STEVENS J 0.025MG AB3 21210 001
LEVOTHYROXINE
SODIUM
LEVOTHYROXINE
SODIUM
MYLAN 0.025MG AB3 76187 001
GENPHARM 0.025MG AB3 76752 001
LEVOTHROID LLOYD 0.025MG AB4 21116 001
LEVOTHYROXINE
SODIUM
MYLAN 0.025MG AB4 76187 001
March 19, 2009 FDA Alert: Risk of Transmission of Blood-borne Pathogens from Shared Use of
Insulin Pens FDA is issuing this alert to remind healthcare providers and patients that insulin pens and
insulin cartridges are never to be shared among patients. Sharing of insulin pens may result in
transmission of hepatitis viruses, HIV, or other blood-borne pathogens.
The FDA has received information that insulin pens may have been shared among numerous patients
(two thousand or more) in one hospital in the United States from 2007-2009
(http://www.wbamc.amedd.army.mil/), and in a smaller number of patients in at least one other hospital.
Although the disposable needles in the insulin pens were reportedly changed for each patient, there is still
a risk of blood contamination of the pen reservoir or cartridge. The current instructions for use for all
insulin pens already state that the pens are not to be shared among patients. The FDA reminds
healthcare providers, healthcare facilities, and patients that each insulin pen (and each insulin pen
cartridge) is designed for single-patient use only and is never to be shared among patients. Insulin pens
are not designed, and are not safe, for one pen to be used for more than one patient, even if needles are
changed between patients because any blood contamination of the pen reservoir could result in
transmission of already existing blood-borne pathogens from the previous user. Identifying the insulin pen
with the name of the patient and other patient identifiers provides a mechanism for verifying that the
correct pen is used on the correct patient, and can help minimize medication errors. Ensure the
identifying patient information does not obstruct the dosing window or other product information such as
the product name and strength.
May 11, 2009 Syncope and Its Consequences in Patients With Dementia Receiving Cholinesterase
Inhibitors (Arch Intern Med. 2009;169(9):867-873)
A population-based cohort study, investigated the relationship between cholinesterase inhibitor use and
syncope-related outcomes using health care databases from Ontario, Canada, with accrual from April 1,
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2002, to March 31, 2004. They identified 19 803 community-dwelling older adults with dementia who were
prescribed cholinesterase inhibitors and 61 499 controls who were not. Results: Hospital visits for
syncope were more frequent in people receiving cholinesterase inhibitors than in controls (31.5 vs 18.6
events per 1000 person-years; adjusted hazard ratio [HR], 1.76; 95% confidence interval
[CI], 1.57-1.98). Other syncope-related events were also more common among people receiving
cholinesterase inhibitors compared with controls: hospital visits for
bradycardia (6.9 vs 4.4 events per 1000 person-years; HR, 1.69; 95% CI, 1.32-2.15), permanent
pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR, 1.49;
95% CI, 1.12-2.00), and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR, 1.18; 95% CI, 1.04-
1.34). Results were consistent in additional analyses in which subjects
were either matched on their baseline co morbidity status or matched using propensity scores.
Conclusions: Use of cholinesterase inhibitors is associated with increased rates of syncope,
bradycardia, pacemaker insertion, and hip fracture in older adults with dementia. The risk of these
previously under recognized serious adverse events must be weighed carefully against the drugs’
generally modest benefits.
May 30, 2009 Tamoxifen and SSRI’s Tamoxifen, a breast cancer medicine used by millions of
women, doesn’t work when taken with antidepressants like Prozac, Paxil, and Zoloft, a study says.
Tumors were more than twice as likely to return after two years in women taking the antidepressants
while on the cancer drug, compared with those taking tamoxifen alone, the study showed. The research,
by Medco Health Solutions Inc., was presented today at a meeting of the American Society of Clinical
Oncology in Orlando. After two years, patients taking both SSRIs and tamoxifen had a 14 percent risk of
tumors recurring, compared with 7.5 percent for women taking the cancer drug alone. The risk increased
to 16 percent among those using Paxil, Prozac or Zoloft, the data showed. “This is the first large
outcomes-based study to reinforce earlier research questioning the use of Paxil and Prozac in patients
taking tamoxifen,” said Robert Epstein, a study author and chief medical officer for Medco
Tamoxifen can’t combat tumors until it mixes inside the body with a liver enzyme called CYP2D6 to morph
into an active tumor fighter called endoxifen. Tamoxifen is metabolized in the liver to N-desmethyltamoxifen
and 4-hydroxytamoxifen (4HT). Tamoxifen and the N-desmethyl metabolite have equal
antiestrogenic properties. However, 4HT, the "nut" in the nutshell, is 100-fold more active than tamoxifen,
though present only in minute concentrations. Jin et al 3 discovered another metabolite, 4-hydroxy-Ndesmethyltamoxifen
(endoxifen), that is more abundant than 4HT but is equally active, which is 100 times
more potent than the parent compound, tamoxifen (another "nut" within the tamoxifen shell). 3 This newer
understanding clearly suggests tamoxifen can be thought of as a prodrug that must be activated to
achieve the therapeutic effect. While this concern is not new, it was first suggested by Dr Flockhart in
2003 and in a 2005 report published by ASCO. Holmes said antidepressants known as selective
serotonin reuptake inhibitors, or SSRIs, shouldn’t be used in patients taking tamoxifen (Journal of
Oncology Practice, Vol 1, No 4 (November), 2005: pp. 155-159). The FDA has not yet weighed in on this
yet but a statement released 6-2-09 The Food and Drug Administration is “looking at adding new
information to the tamoxifen label” to advise women taking the cancer drug against using some
antidepressants. “Effexor doesn’t interfere with tamoxifen so that is the preferred drug for oncologists to
treat hot flashes,” said Brown
A recent trial BMJ 2010;340:c693 studied women living in Ontario aged 66 years or older treated with
tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during
follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment,
and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on
tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with
24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P

and cancer. Findings from these research papers are conflicting and inconclusive, and the American
Diabetes Association cautions against over-reaction until more information is available.
Four different population based studies were reported and published in Diabetelogia and the data within
these studies and between these studies are conflicting and confusing. Until more information is
available, the American Diabetes Association advises patients using insulin not to stop taking it.
For patients using glargine and considering switching to another form of insulin, the data in these studies
make it unclear as to whether any one type of insulin increases the risk of cancer more than other types
of insulin.
Oct 16, 2009 CDC Treatment and Chemoprophylaxis for Children younger than 1 Year of Age
Children younger than 1 year of age are at higher risk for influenza-related complications and have a
higher rate of hospitalization compared to older children. Oseltamivir is not approved for use in children
younger than 1 year of age. However, limited safety data on oseltamivir treatment of seasonal influenza in
children younger than 1 year of age suggest that severe adverse events are rare. Oseltamivir is
authorized for emergency use in children younger than 1 year of age under an EUA issued by FDA,
subject to the terms and conditions of the EUA.
Because infants experience high rates of morbidity and mortality from influenza, infants with 2009 H1N1
influenza virus infections may benefit from treatment using oseltamivir. Emergency Use Authorization of
Tamiflu (oseltamivir)).
Table 2. Dosing recommendations for antiviral treatment or chemoprophylaxis of children younger than 1
year using oseltamivir.
Age
Younger than 3
months
Recommended treatment dose for 5
days
Recommended prophylaxis dose for 10
days
12 mg twice daily Not recommended unless situation judged
critical due to limited data on use in this age
group
3-5 months 20 mg twice daily 20 mg once daily
6-11 months 25 mg twice daily 25 mg once daily
Tamiflu® capsules 75 mg may be compounded using either of two vehicles: Cherry Syrup (Humco®) or
Ora-Sweet® SF (sugar-free) (Paddock Laboratories). Other supplies needed to compound include mortar
and pestle and amber glass or amber polyethyleneterephthalate (PET) bottle.
http://www.cdc.gov/H1N1flu/pharmacist/.
In addition, for children who may not be able to swallow capsules, Tamiflu® capsules may be opened and
mixed with sweetened liquids, such as regular or sugar-free chocolate syrup, if oral suspension is not
available.
July 30, 2009 FDA ALERT FDA has now approved the first single-ingredient oral colchicine
product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares.
Oral colchicine has been used for many years as an unapproved drug with no FDA-approved
prescribing information, dosage recommendations, or drug interaction warnings.
During the drug application review, FDA identified two previously uncharacterized safety concerns
associated with the use of colchicine (marketed as Colcrys).
First, FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published
literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed
cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of
colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These
reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism
of colchicine play a central role in the development of colchicine toxicity.
Second, data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated
that a substantially lower dose of colchicine was as effective as the higher dose traditionally used.
Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to
the higher dose.
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The AGREE (Acute Gout Flare Receiving Colchicine Evaluation) a mulitcenter, randomized, doubleblind,
placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total
over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point
was >50% pain reduction at 24 hours without rescue medication. Results: There were 184 patients in the
intent-totreat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52
patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P= 0.005 and
P = 0.034, respectively versus placebo). Rescue medication was taken within the first 24 hours by 23
patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose
group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had
an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95%
confidence interval [95% CI] 0.7–3.2). High-dose colchicine was associated with significantly more
diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose
colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9–56.9]), 10 (19.2%) had severe
diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR
1.9 [95% CI 0.8–4.8]), none had severe diarrhea, and none had vomiting. (ARTHRITIS & RHEUMATISM
Vol. 62, No. 4, April 2010, pp 1060–1068)
Based on this information, FDA is highlighting important safety considerations found in the approved
prescribing information to assure safe use of Colcrys.
FDA recommends:
• Healthcare professionals not use P-glycoprotein (P-gp) or strong CYP3A4 inhibitors in patients
with renal or hepatic impairment who are currently taking colchicine.
• Healthcare professionals consider a dose reduction or interruption of colchicine treatment in
patients with normal renal and hepatic function if treatment with a P-gp or a strong CYP3A4
inhibitor is required.
• Healthcare professionals prescribe the FDA-approved Colcrys dose for the treatment of acute
gout flares: 1.2 mg followed by 0.6mg in 1 hour (total 1.8mg).
• Healthcare professionals refer to Colcrys’ approved prescribing information for specific dosing
recommendations and additional drug interaction information.
• Patients review the Medication Guide for important safety information
For treatment of prophylaxis of gout flares, the FDA recommended that patients taking an HIV drug
combination cut their initial dose of colchicine by three-fourths, from 0.6 mg twice a day to 0.3 mg
once a day, or, if they're taking 0.6 mg once a day, to 0.3 mg once every other day. For patients
taking fosamprenavir calcium alone, cutting the colchicine dosage in half -- from 0.6 mg twice a day to
0.3 mg twice a day, or from 0.6 mg once a day to 0.3 mg once daily -- is recommended.
As a treatment for familial Mediterranean fever, the FDA recommended a maximum dose of 0.6 mg
colchicine per day in patients taking both protease inhibitors and 1.2 mg daily in patients taking the
single drug.
November 2, 2009 FDA Alert Byetta (exenatide) – Renal Failure
FDA notified healthcare professionals of revisions to the prescribing information for Byetta (exenatide) to
include information on post-marketing reports of altered kidney function, including acute renal failure and
insufficiency. Byetta, an incretin-mimetic, is approved as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.
From April 2005 through October 2008, FDA received 78 cases of altered kidney function (62 cases of
acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. Some cases occurred in
patients with pre-existing kidney disease or in patients with one or more risk factors for developing kidney
problems. Labeling changes include:
• Information regarding post-market reports of acute renal failure and insufficiency, highlighting that
Byetta should not be used in patients with severe renal impairment (creatinine clearance

November 17, 2009 Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert
healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and
Prilosec OTC) New data show that when clopidogrel and omeprazole are taken together, the
effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to
prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole. The
updated label for clopidogrel will contain details of new studies submitted by Sanofi-Aventis and Bristol-
Myers Squibb, the manufacturer of Plavix (clopidogrel).
Omeprazole inhibits the drug metabolizing enzyme (CYP2C19) which is responsible for the conversion of
clopidogrel into its active form (active metabolite). The new studies compared the amount of clopidogrel's
active metabolite in the blood and its effect on platelets (anti-clotting effect) in people who took
clopidogrel plus omeprazole versus those who took clopidogrel alone. A reduction in active metabolite
levels of about 45% was found in people who received clopidogrel with omeprazole compared to those
taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people
receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were
given at the same time or 12 hours apart.
Other drugs that are potent inhibitors of the CYP 2C19 enzyme would be expected to have a similar effect
and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole,
ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. Since the level
of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with
clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and
should also be avoided in combination with clopidogrel.
FDA is aware there are studies, such as the Clopidogrel and Optimization of Gastrointestinal Events
(COGENT) study, that might provide information about the effect of this interaction on clinical outcome.
Although the FDA has not fully reviewed the study results, the applicability of these data is limited
because of the study design and follow-up. Therefore, based on the current scientific information, the
clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the
CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of
Plavix (clopidogrel) is conducting follow-up studies to explore this and other drug interactions.
FDA Update March 12, 2010
The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the
anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the
drug (i.e. "poor metabolizers") and therefore may not receive the full benefits of the drug.
The Boxed Warning in the drug label will include information to:
• Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor
metabolizers do not effectively convert Plavix to its active form in the body.
• Inform healthcare professionals that tests are available to identify genetic differences in
CYP2C19 function.
• Advise healthcare professionals to consider use of other anti-platelet medications or alternative
dosing strategies for Plavix in patients identified as poor metabolizers.
Plavix is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in
patients with cardiovascular disease. Plavix works by decreasing the activity of blood cells called
platelets, making platelets less likely to form blood clots.
November 20, 2009 FDA Early Communication Ongoing Safety Review of Meridia (sibutramine
hydrochloride) preliminary results from the SCOUT study indicating cardiovascular events occurred in
11.4% of patients using sibutramine compared to 10% of patients using a placebo. This difference was
higher than expected, suggesting that sibutramine was associated with an increased cardiovascular risk
in the study population. The additional data from the SCOUT study reviewed by FDA indicate that the
increased risk for cardiovascular events with sibutramine occurred only in patients with a history of
cardiovascular disease.
The results for cardiovascular events for each subgroup of the SCOUT study are found in the table below.
TABLE 1. Cardiovascular Events in the SCOUT Study by Predefined Subgroups
Study Group †
Placebo
(% of patients)
Sibutramine
(% of patients)
Hazard Ratio
(95% Confidence
Interval)
p-value
8

DM Only Group
Total patients (n)
Cardiovascular
Events*
1,178 77
(6.5%)
1,207 79
(6.5%)
1.010 (0.737, 1.383) 0.951
CV Only Group
Total patients (n)
Cardiovascular
Events*
793 66
(8.3%)
759 77
(10.1%)
1.274 (0.915, 1.774) 0.151
CV + DM Group
Total patients (n)
Cardiovascular
Events*
2,901 346
(11.9%)
2,906 403
(13.9%)
1.182 (1.024, 1.354) 0.023††
January 21, 2010 FDA Communication about an Meridia (sibutramine hydrochloride):
Follow-Up to an Early Ongoing Safety Review
FDA notified healthcare professionals that the review of additional data indicates an increased risk of
heart attack and stroke in patients with a history of cardiovascular disease using sibutramine. Based on
the serious nature of the review findings, FDA requested and the manufacturer agreed to add a new
contraindication to the sibutramine drug label stating that sibutramine is not to be used in patients with a
history of cardiovascular disease, including: History of coronary artery disease (e.g., heart attack, angina)
• History of stroke or transient ischemic attack (TIA)
• History of heart arrhythmias
• History of congestive heart failure
• History of peripheral arterial disease
• Uncontrolled hypertension (e.g., > 145/90 mmHg)
January 21, 2010 FDA Warning about Counterfit Alli (orlistat OTC) The U.S. Food and Drug
Administration is warning consumers about a counterfeit and potentially harmful version of Alli 60 mg
capsules (120 count refill kit).
Preliminary laboratory tests conducted by GlaxoSmithKline (GSK)—the maker of the FDA approved overthe-counter
weight-loss product— revealed that the counterfeit version did not contain orlistat, the active
ingredient in its product. Instead, the counterfeit product contained the controlled substance sibutramine.
January 23, 2010 FDA Up DateThe U.S. Food and Drug Administration (FDA) is updating its warning to
the public about a counterfeit version of Alli 60 mg capsules (120 count refill pack) being sold over the
internet, particularly at online auction sites. FDA advises people who believe that they have a counterfeit
product not to use the drug and dispose of it immediately. . The counterfeit product is illegal and unsafe.
Additional FDA laboratory tests on the counterfeit product show that people may be taking 3-times the
usual daily dose (or twice the recommended maximum dose) of sibutramine if they are following the
dosing directions for Alli. Healthy people who take this much sibutramine can experience anxiety, nausea,
heart palpitations, tachycardia (a racing heart), insomnia, and small increases in blood pressure. This
excessive amount of sibutramine is dangerous to people who have a history of cardiovascular disease,
and can lead to elevated blood pressure, stroke, or heart attack..
Consumers who believe they have received counterfeit Alli are asked to contact the FDA's Office of
Criminal Investigations (OCI) by calling 800-551-3989 or by visiting the OCI Web site
(http://www.fda.gov/OCI).
May 26, 2010 FDA Safety Alert Xenical The U.S. Food and Drug Administration has approved a revised
label for Xenical to include new safety information about cases of severe liver injury that have been
reported rarely with the use of this medication. The agency is also adding a new warning about rare
reports of severe liver injury to the OTC Drug Facts label for Alli and is working with the manufacturer to
ensure that consumers can understand this new warning.
Xenical and Alli are medications used for weight-loss that contain different strengths of the same active
ingredient, orlistat. Xenical (orlistat 120 mg) is available by prescription and Alli (orlistat 60 mg) is sold
over-the-counter without a prescription.
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This new safety information, originally announced in August 2009, is based on FDA's completed review
that identified 13 total reports of severe liver injury with orlistat; 12 foreign reports with Xenical and 1 U.S.
report with Alli.
December 3, 2009 FDA Alert Risk of Neural Tube Birth Defects following prenatal exposure to
Valproate The FDA is reminding health care professionals about the increased risk of neural tube defects
and other major birth defects, such as craniofacial defects and cardiovascular malformations, in babies
exposed to valproate sodiumand related products (valproic acid and divalproex sodium) during
pregnancy. Healthcare practitioners should inform women of childbearing potential about these risks, and
consider alternative therapies, especially if using valproate to treat migraines or other conditions not
usually considered life-threatening.
Women of childbearing potential should only use valproate if it is essential to manage their medical
condition. Those who are not actively planning a pregnancy should use effective contraception, as birth
defect risks are particularly high during the first trimester, before many women know they are pregnant.
FDA has required a patient Medication Guide for each antiepileptic drug (AED), including valproate.
Valproate sodium is marketed as Depacon. Dilvalproex sodium is marketed as Depakote, Depakote CP,
Depakote ER. Valproic acid is marketed as Depakene and as Stavzor.
Pregnant women using valproate or other AEDs should be encouraged to enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334; www.aedpregnancyregistry.org).
January 29, 2010 FDA Alert Zyprexa (olanzapine): Use in Adolescents Lilly and FDA notified
healthcare professionals of changes to the Prescribing Information for Zyprexa related to its indication for
use in adolescents (ages 13-17) for treatment of schizophrenia and bipolar I disorder [manic or mixed
episodes]. The revised labeling states that:
Indications and Usage: When deciding among the alternative treatments available for adolescents,
clinicians should consider the increased potential (in adolescents as compared with adults) for weight
gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to
adolescents, and in many cases this may lead them to consider prescribing other drugs first in
adolescents. (Effectiveness and safety of ZYPREXA have not been established in pediatric patients less
than 13 years of age).
February 16, 2010 FDA Drug Safety Communication Erythropoiesis-Stimulating Agents (ESAs):
Procrit, Epogen and Aranesp: FDA and Amgen notified healthcare professionals and patients that all
ESAs must be used under a REMS risk management program. As part of the risk management program,
a Medication Guide explaining the risks and benefits of ESAs must be provided to all patients receiving
an ESA. Under the ESA APPRISE Oncology program (Assisting Providers and Cancer Patients with Risk
Information for the Safe use of ESAs), Amgen will ensure that only those hospitals and healthcare
professionals who have enrolled and completed training in the program will prescribe and dispense ESAs
to patients with cancer. Amgen is also required to oversee and monitor the program to ensure that
hospitals and healthcare professionals are fully compliant with all aspects of the program. FDA is
requiring a REMS because studies show that ESAs can increase the risk of tumor growth and shorten
survival in patients with cancer who use these products. Studies also show that ESAs can increase the
risk of heart attack, heart failure, stroke or blood clots in patients who use these drugs for other conditions
such as Chronic Renal Failure: Box Warning: In clinical studies, patients experienced greater risks for
death, serious cardiovascular events, and stroke when administered erythropoiesis-stimulating agents
(ESAs) to target hemoglobin levels of 13 g/dL and above. Individualize dosing to achieve and maintain
hemoglobin levels within the range of 10 to 12 g/dL.
February 17, 2010 FDA Drug Safety Communication: Product Confusion with Maalox Total Relief
and Maalox Liquid Products
The FDA has received five reports of serious medication errors involving consumers who used Maalox
Total Relief, the upset stomach reliever and anti-diarrheal medication, by mistake, when they had
intended to use one of the traditional Maalox liquid antacid products.
Due to the potential for serious adverse events from product confusion, the maker of Maalox brand
products has agreed to:
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• Change the name of Maalox Total Relief to one that will not include the name "Maalox" and
revise the graphics and information displayed on the front of the product container to help
distinguish the active ingredients and uses of this product from the traditional Maalox antacids.
• An educational program that includes outreach to healthcare professionals and consumers to
inform them about the different products sold under the Maalox brand, including how to select the
appropriate Maalox brand product.
The company expects to begin selling the renamed product in September 2010. Until that time,
healthcare professionals and consumers should be aware of the following:
• Maalox Total Relief contains the active ingredient bismuth subsalicylate and is used to treat
diarrhea, upset stomach associated with nausea, heartburn, and gas due to overindulgence in
food (overeating).Bismuth subsalicylate is chemically related to aspirin and may cause similar
adverse effects such as bleeding. Bismuth subsalicylate has a warning statement stating that it
should not be used in people who have or have a history of gastrointestinal ulcers or a bleeding
disorder.
• The traditional Maalox liquid products including Maalox Advanced Regular Strength and Maalox
Advanced Maximum Strength are well-recognized antacid drug products that contain aluminum
hydroxide, magnesium hydroxide, and simethiconeMaalox Total Relief should not be confused
with traditional Maalox liquid antacid products.
FDA is concerned about the public health impact of medication mix-ups with products that have the same
names or portions of the same name but contain different active ingredients. The agency encourages
drug companies to consider the potential for name confusion when choosing OTC product names.
February 18, 2010 FDA Drug Safety Communication: New safety requirements for long-acting
inhaled asthma medications called Long-Acting Beta-Agonists (LABAs)
FDA notified healthcare professionals and consumers that, due to safety concerns, FDA is requiring a risk
management strategy (REMS) and class-labeling changes for all LABAs. The REMS will require a revised
Medication Guide written specifically for patients, and a plan to educate healthcare professionals about
the appropriate use of LABAs. These changes are based on FDA's analyses of studies showing an
increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and
adult patients as well as death in some patients using LABAs for the treatment of asthma.
Healthcare professionals are reminded that to ensure the safe use of these products:
• Single-ingredient LABAs should only be used in combination with an asthma controller
medication; they should not be used alone.
• LABAs should only be used long-term in patients whose asthma cannot be adequately controlled
on asthma controller medications.
• Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid
should use a combination product containing both an inhaled corticosteroid and a LABA, to
ensure compliance with both medications.
FDA has determined that the benefits of LABAs in improving asthma symptoms outweigh the potential
risks when used appropriately with an asthma controller medication in patients who need the addition of
LABAs. FDA believes the safety measures recommended will improve the safe use of these drugs.
American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting. We are
concerned with the FDA's recommendation that after asthma control has been achieved with a
combination of LABAs and inhaled corticosteroids, LABA use should be stopped as soon as possible.
“Their recommendations really run counter to our guidelines." They also state that combination therapy
has been very effective, showing decreased morbidity, hospitalizations, and exacerbations. "The indices
of safety that have been raised [by the FDA] really do not appear in the literature, and we really need to
see new data before making dramatic changes in our recommendations." In addition, the AAAAI "does
not want to see insurers or pharmacy benefit managers erecting more barriers because of this
recommendation that will result in patients going out of control or becoming unstable before a physician
or healthcare provider can continue their medication,"
February 19, 2010 FDA approves Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide
Diphtheria CRM197 Conjugate Vaccine - Menveo
For active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis
serogroups A, C, Y and W-135 when administered to individuals 11 through 55 years of age.
• Menveo consists of a liquid vaccine component (MenCYW-135 liquid conjugate component) and
a lyophilized vaccine component (MenA lyophilized conjugate component). Reconstitute the
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MenA lyophilized conjugate component with the MenCYW-135 liquid conjugate component
immediately before administration. (dose 0.5 ml IM)
• In clinical trials, the most frequently occurring adverse events in all subjects who received
MENVEO were pain at the injection site (41%), headache (30%), myalgia (18%), malaise (16%)
and nausea (10%).
• In study participants aged 11-18 years, non-inferiority of MENVEO to Menactra was
demonstrated for all four serogroups using the primary endpoint (hSBA seroresponse). The
percentages of subjects with hSBA seroresponse were statistically higher for serogroups A, W,
and Y in the MENVEO group, as compared to the Menactra group, however the clinical relevance
of higher post-vaccination immune responses is not known.
• In study participants aged 19-55 years, non-inferiority of MENVEO to Menactra was
demonstrated for all four serogroups using the primary endpoint (hSBA seroresponse) The
percentage of subjects with hSBA seroresponse was statistically higher for serogroups C, W, and
Y in the MENVEO group, as compared to the Menactra group; however the clinical relevance of
higher post-vaccination immune responses is not known.
February 22, 2010 FDA Drug Safety Communication: Ongoing review of Avandia (rosiglitazone)
and cardiovascular safety
FDA is reviewing data, submitted in August 2009, from a large, long-term clinical study on possible risks
with the diabetes drug, Avandia* (rosiglitazone). The clinical study, called the Rosiglitazone Evaluated for
Cardiovascular Outcomes and Regulation of Glycemia in Diabetes or RECORD study was designed to
evaluate the cardiovascular safety of rosiglitazone, a medication used to treat type 2 diabetes mellitus.
In addition to the RECORD study, a number of observational studies of the cardiovascular safety of
rosiglitazone have been published. FDA has been reviewing these on an ongoing basis.
There was no significant treatment difference in any of the secondary composite endpoints except an
increase in heart failure, which is a well-known side effect of drugs in this class, including Actos
(pioglitazone). The increase in risk of heart failure is consistent with the warnings contained in the current
drug label. The RECORD study findings were published in the June 2009 issue of Lancet.
Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) Trial is designed to answer two separate
questions. The first question is to test the cardiovascular effects of long-term treatment with rosiglitazone
or pioglitazone when used as part of standard of care compared to similar standard of care without
rosiglitazone or pioglitazone in patients with type 2 diabetes who have a history of or are at risk for
cardiovascular disease. The second question will compare the effects of long-term supplementation of
vitamin D on death and cancer. The FDA Advisory Committee is scheduled to review rosiglitazone on July
13 and 14, 2010’
May 28, 2010 Update: Dr David Graham from the FDA and collaborators from CMS have reported the
results of an analysis of over 227 000 subjects, where rosiglitazone was compared with pioglitazone and
rosiglitazone significantly increased the risk of stroke by 27%, heart failure by 25%, death by 13%, and
AMI or death by 11%. The increased risk of AMI alone (6%) was not statistically significant. "We suspect
that fewer elderly patients survive their AMI long enough to reach the hospital, so that AMI/death is a
better measure," Graham wrote.They want to submit this data to JAMA for publication but a draft of the
article is available on-line from one of the authors. Graham's email goes on to say that, in his study, the
number needed to harm was "59 patients treated with rosiglitazone for one year to produce one excess
case of any of our outcomes. This translates to 48 000 excess events attributable to rosiglitazone among
patients age 65 years or older between 1999 and June 2009. Given that 62% of rosiglitazone use has
been in patients below age 65, the actual national impact is probably 100 000 or more."
February 24, 2010 Influenza Vaccine for 2010 vaccine experts voted that everyone 6 months and older
should get a flu vaccine next season. CDC’s Advisory Committee on Immunization Practices (ACIP) voted
for “universal” flu vaccination in the U.S. to expand protection against the flu to more people. Next
season’s vaccine will protect against the 2009 H1N1 pandemic virus and 2 other flu viruses.
Update MMWR April 30, 2010 / 59(16);485-486
Persons aged ≥65 years are at greater risk for hospitalization and death from seasonal influenza
compared with other age groups, and they respond to vaccination with lower antibody titers to influenza
hemagglutinin (an established correlate of protection against influenza) compared with younger adults.
On December 23, 2009, the Food and Drug Administration (FDA) licensed an injectable inactivated
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trivalent influenza vaccine (Fluzone High-Dose, Sanofi-Pasteur) that contains an increased amount of
influenza virus hemagglutinin antigen compared with other inactivated influenza vaccines such as
Fluzone. Fluzone High-Dose is licensed as a single dose for use among persons aged ≥65 years and will
be available beginning with the 2010--11 influenza season. The Advisory Committee on Immunization
Practices (ACIP) reviewed data from prelicensure clinical trials on the safety and immunogenicity of
Fluzone High-Dose and expressed no preference for the new vaccine over other inactivated trivalent
influenza vaccines. This report summarizes the FDA-approved indications for Fluzone High-Dose and
provides guidance from ACIP for its use.
Standard dose inactivated trivalent influenza vaccines contain a total of 45 µg (15 µg of each of the three
recommended strains) of influenza virus hemagglutinin antigen per 0.5mL dose. In contrast, Fluzone
High-Dose is formulated to contain a total of 180 µg (60 µg of each strain) of influenza virus
hemagglutinin antigen in each 0.5mL dose. Like other inactivated influenza vaccines, Fluzone High-Dose
is administered as an intramuscular injection. Fluzone High-Dose is available as a single-dose prefilled
syringe formulation and is distinguished from Fluzone by a gray syringe plunger rod. As with other 2010--
11 influenza vaccines, Fluzone High-Dose will contain antigens of the three recommended virus strains:
A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like.
Immunogenicity data from three studies among persons aged ≥65 years indicated that, compared with
standard dose Fluzone, preparations of Fluzone High-Dose elicited significantly higher hemagglutination
inhibition (HI) titers against all three influenza virus strains that were included in seasonal influenza
vaccines recommended during the study period. Solicited injection site reactions and systemic adverse
events were more frequent after vaccination with Fluzone High-Dose compared with standard Fluzone,
but typically were mild and transient. In the largest study, 915 (36%) of 2,572 persons who received
Fluzone High-Dose, compared with 306 (24%) of 1,275 persons who received Fluzone, reported injection
site pain ≤7 days after vaccine administration. In the same study, significantly more Fluzone High-Dose
recipients (1.1%) reported moderate (>100.4°F--≤102.2°F [>38°C--≤39°C]) to severe (>102.2°F [>39°C])
fever, compared with Fluzone recipients (0.3%). A 3-year post-licensure study of the vaccine
effectiveness of Fluzone High-Dose compared with standard dose inactivated influenza vaccine (Fluzone)
was begun in 2009 and should be completed in 2012.
February 24, 2010 FDA Approves Pneumococcal Disease Vaccine with Broader Protection
Prevnar 13, a pneumococcal 13-valent conjugate vaccine for infants and young children ages 6 weeks
through 5 years. Prevnar 13 will be the successor to Prevnar, the pneumococcal 7-valent conjugate
vaccine licensed by the FDA in 2000 to prevent invasive pneumococcal disease (IPD) and otitis media.
The new vaccine extends the protection to six additional types of the disease causing bacteria.
The vaccine is administered in a four-dose schedule given at 2, 4, 6 and 12-15 months of age. The
vaccine is available in single-dose, pre-filled syringes.
The seven Streptococcus pneumoniae serotypes against which Prevnar is directed accounted for about
80 percent of IPD in young children in North America at the time that the vaccine was licensed. With the
use of Prevnar, by 2007 the overall rate of IPD caused by these seven serotypes in children less than 5
years old was reduced by 99 percent. However, at that time, it was also shown that of the remaining
invasive pneumococcal disease in this age group, 62 percent are caused by the six additional serotypes
that will be included in Prevnar 13.
ACIP Recommendations: MMWR March 12, 2010
No previous PCV7/PCV13 vaccination. The ACIP recommendation for routine vaccination with PCV13
and the immunization schedules for infants and toddlers through age 59 months who have not received
any previous PCV7 or PCV13 doses are the same as those previously published for PCV7. PCV13 is
recommended as a 4-dose series at ages 2, 4, 6, and 12--15 months. Infants receiving their first dose at
age ≤6 months should receive 3 doses of PCV13 at intervals of approximately 8 weeks (the minimum
interval is 4 weeks). The fourth dose is recommended at age 12--15 months, and at least 8 weeks after
the third dose (Table 2).
Children aged 7--59 months who have not been vaccinated with PCV7 or PCV13 previously should
receive 1 to 3 doses of PCV13, depending on their age at the time when vaccination begins and whether
underlying medical conditions are present (Table 2). Children aged 24--71 months with chronic medical
conditions that increase their risk for pneumococcal disease should receive 2 doses of PCV13.
Interruption of the vaccination schedule does not require reinstitution of the entire series or the addition of
extra doses.
Incomplete PCV7/ PCV13 vaccination. Infants and children who have received 1 or more doses of
PCV7 should complete the immunization series with PCV13 (Table 3). Children aged 12--23 months who
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have received 3 doses of PCV7 before age 12 months are recommended to receive 1 dose of PCV13,
given at least 8 weeks after the last dose of PCV7. No additional PCV13 doses are recommended for
children aged 12--23 months who received 2 or 3 doses of PCV7 before age 12 months and at least 1
dose of PCV13 at age ≥12 months.
Similar to the previous ACIP recommendation for use of PCV7, 1 dose of PCV13 is recommended for all
healthy children aged 24--59 months with any incomplete PCV schedule (PCV7 or PCV13). For children
aged 24--71 months with underlying medical conditions who have received any incomplete schedule of

about PCV2, a contaminant in RotaTeq. Gordon Allan, PhD, a professor at The Queens University Belfast
in Belfast, Northern Ireland, rang an alarm bell with what resembled a passing remark about how the virus
triggers postweaning multisystemic wasting syndrome.
"PCV2 in a lot of ways is a strange virus," Dr. Allan said. To get "good disease in pigs with PCV2," one
must infect them with the virus and then stimulate their immune system, either by reinfecting them with
the virus or vaccinating them. He raised the possibility of this chain of events occurring with sequential
doses of rotavirus vaccine.
May 14, 2010 FDA Revises Recommendations for Rotavirus Vaccines
The U.S. Food and Drug Administration today revised its recommendations for rotavirus vaccines for the
prevention of the disease in infants and has determined that it is appropriate for clinicians and health care
professionals to resume the use of Rotarix and to continue the use of RotaTeq.
The agency reached its decision based on a careful evaluation of information from laboratory results from
the manufacturers and the FDA’s own laboratories, a thorough review of the scientific literature, and input
from scientific and public health experts, including members of the FDA’s Vaccines and Related
Biological Products Advisory Committee that convened on May 7, 2010 to discuss these vaccines.
The FDA also considered the following in its decision:
• Both vaccines have strong safety records, including clinical trials involving tens of thousands of
patients as well as clinical experience with millions of vaccine recipients.
• The FDA has no evidence that PCV1 or PCV2 pose a safety risk in humans, and neither is known
to cause infection or illness in humans.
• The benefits of the vaccines are substantial, and include prevention of death in some parts of the
world and hospitalization for severe rotavirus disease in the United States. These benefits
outweigh the risk, which is theoretical.
March 28, 2010 FDA warns that of the 4 million prescriptions for nitroglycerine tablets sold in the
US last year, that most were not FDA approved nor was their safety or effectivenss vetted by the
FDA.
The FDA notified the two major unapproved manufacturers Glenmark Generics and Kronec tthat they had
not meet the rules of the FDA and that they should discontinue manufacturing in the nest 90 days and
marketing of these unapproved nitroglycerine tablets in the next 6 months. The companies said that they
would comply but they took issue with the FDA saying that these products were pre 1938 FDA regulations
and thus grandfathered and not required for FDA review. The FDA has not evaluated these products but
they are NOT FDA approved and thus we are ordering them off the market. Pfizer’s Nitrostat is the only
FDA approved nitroglycerine tablet and it is priced slightly above the other two $21.99 vs. $19.99
May 2010 FDA Action against Johnson and Johnson and McNeil Consumer Healthcare
Ingredients used by Johnson & Johnson in some of the 40 varieties of children's cold medicines recalled
last week were contaminated with bacteria, according to a report by the Food and Drug Administration.
Agency officials said Tuesday none of the company's finished products tested positive for the
contaminants, though such testing is not definitive. "We think the risk to consumers at this point is
remote," said Deborah Autor, director of FDA's drug compliance office. The FDA report, which was posted
online, lists more than 20 manufacturing problems found at the McNeil Consumer Healthcare plant in Fort
Washington, Pa., where the formulas were made. The recalled products include children and infant
formulations of Tylenol, Motrin, Zyrtec and Benadryl. FDA inspectors visited the plant in mid-April and
wrapped up their inspection Friday. J&J issued its "voluntary" recall later that night. Among other
problems, FDA inspectors said the company did not have laboratory facilities to test drug ingredients and
failed to follow up on customer complaints. J&J did not investigate more than 46 complaints received in
the last year about "black or dark specks" in Tylenol products, according to the FDA's report. Additionally,
inspectors found some pieces of equipment covered with thick layers of dust, while others were held
together with duct tape. In a statement Tuesday, J&J called the problems cited by the FDA "unacceptable
to us, and not indicative of how McNeil Consumer Healthcare intends to operate." The FDA reiterated that
serious medical problems with the products are unlikely, but advised consumers to stop using the
medicine as a precaution. Parents are instructed to use generic alternatives instead. J&J has said some
of the recalled medicines may have a higher concentration of the active ingredient than listed on the
bottle. Others may contain particles, while still others may contain inactive ingredients that do not meet
testing requirements. "That warning letter brought us to the point where we thought it was necessary to sit
down with management and discuss our concerns," Autor said. FDA officials said they are considering
taking additional action against J&J, ranging from issuing more warning letters to pursuing criminal action.
15

The FDA’s Reproductive Health Advisory Committee is scheduled to meet on June 18, 2010 to
review the request from Boehringer Ingelheim to approve flibanserin for the treatment of Female
Hypoactive Sexula Desire Disorder or HSDD. Flibanserin (BIMT -17) was originally studied in Europe
for the treatment of depression as it as effects on several of the endogenous neurotransmitters including
reducing serotonin levels while increasing levels of norepinephrine and dopamine. While the trials in
patients with major depressive disorder were not beneficial it did suggest that many women experienced
an unexpected side effect of boosting libido which prompted the company to study this agent for HSDD.
The trials to date have included more than 5,000 premenopausal women ages 18-50 in the US, Canada
and Europe with a diagnosis of HSDD. The 100 mg daily dose increased the number of satisfying sexual
experiences that these women reported from the previous month (a key benchmark that the FDA has set
for approval of agents in this area) from an average of 2.7 up to 4.5, compared to 3.7 among those taking
placebo. The primary adverse effects seen to date have been nausea, dizziness and drowsiness and no
serious complications have been reported to date
Recent findings presented at the 58th Annual Clinical Meeting of the American College of Obstetricians
and Gynecologists in San Francisco, include data from a pre-specified pooled analysis of two pivotal
North American trials (DAISY® and VIOLET®) assessing flibanserin 100mg in pre-menopausal women
suffering from HSDD. The pooled analysis included 1,378 pre-menopausal women with HSDD treated
with either flibanserin 100mg or placebo for 24 weeks. The women evaluated their overall improvement
in "bothersome decreased sexual desire" using the Patient's Global Impression of Improvement (PGI-I),
which is a 7-point scale from 1 (very much improved) through 4 (no change) to 7 (very much worse). By
24 weeks, 48.3 percent of women receiving flibanserin and 30.3 percent of women receiving placebo
reported feeling very much improved, much improved or minimally improved (p

June 13, 2010 Modest lung-cancer signal with angiotensin-receptor blockers
a significant excess of fatal cancers was observed in the CHARM study with the ARB candesartan
(Atacand, AstraZeneca), published in 2003, but that the investigators concluded this finding was likely
due to chance. In the past few years there have been several other multicenter trials with ARBs, so he
and his colleagues decided to perform a meta-analysis of all the available literature and all of the data
publicly available on the FDA website.
New cancer data were available for 61 950 patients from five trials, including only three of the seven FDAapproved
ARBs; most patients in this meta-analysis (85.7%) received telmisartan (Micardis, Boehringer
Ingelheim) as the study drug; the other patients received losartan or candesartan. The five trials with new
cancer data were ONTARGET, PROFESS, LIFE, TRANSCEND, and CHARM-Overall. In addition, data
were available for cancer deaths in LIFE, TRANSCEND, VALIANT, and Val-HeFT.
In the meta-analysis, patients randomly assigned to receive ARBs had a significantly increased risk of
new cancer occurrence, compared with those in the control groups (7.2% vs 6.0%; risk ratio [RR] 1.08;
p=0.016). When analysis was limited to trials where cancer was a prespecified end point, the RR was
1.11 (p=0.001). Dr Sipahi said the number needed to treat to cause one excess cancer was calculated to
be 105 patients for four years, meaning the risk for the individual patient is not huge, "given the millions of
patients on these drugs, this is an important number, because it gives us an idea of potentially how many
excess cancers could be caused by these medications. On a population level, I think these are very
concerning signals."
Among the malignancies examined—lung, breast, and prostate—only new lung-cancer occurrence was
significantly higher in those randomly assigned to ARBs than in control subjects (0.9% vs 0.7%; RR 1.25;
p=0.01). There was also a "weak trend" for an increased risk of prostate cancer with ARB use, Sipahi
said.
In summary this meta-analysis may be viewed as "inconclusive or hypothesis-generating," and the authorf
admits the data "could be viewed as preliminary, so we need more studies in this area." First, this should
involve "the US FDA looking at the individual patient-level data, which they have and we don't have, to
clarify this cancer risk with ARBs. Until this is done wwe should probably use ACE inhibitors first and
consider ARBs when patients do not tolerate an ACE inhibitor. Lancet Oncol 2010; DOI:10.1016/S1470-
2045(10)70106-6. Available at http://www.thelancet.com.
June 14, 2010 The FDA is conducting a safety review of the angiotensin receptor blocker (ARB)
olmesartan (Benicar, Daiichi Sankyo) after determining that diabetic patients taking the drug in two
completed phase 3 trials may have had an excess risk of cardiovascular death. The safety announcement
says that the FDA's review is "ongoing, and the agency has not concluded that Benicar increases the risk
of death. FDA currently believes that the benefits of Benicar in patients with high blood pressure continue
to outweigh its potential risks." The agency also notes that "other controlled clinical trials evaluating
Benicar and other ARBs have not suggested an increased risk of cardiovascular-related death."
In the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, conducted
in Europe, 4447 patients with diabetes and at least one additional cardiovascular risk factor, but no
evidence of renal dysfunction, were randomized to receive either olmesartan at 40 mg/day (n=2232) or
placebo (n=2215). The trial, sponsored by Sankyo Pharma, ended in July 2009.
There were 15 cardiovascular deaths—including seven cases of sudden death, five fatal MIs, two fatal
strokes, and one death related to coronary revascularization—in the olmesartan group compared with a
total of three CV deaths—one sudden death and two fatal strokes—in the control group.
In the Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial
(ORIENT), conduced in Japan and Hong Kong, 566 patients with diabetes and renal dysfunction were
randomized to receive olmesartan at 10 mg/day to 40 mg/day (n=282) or placebo (n=284).
Of the 10 cardiovascular deaths in the olmesartan group, five were sudden death, one was a fatal MI,
three were fatal strokes, and one was of unknown CV cause. Three patients in the control group died, two
from sudden death and one from MI. ORIENT, sponsored by Daiichi Sankyo, was completed in February
2009.
"In considering the results of these trials, it is important to remember that numerous clinical trials with
olmesartan as well as trials with other ARBs have not suggested an increased risk of cardiovascularrelated
death," the FDA announcement notes. Still, the "FDA plans to review the primary data from the
two trials and the total clinical-trial data on olmesartan.
17

Quadravalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine – Gardasil by
Merck (1P)
Indications: Gardasil is a quadravalent, noninfectious, recombinant vaccine prepared from highly purified
virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6,11,16 and 18. It is indicated for
girls and women 9-26 years of age for the prevention of the following diseases caused by Human
Papillomavirus (HPV) types 6,11,16 and 18:
Cervical cancer
Genital warts (condyloma acuminata)
And the following precancerous or dysplastic lesions:
Cervical adenocarcinoma in situ (AIS)
Cervical intraepithelial neoplasia (CIN) grade 2 and 3
Vulvar intraepithelial neoplasia (VIN) grade 2 and 3
Vaginla intraepithelial neoplasia (VaIN) grade 2 and 3
Cervical intraepithelial neoplasia (CIN) grade 1
UPDATE Oct 16, 2009
Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of genital warts
(condyloma acuminata) caused by HPV types 6 and 11
UPDATE: March 19, 2008
Merck & Co. announced that the U.S. Food and Drug Administration (FDA) has accepted, and designated
for priority review, the supplemental Biologics License Application (sBLA) for GARDASIL® [Human
Papillomavirus Quadrivalent] (Types 6, 11, 16, 18) Vaccine, Recombinant] for the potential use in women
aged 27 through 45.
Clinical Pharmacology: Human papillomavirus (HPV) causes squamous cell cervical cancer and its
histologic precursor lesions. HPV is the most common sexually-transmitted infection in the US. The CDC
estimates that about 6.2 million Americans become infected with genital HPV each year and that over half
of all sexually active men and women become infected at some time in their lives. They also estimate that
on average, there are 9,710 new cases of cervical cancer and 3,700 deaths attributed to in the US each
year. Worldwide it is the second most common cancer in women (after breast cancer); estimated to cause
over 470,000 new cases and 223,000 deaths each year.
Cervical cancer prevention focuses on routine screening (IE pap smears) and early intervention including
removing premalignant dysplastic lesions, which has reduced cervical cancer rates by about 75% in
compliant individuals. While the vaccine does not protect against types of HPV not contained within the
vaccine it does protect against the most common HPV types.
HPV 16 and 18 cause approximately: 70% of all cervical cancers, AIS, CIN 3, VIN 2/3, and VaIN
2/3 cases and 50% of CIN 2 cases
HPV 6,11,16 and 18 cause approximately: 35-50% of all CIN 1, VIN 1, and VaIN 1 cases and
90% of genital wart cases
The vaccine contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg
of HPV 16 L1 protein and 20 mcg of HPV 18 L1 protein per 0.5 ml dose with an aluminum adjuvant and is
preservative free.
Clinical Trials: Gardasil was evaluated in 4 placebo-controlled, double-blind, randomized Phase II and III
trials. One Phase II trail only evaluated the HPV 16 component of the vaccine but all of the others
evaluated the approved quadravalent vaccine. The Phase III trails were FUTURE I and II (Females
United To Unilaterally Reduce Endo/Endocervical Disease) FUTURE I had 5442 women and FUTURE II
had 12,157 women all 16 to 26 years of age at enrollment with follow-ups of 2 to 4 years. All subjects
received either the vaccine or placebo on the day of enrollment and 2 and 6 months thereafter. Patients
were included without prescreening fro the presence of HPV infection and the efficacy analysis allowed
enrollment of subjects regardless of baseline HPV status. Subjects who were infected with a particular
vaccine HPV type (and who may have already had disease due to that infection) were not eligible for
prophylactic efficacy evaluations for that type.
18

The primary analysis of efficacy was by per-protocol efficacy (PPE) population, consisting of individuals
who received all three doses of the vaccine within one year of enrollment and did not have major
deviations from the study protocol and were naïve (IE PCR negative and seronegative) to the relevant
HPV types (Types 6,11,16 and 18) prior to dose 1 and through 1 month post dose 3 (IE 7 months).
Efficacy was measured starting after the month 7 visit.
73% of subjects were naïve (IE PCR and seronegative) for all 4 HPV Types at enrollment, 27% had
evidence of prior exposure to or ongoing infection with at least one 4 HPV types in the vaccine and of
these subjects 74% had only one of the HPV types in the vaccine.
Analysis of Efficacy of Gardasil In the PPE Population (Primary Prevention)
Gardasil
Placebo
Population N Cases N Cases % Efficacy (95% CI)
HPV 16 or 18 related CIN 2/3 or AIS
Protocol 005 * 755 0 750 12 100 (65.1, 100)
Protocol 007 231 0 230 1 100 (-3734, 100)
FUTURE I 2200 0 2222 19 100 (78.5, 100)
FUTURE II 5301 0 5258 21 100 (80.9, 100)
Combined 8487 0 8460 53 100 (92.9, 100)
protocols
HPV 6, 11, 16 and 18 related CIN (CIN 1, CIN 2/3) or AIS
Protocol 007 235 0 233 3 100 (-137.8, 100)
FUTURE I 2240 0 2258 37 100 (89.5, 100)
FUTURE II 5383 4 5370 43 90.7 (74.4, 97.6)
Combined 7858 4 7861 83 95.2 (87.2, 98.7)
protocols
HPV 6, 11, 16, 18 related Genital Warts
Protocol 007 235 0 233 3 100 (-139.5, 100)
FUTURE I 2261 0 2279 29 100 (86.4, 100)
FUTURE II 5401 1 5387 59 98.3 (90.2, 100)
Combined 7897 1 7899 91 98.9 (93.7, 100)
protocols
• Protocol 005 only evaluated HPV 16
• All P-values were less than 0.001
Efficacy in subjects with current or prior infection: There was no clear evidence of protection from disease
caused by HPV types for which the subjects were PCR positive and/or seropositive at baseline but
subjects were protected from clinical disease caused by the remaining vaccine HPV types.
Gardasil does not prevent infection with the HPV types not contained in the vaccine. Cases of disease
due to non-vaccine types were observed among recipients of Gardasil and placebo in both Phase II and
III trials.
The immunogenicity of Gardasil was assessed in 8915 women 18-26 years of age (Gardasil N=4666 and
placebo N=4249) and also in female adolescents 9-17 years of age (Gardasil N=1471 and placebo
N=583). Overall 99.8%, 99.8%, 99.8% and 99.5% of girls and women who received Gardasil became
anti- HPV 6, anti HPV 11, anti HPV 16 and anti HPV 18 were seropositive, respectively, by 1 month post
dose 3 across all age groups tested. The geometric mean titer (GMT) peaked at month 7 and declined
through month 24 and then stabilized through month 36 at levels significantly above baseline. The
duration of immunity following a complete schedule of immunization with Gardasil has not been
established. These immunogenicity trials are the basis for the FDA approval in girls from 9-15 as the
GMTs were similar to those seen in women from 16 to 26 years of age.
19

Contraindications: hypersensitivity to the components of the vaccine and individuals who develop
symptoms indicative of hypersensitivity after receiving a dose of Gardasil should not receive further
doses.
Precautions: remember that the vaccine will not prevent all cases of HPV infection and it is not a
substitute for routine cervical cancer screening (IE pap testing) and it does not prevent other types of
sexually transmitted diseases. The vaccine does not treat active genital warts, cervical cancer, CIN, VIN,
or VaIN. The vaccine dose not protect against non-vaccine types of HPV.
Gardasil is not recommended for use in pregnant women (Pregnancy category B).Merck is maintaining a
Pregnancy Registry. Limited data but 15 cases of congenital anomaly in pregnancies that occurred in the
vaccine treated patients vs. 16 cases in the placebo group.
Patients with impaired immune response, on immunosuppressive therapy or HIV positive may have
reduced antibody response to active immunization.
Drug Interactions: Use with other vaccines is limited to concomitantly administered Hepatitis B vaccine
at a separate injection site where no loss of effects was observed. Data on any other vaccine is not
available.
Use of hormonal contraception did not alter vaccine efficacy in the study populations.
Adverse Effects: Vaccine-related common adverse effects were evaluated using a vaccination report
card (VRC)-aided surveillance for 14 days after each injection of Gardasil or placebo,
20

Vaccine-related Injection-site and Systemic Adverse experiences
Gardasil Aluminum Placebo Saline Placebo
Adverse Experience N=5088 N=3470 N=320
Injection Site
Pain 83.9% 75.4% 48.6%
Swelling 25.4% 15.8% 7.3%
Erythema 24.6% 18.4% 12.1%
Pruritis 3.1% 2.8% 0.6%
Fever was reported in 10.3% of Gardasil patients vs. 8.6% of placebo treated patients. Mild to moderate
swelling and erythema did seem to increase slightly with each subsequent dose over the 3 dose series.
All-cause Common Systemic Adverse Experiences
Adverse Experience Gardasil Placebo
(day’s 1-15 postvaccination) N=5088 N=3790
Pyrexia 13.0% 11.2%
Nausea 6.7% 6.6%
Nasopharyngitis 6.4% 6.4%
Dizziness 4.0% 3.7%
Diarrhea 3.6% 3.5%
Vomiting 2.4% 1.9%
Myalgia 2.0% 2.0%
Cough 2.0% 1.5%
Toothache 1.5% 1.4%
Upper respiratory tract infection 1.5% 1.5%
Malaise 1.4% 1.2%
Arthralgia 1.2% 0.9%
Insomnia 1.2% 0.9%
Nasal congestion 1.1% 0.9%
Dosage/Cost: Gardasil is to be administered IM as 3 separate 0.5 ml doses as follows:
Initial dose (girls and women aged 9-26 years as well as boys and men aged 9-26 years) as
elected
Second dose; 2 months after the first dose
Third dose: 6 months after the first dose
21

Gardasil should be administered IM in the deltoid region of the upper arm or in the higher anterolateral
area of the thigh. (Subcutaneous and interdermal administration have not been studied and are not
recommended).
No reconstitution or dilution is necessary. Keep refrigerated between 2-8 degrees C or 36-46 degrees F.
Shake well before use to maintain suspension of the vaccine. Available in both a single dose vial and a
single dose pre-filled syringe. Cost is about $120.00 per dose of $360.00 for the 3 dose series.
Summary: This is the first FDA approved vaccine that has the potential to significantly reduce the risk of
the second leading cancer in women (cervical cancer) and the leading cause of sexually transmitted
disease. While it is not a means to reduce recommended monitoring or screening for cervical cancer and
it is not a reason to neglect the need for safe sexual practices it is a major therapeutic breakthrough that
should be of significant public health benefit worldwide. The Advisory Committee on Immunization
Practices (ACIP) (Minimum age: 9 years)
• Administer the first dose of the HPV vaccine series to females at age 11–12 years.
• Administer the second dose 2 months after the first dose and the third dose 6 months after the first
dose.
• Administer the HPV vaccine series to females at age 13–18 years if not previously vaccinated. HPV
vaccination is recommended for all females aged

SAXAGLIPTIN - Onglyza (Bristol-Myers Squibb / Astra Zeneca) 1S
INDICATIONS: Saxagliptin is indicated for use as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus. It has been evaluated for use as monotherapy or in
combination with other antidiabetic agents, including metformin, sulfonylureas, and thiazolidinediones. It
has not been assessed in combination with insulin.
Saxagliptin and sitagliptin share the same Food and Drug Administration (FDA)-approved indication.
CLINICAL PHARMACOLOGY: Saxagliptin is a reversible, competitive dipeptidyl peptidase-4 (DPP-4)
inhibitor. DPP-4 inhibitors lower blood glucose by preventing the breakdown of glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus prolonging the activity of these
peptides. Saxagliptin is 10-fold more potent than sitagliptin and vildagliptin at inhibiting DPP-4. The
saxagliptin active metabolite is 2-fold less potent than saxagliptin. Both saxagliptin and its active
metabolite are more selective for inhibition of DPP-4 than DPP-8 (400- and 950-fold) and DPP-9 (75- and
160-fold). Saxagliptin and its active metabolite have exhibited slow dissociation from DPP-4, with a halflife
of dissociation of 50 and 23 minutes, respectively. Plasma DPP-4 inhibition 24 hours after saxagliptin
2.5 and 400 mg doses was 50% and 79% of predose, respectively. Maximal inhibition was observed at a
150 mg dose.
After an oral glucose load or meal, saxagliptin DPP-4 inhibition results in a 2- to 3-fold increase in
circulating levels of active GLP-1 and GIP, decreased glucagon concentration, and increased insulin
secretion from pancreatic beta-cells.
PHARMACOKINETICS: Saxagliptin has high oral bioavailability (75% in animal models). Systemic
exposure is dose-proportional over doses from 2.5 to 400 mg. Peak concentrations (C max ) of saxagliptin
are reached within 2 hours of oral administration; C max of the active metabolite are reached within 4 hours.
Administration with a high-fat meal slightly delayed absorption (approximately 20 minutes), but was
associated with a 27% increase in overall exposure.
Saxagliptin is metabolized via CYP 3A4/5. Mean saxagliptin half-life is 2.2 to 3.8 hours; the half-life of the
active metabolite is 3 to 7.4 hours. 6 Approximately 70% of the dose is recovered in the urine as
saxagliptin or the active metabolite; 12% to 29% was recovered as the parent drug.
Saxagliptin pharmacokinetics did not differ by gender, although levels of the active metabolite were
increased approximately 25% in females.
Saxagliptin C max were increased 1.2-fold and area under the curve (AUC) values were increased 1.6-fold
in elderly subjects compared with younger subjects. Elderly subjects had a greater volume of distribution
and reduced metabolic and renal clearance of saxagliptin. Age-related decline in renal function accounted
for 50% of the difference in pharmacokinetics. Dosage adjustments on the basis of age are not
necessary.
In patients with hepatic function impairment (Child-Pugh class A, B, or C), a trend toward increased
saxagliptin levels (AUC increased 10% to 77%) and reduced levels of the active metabolite (AUC reduced
by 7% to 33%) were observed; however, routine dosage adjustments do not appear necessary.
In patients with mild renal impairment, the AUC of saxagliptin and its active metabolite were 20% and
70%, higher, respectively, than those in patients with healthy renal function. In patients with moderate to
severe renal impairment, AUC levels of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold
higher than in patients with healthy renal function. Dose restrictions are advised for patients with
moderate and severe renal impairment and patients with end-stage renal disease requiring hemodialysis.
23

Table 1. Pharmacokinetics of Saxagliptin and Sitagliptin
Saxagliptin
Sitagliptin
T max
a
2 h 1 to 4 h
Half-life 2.5 h 12.4 h
Protein binding Negligible 38%
Metabolism CYP3A4/5 Minor
Active metabolite Yes No
Elimination Urine; 70% as metabolites, 12% to 29% unchanged drug Urine; 79% unchanged drug
a T max = time to maximum plasma concentration.
COMPARATIVE EFFICACY: Saxagliptin monotherapy was assessed in a 12-week, randomized, doubleblind,
placebo-controlled study enrolling 423 drug-naive patients with type 2 diabetes and inadequate
glycemic control (baseline A 1c between 6.8% and 9.7%). Mean baseline A 1c was 7.7% to 8%. Mean age
was 51.4 to 55.2 years; approximately 60% were men and approximately 85% were white. Following a 2-
week washout period, patients received saxagliptin 2.5, 5, 10, 20, or 40 mg, or placebo once daily for 12
weeks (low-dose cohort) or saxagliptin 100 mg or placebo once daily for 6 weeks (high-dose cohort). The
primary outcome was the saxagliptin dose response assessed as change in A 1c from baseline at week 12.
Saxagliptin reduced A 1c by 0.7% to 0.9% from an average baseline of 7.9% compared with a 0.27%
reduction with placebo (P < 0.007). Placebo-subtracted adjusted mean changes from baseline to week 12
for saxagliptin ranged from −0.45% to −0.63%. An A 1c of less than 7% was achieved in 41% to 53% of
saxagliptin-treated patients with a baseline A 1c of 7% or more compared with only 20% of placebo
recipients. Placebo-subtracted reductions in fasting serum glucose were 14 to 25 mg/dL in the low-dose
cohort. Postprandial glucose levels at 60 minutes after a meal were reduced 24 to 41 mg/dL compared
with placebo. Additional study results are summarized in Table 2. In the high-dose cohort, the mean
change in A 1c following 6 weeks of therapy was −1.09% in the saxagliptin group compared with −0.36% in
the placebo group. Of the patients with an A 1c of 7% or more than baseline, an A 1c of less than 7% was
achieved in 66% on saxagliptin compared with 22% on placebo. Reductions in fasting serum glucose
were evident within 2 weeks in all saxagliptin-treatment groups. (Diabetes Obes Metab. 2008;10(5):376-
386)
Table 2. Results of the Saxagliptin Dose-Ranging Study in the Treatment
of Patients With Type 2 Diabetes
Placebo
Saxagliptin
2.5 mg 5 mg 10 mg 20 mg 40 mg
A 1c < 7% 10/50
(20%)
20/40 (50%) 16/34 (47%) 20/49 (41%) 21/42
(50%)
21/40
(53%)
A 1c adjusted mean
change from baseline
(95% CI a )
−0.27
(−0.49 to
−0.05)
−0.72
(−0.97 to
−0.48)
−0.9
(−1.17 to
−0.63)
−0.81
(−1.03 to
−0.58)
−0.74
(−0.98 to
−0.5)
−0.8
(−1.04 to
−0.56)
Fasting serum glucose
adjusted mean change
from baseline (95% CI)
2.81 mg/dL
(−5.25 to
10.87)
−10.85
mg/dL
(−19.92 to
−1.77)
−21.68
mg/dL
(−31.11 to
−12.24)
−15.91
mg/dL
(−24.1 to
−7.71)
−13.61
mg/dL
(−22.42 to
−4.8)
−16.36
mg/dL
(−25.42 to
−7.3)
Postprandial glucose at
60 min, adjusted mean
change from baseline
(95% CI)
−1.41
mg/dL
(−13.39 to
10.56)
−24.42
mg/dL
(−37.67 to
−11.16)
−35.3
mg/dL
(−50.75 to
−19.86)
−41.04
mg/dL
(−53.13 to
−28.94)
−27.54
mg/dL
(−41.27 to
−13.8)
−33.98
mg/dL
(−47.2 to
−20.75)
Body weight mean −1.03 kg −0.94 kg −0.23 kg −1.28 kg −0.11 kg 0.51 kg
24

change from baseline
(95% CI)
(−1.8 to
−0.27)
(−1.64 to
−0.23)
(−1.07 to
0.6)
(−2.09 to
−0.47)
(−0.81 to
0.59)
(−0.41 to
1.42)
a CI = confidence interval.
Saxagliptin monotherapy was also evaluated in a randomized, double-blind, placebo-controlled study
enrolling 401 drug-naive patients with type 2 diabetes mellitus and A 1c of 7% to 10% (mean, 7.9%).
Patients received saxagliptin 2.5, 5, or 10 mg once daily, or placebo for 24 weeks. An additional openlabel
cohort of 66 patients with A 1c between 10% and 12% received saxagliptin 10 mg once daily.
Placebo-subtracted reductions in A 1c from baseline to week 24 were −0.62% with saxagliptin 2.5 mg,
−0.64% with saxagliptin 5 mg, and −0.73% with saxagliptin 10 mg (all P < 0.0001). Fasting plasma
glucose was also reduced at each dose, with placebo-subtracted reductions of 21 mg/dL with 2.5 mg, 15
mg/dL with 5 mg, and 23 mg/dL with 10 mg (all P < 0.0075). Postprandial glucose AUC was also reduced
with all 3 saxagliptin doses. Achievement of a target A 1c of less than 7% at week 24 was achieved in 35%
of patients in the 2.5 mg group (P = 0.1141), 38% in the 5 mg group (P = 0.0443), and 41% in the 10 mg
group (P = 0.0133) compared with 24% of placebo-treated patients. In the open-label cohort, A 1c was
reduced 1.9% and fasting plasma glucose was reduced 33 mg/dL. (Current Medical Research and
Opinion, 2009; 25:2401-2411).
Saxagliptin was evaluated as monotherapy or in combination with metformin as initial therapy in a
randomized, double-blind study enrolling 1,306 drug-naive patients with type 2 diabetes. They were
required to have an A 1c of 8% to 12%, fasting C-peptide concentration of at least 1 ng/mL, and body mass
index no more than 40 kg/m 2 . Patients received saxagliptin 5 mg plus metformin 500 mg, saxagliptin 10
mg plus metformin 500 mg, saxagliptin 10 mg plus placebo, or metformin 500 mg plus placebo daily by
mouth for 24 weeks. During weeks 1 to 5, the dosage of the metformin was increased by 500 mg/day
based on fasting plasma glucose level, up to maximum of 2,000 mg/day. Mean daily metformin doses at
week 24 were comparable in the 3 metformin groups (1,790, 1,776, and 1,817 mg, respectively). The
primary outcome for the study was the change in A 1c from baseline to week 24. The greatest
improvements in the primary outcome occurred with the combination regimens rather than either
monotherapy regimen (see Table 3). Postprandial blood glucose AUC was also reduced to a greater
extent with the combination regimens rather than either monotherapy regimen (P < 0.0001) (Diabetes
Obes Metab. 2009;11(6):611-622).
Table 3. Monotherapy vs Combination Initial Therapy in the Treatment of Patients
With Type 2 Diabetes
Saxagliptin 5 mg +
Metformin (n = 320)
Saxagliptin 10 mg +
Metformin (n = 323)
Saxagliptin 10
mg (n = 335)
Metformin
(n = 328)
Mean A 1c baseline 9.4% 9.5% 9.6% 9.4%
Adjusted mean A 1c change −2.5% a,b −2.5% a,b −1.7% −2%
Mean A 1c week 24 6.9% 7% 7.9% 7.5%
Fasting plasma glucose
change
−60 mg/dL a,c −62 mg/dL a,b −31 mg/dL −47 mg/dL
A 1c < 7% 60.3% a,b 59.7% a,b 32.2% 41.1%
NNT d —A 1c < 7%
(compared with metformin
monotherapy)
5.2 5.4 — —
A 1c < 6.5% 45.3% a,b 40.6% a,e 20.3% 29%
NNT—A 1c < 7%
(compared with metformin
monotherapy)
6.1 8.6 — —
a P < 0.0001 vs saxagliptin 10 mg.; b P < 0.0001 vs metformin.; c P = 0.0002 vs metformin.
d NNT = number needed to treat.; e P = 0.0026 vs metformin.
25

An additional randomized study assessed saxagliptin in combination with metformin in 743 patients with
type 2 diabetes mellitus with inadequate glycemic control (A 1c , 7% to 10%) on a stable metformin dose
(1,500 to 2,550 mg/day). Patients received saxagliptin 2.5, 5, or 10 mg, or placebo once daily in addition
to their stable metformin dose for 24 weeks. Mean baseline A 1c was 8% and the mean fasting plasma
glucose was 176 mg/dL. All saxagliptin doses were associated with reductions in A 1c (all P < 0.0001),
fasting plasma glucose (all P < 0.0001), and postprandial glucose AUC (all P < 0.0001), and a greater
percentage of patients achieving an A 1c of less than 7% (Table 4). Weight was not altered relative to
placebo. In a long-term extension of this study, placebo subtracted changes in A 1c from baseline through
102 weeks were −0.62% with saxagliptin 2.5 mg, −0.72% with saxagliptin 5 mg, and −0.52% with
saxagliptin 10 mg. The percentage of patients who discontinued from the study or who required additional
drug therapy because of lack of glycemic control were 58.3% in the saxagliptin 2.5 mg group, 51.8% in
the saxagliptin 5 mg group, and 56.9% in the saxagliptin 10 mg group, compared with 71.5% in the group
receiving metformin alone (Diabetes Care 2009;32:1649–1655)
Table 4. Saxagliptin Added to Metformin in the Treatment of Patients With Type 2 Diabetes
Placebo
Saxagliptin
2.5 mg 5 mg 10 mg
A 1c adjusted mean change from baseline +0.13% −0.59% a −0.69% a −0.58% a
Fasting serum glucose adjusted mean change
from baseline
+1.24
mg/dL
−14.31 −22.03 −20.5
mg/dL a mg/dL a mg/dL a
Body weight mean change from baseline −1 kg −1.5 kg −0.9 kg −0.5 kg
A 1c < 7% 17% 37% a 44% a 44% a
NNT—A 1c < 7% — 5 3.7 3.7
a P < 0.0001 vs placebo.
Saxagliptin was also assessed as an addition to submaximal-dose sulfonylurea in comparison with
uptitration of the sulfonylurea dose in a randomized, double-blind, double-dummy study enrolling 768
patients with type 2 diabetes and A 1c of 7.5% to 10% on a submaximal sulfonylurea dose. Eligible patients
entered a 4-week period during which they discontinued their current sulfonylurea and received openlabel
glyburide 7.5 mg daily. Patients received saxagliptin 2.5 or 5 mg once daily plus glyburide 7.5 mg, or
placebo plus glyburide 10 mg for 24 weeks. Doses were administered twice daily before the morning and
evening meals, with saxagliptin dosed in the morning and the glyburide dose split twice daily. Blinded
uptitration of the glyburide dose was allowed in the glyburide-only arm to a maximum total daily dose of
15 mg; 92% of these patients were uptitrated to 15 mg dose by week 24. Reductions in A 1c and fasting
plasma glucose were greater in the saxagliptin treatment groups (Table 5). Postprandial glucose AUC
was also reduced to a greater extent with both saxagliptin regimens compared with glyburide alone (Int J
Clin Pract, September 2009, 63, 9, 1395–1406)
Table 5. Saxagliptin + Glyburide vs Glyburide Alone in the Treatment of Patients With Type 2 Diabetes
Saxagliptin 2.5 mg
+ Glyburide 7.5 mg
(n = 320)
Saxagliptin 5 mg
+ Glyburide 7.5 mg
(n = 323)
Glyburide
≤ 15 mg
(n = 335)
Mean A 1c baseline 8.4% 8.5% 8.4%
Adjusted mean A 1c change −0.54% a −0.64% a +0.08%
Mean A 1c week 24 7.8% 8.7% 8.5%
Fasting plasma glucose change −7 mg/dL b −10 mg/dL c +1 mg/dL
A 1c < 7% 22.4% a 22.8% a 9.1%
26

NNT—A 1c < 7% (compared with
glyburide monotherapy)
7.5 7.3 —
A 1c < 6.5% Not reported 10.4% d 4.5%
NNT—A 1c < 6.5% (compared with
glyburide monotherapy)
— 17 —
a P < 0.0001 vs glyburide alone; b P = 0.0218 vs glyburide alone; c P = 0.002 vs glyburide alone;
d P = 0.0117 vs glyburide alone.
Results from a study assessing saxagliptin added to a thiazolidinedione were also reported in a meeting
abstract. This randomized, double-blind, placebo-controlled study enrolled 565 patients with type 2
diabetes inadequately controlled (A 1c of 7% to 10.5%, mean 8.3%) on stable thiazolidinedione therapy
(pioglitazone 30 or 45 mg or rosiglitazone 4 or 8 mg). Patients received saxagliptin 2.5 or 5 mg, or
placebo once daily in conjunction with their stable thiazolidinedione dose for 24 weeks. Glycemic control
was improved with the addition of either saxagliptin dose (Table 6). Postprandial glucose AUC was also
reduced to a greater extent with saxagliptin (Diabetologia. 2008;51(suppl 1):S342).
Table 6. Saxagliptin + a Thiazolidinedione in the Treatment of Patients With Type 2 Diabetes
Saxagliptin 2.5 mg
+ Thiazolidinedione
Saxagliptin 5 mg
+ Thiazolidinedione
Placebo +
Thiazolidinedione
Adjusted mean A 1c change −0.66% (P = 0.0007) −0.94% (P < 0.0001) −0.3%
Fasting plasma glucose change −14.3 mg/dL (P =
0.0053)
−17.3 mg/dL (P =
0.0005)
−2.8 mg/dL
A 1c < 7% 42.2% (P = 0.001) 41.8% (P = 0.0013) 25.6%
NNT—A 1c < 7% (compared with
thiazolidinedione monotherapy)
6 6.2 —
Additional studies, not yet published but included in the new drug application, assessed saxagliptin when
added to a thiazolidinedione, and as initial therapy in conjunction with metformin.
Ongoing clinical trials obtained from ClinicalTrials.gov include several studies of saxagliptin as first-line
therapy in patients with type 2 diabetes not controlled with diet and exercise, several studies assessing
saxagliptin use in conjunction with metformin, and 1 assessing saxagliptin added to insulin or insulin plus
metformin.
CONTRAINDICATIONS - There are no contraindications listed in the prescribing information.
WARNINGS AND PRECAUTIONS - When used in conjunction with an insulin secretagogue (eg,
sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of
hypoglycemia.
Saxagliptin, like other antidiabetic drugs, has not been established to reduce macrovascular risk in clinical
studies.
Safety and effectiveness of saxagliptin have not been established in patients younger than 18 years of
age.
Saxagliptin is in Pregnancy Category B. Teratogenicity was not observed in animal studies. Saxagliptin
has not been studied in pregnant women. It should be used during pregnancy only if clearly needed.
Saxagliptin is excreted in the milk of lactating rats at approximately 1:1 ratio with plasma drug
concentrations. It is not know if it is excreted in human milk. Caution is advised if saxagliptin is
administered to a breast-feeding woman.
27

Contraindications
Table 7. Contraindications, Warnings and Precautions Included in the
Product Labeling of Saxagliptin and Sitagliptin
History of serious hypersensitivity to the agent
Warnings and precautions
Saxagliptin
Sitagliptin
Dosage adjustment in renal insufficiency X X
Hypoglycemia risk with concomitant sulfonylurea X X
Serious allergic and hypersensitivity reactions
No data on macrovascular risk reduction X X
Special populations
Children Not established Not established
Pregnancy Category B B
Breast-feeding mothers Caution Caution
ADVERSE REACTIONS: The most common adverse reactions, occurring in more than 5% of treated
patients in clinical trials, were upper respiratory tract infection, urinary tract infection, and headache.
Peripheral edema was reported more commonly in patients treated with saxagliptin in combination with a
thiazolidinedione than in patients treated with placebo with a thiazolidinedione.
Hypoglycemia occurred more commonly in patients treated with the combination of saxagliptin plus a
sulfonylurea than in patients treated with placebo plus a sulfonylurea. Confirmed hypoglycemia (glucose
50 mg/dL or less) was observed infrequently in saxagliptin clinical trials.
Hypersensitivity-related events, such as urticaria or facial edema, occurred more frequently in patients
treated with saxagliptin compared with placebo (1.5% vs 0.4%).
Small, dose-dependent reductions in mean absolute lymphocyte count were observed; the clinical
significance of this observation has not been determined. In patients with unusual or prolonged infection,
lymphocyte count should be measured.
Saxagliptin dosages of up to 40 mg daily were not associated with effects on QTc interval. In an
assessment of pooled results from 8 saxagliptin studies in which overall saxagliptin exposure was 3,758
patient-years and 81% of patients had at least 1 cardiovascular risk factor in addition to diabetes, there
was no evidence of increased cardiovascular risk with saxagliptin as monotherapy or in combination with
other diabetes agents. The hazard ratio (HR) for major adverse cardiovascular events (eg, stroke,
myocardial infarction, cardiovascular death) relative to comparator agents (eg, placebo, metformin,
glyburide) was 0.44 (95% CI, 0.24 to 0.82; 0.7% vs 1.4%) and the HR for acute cardiovascular events,
including cardiac revascularization procedures, was 0.59 (95% CI, 0.35 to 1; 1.1% vs 1.8%).
DRUG INTERACTIONS: Coadministration of saxagliptin with strong CYP3A4/5 inhibitors resulted in
increased saxagliptin concentrations. The saxagliptin dose should be limited to 2.5 mg daily in patients
concomitantly receiving strong CYP3A4/5 inhibitors (eg, ketoconazole, atazanavir, clarithromycin,
indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Increases in saxagliptin exposure
may also occur with moderate CYP3A4/5 inhibitors (eg, diltiazem, amprenavir, aprepitant, erythromycin,
fluconazole, fosamprenavir, grapefruit juice, verapamil); however, routine dosage adjustment is not
recommended.
Coadministration of saxagliptin with CYP3A4/5 inducers was associated with a reduction in saxagliptin
X
X
28

exposure, but no change in exposure to the active metabolite or in DPP-4 activity inhibition. Saxagliptin
dosage adjustments are not necessary.
Clinically important pharmacokinetic interactions have not been observed between saxagliptin and
digoxin, metformin, glyburide, pioglitazone, or simvastatin. Coadministration of saxagliptin with
magnesium and aluminum hydroxides plus simethicone, famotidine, or omeprazole did not alter the
pharmacokinetics of saxagliptin or its active metabolite.
DOSING: The recommended dosage is 2.5 or 5 mg once daily taken regardless of meals. The 2.5 mg
daily dosage is recommended for patients with moderate or severe renal impairment, or end-stage renal
disease (creatinine clearance [CrCl] 50 mL/min or less), and for patients also taking strong CYP3A4/5
inhibitors (eg, ketoconazole). For patients with end-stage renal disease undergoing hemodialysis,
saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients
undergoing peritoneal dialysis.
Usual dose
Dose in special populations
Renal
impairment
Hepatic
impairment
Table 8. Dosing Recommendations for Saxagliptin and Sitagliptin
Saxagliptin
2.5 to 5 mg once daily
with or without food
2.5 mg once daily
if CrCl ≤ 50 mL/min
No dosage adjustment
Sitagliptin
100 mg once daily with or without food
50 mg once daily if CrCl 30 to 50 mL/min,
25 mg once daily if CrCl < 30 mL/min
No dosage adjustment
Elderly No dosage adjustment No dosage adjustment
Drug
interactions
2.5 mg once daily if on potent
CYP3A4/5 inhibitor
No dosage adjustment
PRODUCT AVAILABILITY/COST and STORAGE: Saxagliptin received FDA approval on July 31, 2009.
It is available as 2.5 and 5 mg tablets. The 5 mg tablets are supplied in bottles of 30, 90, and 500, as well
as a unit-dose blister package of 100 tablets; the 2.5 mg tablets are supplied in bottles of 30 and 90.
Onglyza costs $189.98/30 tabs in either strength and Januvia costs $193.58/30 100mg tabs on
drugstore.com. Saxagliptin tablets should be stored at room temperature (20° to 25°C; 68° to 77°F), with
excursions permitted between 15° and 30°C (59° and 86°F).
Table 9. Available Dosage Forms and Packaging for Saxagliptin and Sitagliptin
Saxagliptin
Onglyza
2.5 mg tablets (30s and 90s)
5 mg tablets (30s, 90s, 500s, and
UD a 100s)
a UD = unit-dose.
Sitagliptin
Januvia
25 mg tablets (30s, 90s, and UD 100s)
50 mg tablets (30s, 90s, and UD 100s)
100 mg tablets (30s, 90s, 500s, 1,000s, and UD 100s)
Janumet
Sitagliptin 50 mg/metformin hydrochloride 500 mg (60s, 180s,
1,000s, and UD 50s)
Sitagliptin 50 mg/metformin hydrochloride 1,000 mg (60s, 180s,
1,000s, and UD 50s)
CONCLUSION: Saxagliptin is an alternative to sitagliptin for the treatment of patients with type 2
diabetes. It is intended to be used as an adjunct to diet and exercise to improve glycemic control in adults
29

with type 2 diabetes mellitus. It can be use as monotherapy or in combination with other antidiabetic
agents, including metformin, sulfonylureas, and thiazolidinediones. The safety and efficacy of combining
saxagliptin with insulin has not been assessed.
Saxagliptin and sitagliptin appear to have very similar efficacy in the treatment of patients with type 2
diabetes. Both drugs can be given once daily without regards to meals and are generally well tolerated.
Postmarketing experience and direct comparative studies are necessary to determine which drug may be
more efficacious and/or safer.
3-9-2010 the companies announced a new outcome trial SAVOR – TIMI 53 whioch will enroll ~12,000
patients with CHD or multiple risk factors and follow them for about 5 years
30

Liraglutide – Victoza by Novo-Nordisk
INDICATIONS: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use:
•Not recommended as first-line therapy for patients inadequately controlled on diet and exercise.
•Has not been studied sufficiently in patients with a history of pancreatitis. Use caution.
•Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
•Has not been studied in combination with insulin.
CLINICAL PHARMACOLOGY: Liraglutide is a human analog of the glucagon-like peptide-1 (GLP-1) with
97% amino acid sequence homology to endogenous human GLP-1. It differs from human GLP-1 by the
addition of a C14 fatty acid. As a GLP-1 analog, it induces its activity through a glucose-dependent
stimulation of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying, and
reduction in appetite. Liraglutide also improves beta cell function in patients with type 2 diabetes.
GLP-1 has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes,
dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is
stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after
subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once
daily administration, is a result of self-association that delays absorption, plasma protein binding and
stability against metabolic degradation by DPP-IV and NEP.
Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after
treatment to steady state with 0.6, 1.2 and 1.8 mg liraglutide or placebo. Compared to placebo, the
postprandial plasma glucose AUC0-300min was 35% lower after liraglutide 1.2 mg and 38% lower after
liraglutide 1.8 mg.
PHARMACOKINETICS: Liraglutide is slowly absorbed following subcutaneous administration, reaching
peak levels at 9 to 12 hours after dosing. Absolute bioavailability is 51%. Pharmacokinetics were similar
with administration in the upper arm, abdomen, and thigh. A dose-proportional increase in exposure was
observed with increasing doses over a dose range of 1.25 to 12.5 mcg/kg.
Liraglutide 20 mcg/kg administered once daily subcutaneously exhibited less peak to trough variation
than exenatide 10 mcg/kg administered twice daily subcutaneously.
Liraglutide has a half-life of 11 to 15 hours following subcutaneous administration; allowing for once daily
subcutaneous administration. Liraglutide is metabolized to a number of minor metabolites, which are
excreted in the urine and feces. Liraglutide excretion in the urine is negligible.
Liraglutide pharmacokinetics were not substantially altered in subjects with renal function impairment,
including subjects with severe renal function impairment (creatinine clearance less than 30 mL/min) or
end-stage renal disease requiring dialysis. Liraglutide is not significantly removed by dialysis. Liraglutide
exposure appears to be reduced in patients with hepatic function impairment. Patients with renal or
hepatic function impairment should be dosed according to their glycemic control.
Elderly -Age had no effect on the pharmacokinetics of liraglutide based on a pharmacokinetic study in
healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80
years of age.
Gender -Based on the results of population pharmacokinetic analyses, females have 34% lower weightadjusted
clearance of liraglutide compared to males. Based on the exposure response data, no dose
adjustment is necessary based on gender.
Race and Ethnicity -Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the
results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/Non-
Hispanic subjects.
31

COMPARATIVE EFFICACY: Monotherapy
In this 52-week trial, 746 patients were randomized to liraglutide 1.2 mg, liraglutide 1.8 mg, or glimepiride
8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks,
increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with
liraglutide 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA1c compared to
glimepiride. The percentage of patients who discontinued due to ineffective therapy was 3.6% in the
liraglutide 1.8 mg treatment group, 6.0% in the liraglutide 1.2 mg treatment group, and 10.1% in the
glimepiride-treatment group. LEAD-3 Mono Lancet,2009:373:473-481
Results of a 52-week monotherapy trial (Intent to treat using LOCF)
Liraglutide
1.8 mg
Liraglutide 1.2
mg
Glimepiride
8 mg
Intent-to-Treat Population (N) 246 251 248
HbA1c (%) (Mean) Baseline 8.2 8.2 8.2
Change from Baseline -1.1 -0.8 -0.5
Difference from glimepiride arm -0.6** -0.3*
(adjusted mean)
Patients (%) achieving A1c

Difference from
glimepiride + metformin
arm (adjusted mean)
Patients (%) achieving A1c

Difference from placebo + -47** -46**
glimepiride (adjusted mean)
Body Weight (kg) mean baseline 83 80 81.9 80.6
Change from baseline (adjusted -0.2 +0.3 -0.1 +2.1
mean)
Difference from placebo + -0.1 +0.4
glimepirise (adjusted mean)
**p-value

Add-on to Metformin and Thiazolidinedione
In this 26-week trial, 533 patients were randomized to liraglutide 1.2 mg, liraglutide 1.8 mg or placebo, all
as add-on to rosiglitazone (8 mg) plus metformin (2000 mg). Patients underwent a 9 week run-in period
(3- week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone
(starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with
increasing weekly increments of 500 mg to a final dose of 2000 mg/day). Only patients who tolerated the
final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose
maintenance phase were eligible for randomization into the trial.
Treatment with liraglutide as add-on to metformin and rosiglitazone produced a statistically significant
reduction in mean HbA1c compared to placebo add-on to metformin and rosiglitazone. The percentage of
patients who discontinued due to ineffective therapy was 1.7% in the liraglutide 1.8 mg + metformin +
rosiglitazone treatment group, 1.7% in the liraglutide 1.2 mg + metformin + rosiglitazone treatment group,
and 16.4% in the placebo + metformin + rosiglitazone treatment group. (LEAD-4 Met+TZD). Diabetes
Care 2009; 32: 1224–1230.
Results of a 26-week trial of liraglutide as add-on to metformin and thiazolidinedione
Liraglutide 1.8
mg + metformin
+ rosiglitazone
Liraglutide 1.2
mg + metformin
+ rosiglitazone
Placebo +
metformin +
rosigltazone
Intent to treat (N) 178 177 175
HbA1c (%) mean baseline 8.6 8.5 8.4
Change from baseline (adjusted -1.5 -1.5 -0.5
mean)
Difference from placebo + -0.9** -0.9**
metformin + rosiglitazone
(adjusted mean)
% Patients with A1c

hypoglycemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year;
rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycemia). Two patients
taking both exenatide and a sulfonylurea had a major hypoglycemic episode. Liraglutide once a day
provided significantly greater improvements in glycemic control than did exenatide twice a day, and was
generally better tolerated.
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS:
Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma
(MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Risk of Thyroid C-cell Tumors BLACK BOX WARNING
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas
and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical
Toxicology. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant
increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to
controls. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid
carcinoma (MTC), in humans. It is unknown whether monitoring with serum calcitonin or thyroid
ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the
risk and symptoms of thyroid tumors.
Pancreatitis
In five clinical trials including more than 3,900 people, there were seven cases of pancreatitis in patients
using liraglutide and one case in a patient using another diabetes medicine. This constituted a 4:1
imbalance of pancreatitis cases, when considering the number of patient exposures (2.2 vs. 0.6 cases per
1000 patient-years). Five cases were reported as acute pancreatitis and two cases with were reported as
chronic pancreatitis.
Patients taking liraglutide should be aware of the symptoms of pancreatitis, such as severe abdominal
pain that may also radiate into the back, possibly with nausea, and vomiting. If patients experience these
symptoms, they should immediately talk to their healthcare professional.
Use with Medications Known to Cause Hypoglycemia
Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) may have an
increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring
the assistance of another person for treatment occurred in 7 liraglutide-treated patients and in no
comparator-treated patients. Six of these 7 patients treated with liraglutide were also taking a
sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other
insulin secretagogues.
ADVERSE REACTIONS:
The incidence of withdrawal due to adverse events was 7.8% for liraglutide-treated patients and 3.4% for
comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was
driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of liraglutide
treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to
withdrawal for liraglutide-treated patients were nausea (2.8% versus 0% for comparator) and vomiting
(1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred
during the first 2-3 months of the trials.
Adverse events reported in ≥ 5% of liraglutide treated patients or ≥5% of glimepiride-treated
patients: 52-week monotherapy trial
All Liraglutide
N = 497
Glimepiride
N = 248
Adverse Event Term (%) (%)
Nausea 28.4 8.5
Diarrhea 17.1 8.9
Vomiting 10.9 3.6
Constipation 9.9 4.8
Upper Respiratory Tract
Infection
9.5 5.6
36

Headache 9.1 9.3
Influenza 7.4 3.6
Urinary Tract Infection 6.0 4.0
Dizziness 5.8 5.2
Sinusitis 5.6 6.0
Nasopharyngitis 5.2 5.2
Back Pain 5.0 4.4
Hypertension 3.0 6.0
Add-on to Metformin + Rosiglitazone
All Liraglutide
+ Metformin +
Rosiglitazone
N= 355
Adverse Event Term (%) (%)
Nausea 34.6 8.6
Diarrhea 14.1 6.3
Vomiting 12.4 2.9
Decreased Appetite 9.3 1.1
Anorexia 9.0 0.0
Headache 8.2 4.6
Constipation 5.1 1.1
Fatigue 5.1 1.7
Placebo +
Metformin +
Rosiglitazon
e N = 175
Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients
treated with liraglutide may develop anti-liraglutide antibodies. Approximately 50-70% of Liraglutidetreated
patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of
antiliraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of
serum) of anti-liraglutide antibodies were detected in 8.6% of these liraglutide-treated patients. Crossreacting
antiliraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the
liraglutide-treated patients in the 52-week monotherapy trial and in 4.8% of the liraglutide-treated patients
in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for
neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of
native GLP-1 was not assessed.
In clinical trials of liraglutide, events from a composite of adverse events potentially related to
immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of liraglutide-treated patients and
among 0.4% of comparator-treated patients.
Papillary thyroid carcinoma
In clinical trials of liraglutide, there were 6 reported cases of papillary thyroid carcinoma in patients treated
with Victoza and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most
of these papillary thyroid carcinomas were

Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or
1.8 mg (6 mg/mL, 3 mL). Cost for 1.2 mg dose per month is similar to Byetta 10 ug pen $271.45/pen at
drugstore.com/ The cost AWP for 3 pens (1.8mg dose/day) is $450.78 per month and for the 1.2 mg
dose/day or 2 pens per month is $300.56
For all patients, liraglutide should be initiated with a dose of 0.6 mg per day for one week. The 0.6 mg
dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not
effective for glycemic control. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg.
If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.
When initiating liraglutide, consider reducing the dose of concomitantly administered insulin
secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia
CONCLUSIONS:
Liraglutide will offer an alternative to exenatide; one head to head study found slightly better A1c
reductions and fewer adverse effects with liraglutide vs exenatide. Liraglutide offers an advantage of once
daily administration compared with the twice a day dosing regimen required with the current exenatide
formulation. Liraglutide has no outcome data to date and exenatide does have some limited data from the
ACCORD Trial which did lead the ADA to place it in a less evidence based second level for treatment of
patients with Type 2 diabetes. Exenatide LAR a once a week formulation has been submitted to the FDA
for approval and an outcome trial is under way with this formulation. The companies are proposing to sell
the once-weekly version under the name Bydureon. The Food and Drug Administration asked for
clarification of manufacturing processes, labeling and a risk-management plan, the companies said
3/16/2010 in a statement. The FDA didn’t request new tests or information related to quality-control
violations identified in a December inspection of the plant where the drug is made.
To ensure that the benefits of Victoza continue to outweigh any risks, FDA has required a Risk Evaluation
and Mitigation Strategy (REMS) as part of the Victoza approval. This REMS includes a patient Medication
Guide with every prescription and a Communication Plan.
However, as part of FDA's commitment to post marketing safety evaluation, the Agency is
requiring the manufacturer of Victoza to conduct a 5 year epidemiological study using a large healthcare
claims database to compare the development of thyroid cancer among patients with T2DM who use
Victoza to those who are not using this medicine. In addition, FDA is requiring the manufacturer to
develop a medullary thyroid cancer registry to monitor how many cases of medullary thyroid cancer occur
each year for at least 15 years to see whether there is any association of this specific type of thyroid
cancer with Victoza therapy.
Victoza was not associated with an increased risk for cardiovascular events in people who were mainly at
low risk for these events. FDA approved Victoza, however, with several post-marketing requirements
under the Food and Drug Administration Amendments Act (FDAAA) to ensure that the company will
conduct studies to provide additional information on the safety of this product. FDA is requiring a post
approval study that specifically evaluates cardiovascular safety in a higher risk population as part of the
Agency's commitment to post marketing safety evaluation.
On May 6, 2010 the company announced the start of this trtial called LEADER (Liraglutide Effect and
Action in Diabetes: Evaluation of Cardiovascular Outcome Results) is a long-term, multicentre,
international, randomised, double-blind, placebo-controlled, phase 3b trial which will include around 9,000
patients over a five-year period. The trial will compare liraglutide added to standard of care with standard
of care alone in people with type 2 diabetes.
In summary, until we have much better long term safety data and clinical outcomes in patients with Type
2 diabetes, I would recommend that we not rush to use this new agent when we have several agents with
good evidence and longer term safety data.
The U.K.'s National Institute for Health and Clinical Excellence gave the nod to Novo Nordisk's new
diabetes drug Victoza. The approval is pretty darn limited, and the cost-effectiveness agency wants more
data to justify broader use.
NICE gave Victoza the okay for use in obese patients already taking two oral diabetes meds. The
approval is only for the 1.2 mg injection, not in higher doses. And therapy should only be continued if the
38

patient loses at least 3 percent of his or her body weight after six months of therapy and sees A1c
reduced by at least one percentage point.
ADA/EASD Guidelines 2008 Update (Diabetes Care 2009; 32:193–203)
AACE/ACE Glycemic Control Algorithm Consensus Panel (Endocr Pract. 2009;15: 541-59)
Management of Patients With A1C Levels of 6.5% to 7.5%
Monotherapy
For the patient with an A1C level within the range of 6.5% to 7.5%, it is possible that a single agent might
achieve the A1C goal of 6.5%. In this setting, metformin, TZDs, DPP-4 inhibitors, and a-glucosidase
inhibitors (AGIs) are recommended. Because of its safety and efficacy, metformin is the cornerstone of
monotherapy and is usually the most appropriate initial choice for monotherapy unless there is a
contraindication, such as renal disease, hepatic disease, gastrointestinal intolerance, or risk of lactic
acidosis.
Dual Therapy
As a result of its safety and efficacy, metformin should be the cornerstone of dual therapy for most
patients. When metformin is contraindicated, a TZD may be used as the foundation for this group of
options. Because metformin or a TZD will serve as an insulin sensitizer, the second component of the
dual therapy is usually an incretin mimetic, DPP-4 inhibitor, glinide, or sulfonylurea. These agents are
recommended in the following order: incretin mimetic,
DPP-4 inhibitor, or an insulin secretagogue such as a glinide and sulfonylurea
Triple Therapy
We consider the following 6 options for triple therapy
1. Metformin + GLP-1 agonist + TZD
2. Metformin + GLP-1 agonist + glinide
3. Metformin + GLP-1 agonist + sulfonylurea
4. Metformin + DPP-4 inhibitor + TZD
5. Metformin + DPP-4 inhibitor + glinide
6. Metformin + DPP-4 inhibitor + sulfonylurea
39

Insulin Therapy
When triple therapy fails to achieve glycemic control, it is likely that the insulin-secretory capacity of the
beta cells has been exceeded; thus, insulin therapy is needed. One can then institute therapy as basal,
premixed, prandial, or basal-bolus insulin. At this point, the list of avail Metformin is the most commonly
used and safest medication to combine with insulin.
Patients With A1C Levels of 7.6% to 9.0%
Management of patients with an A1C value in the range of 7.6% to 9.0% is similar to that just described,
except that one can bypass the use of monotherapy and proceed directly to dual therapy because
monotherapy is unlikely to be successful in this group.
1. Metformin + GLP-1 agonist
2. Metformin + DPP-4 inhibitor
3. Metformin + TZD
4. Metformin + sulfonylurea
5. Metformin + glinide
Triple Therapy
When dual therapy does not achieve the A1C goal, a third agent should be added. The options for triple
therapy for patients with an A1C in this range are similar to those recommended for patients with lower
A1C values. We consider the following 5 options:
1. Metformin + GLP-1 agonist + TZD
2. Metformin + DPP-4 inhibitor + TZD
3. Metformin + GLP-1 agonist + sulfonylurea
4. Metformin + DPP-4 inhibitor + sulfonylurea
5. Metformin + TZD + sulfonylurea
Patients With A1C Levels of >9.0%
Combination Therapy
For drug-naïve patients with A1C levels of >9%, it is unlikely that use of 1, 2, or even 3 agents (other than
insulin) will achieve the A1C goal of ≤6.5%. If the patient is asymptomatic, particularly with a relatively
recent onset of diabetes, a good probability exists for preservation of some
endogenous beta-cell function, implying that dual therapy or triple therapy may be sufficient. We consider
the following 8 options:
1. Metformin + GLP-1 agonist
2. Metformin + GLP-1 agonist + sulfonylurea
3. Metformin + DPP-4 inhibitor
4. Metformin + DPP-4 inhibitor + sulfonylurea
5. Metformin + TZD
6. Metformin + TZD + sulfonylurea
7. Metformin + GLP-1 + TZD
8. Metformin + DPP-4 inhibitor + TZD
Insulin Therapy
Insulin therapy for patients with A1C levels exceeding 9.0% follows the same principles as outlined
previously for patients with A1C values of ≤9.0%. One can prescribe basal insulin, premixed insulins, or
basal-bolus insulin
NOTE
“We believe that this algorithm represents the treatment preferences of most clinical
endocrinologists, but in the absence of meaningful comparative data, it is not necessarily
an official AACE position. Because of the insufficient number or total absence of RCTs for many
combinations of therapies, the participating clinical experts used their judgment and experience.”
40

ZOLEDRONIC ACID INJECTION in Paget Disease and Osteoporosis – Reclast (Novartis)
INDICATIONS: Zoledronic acid has been approved for the treatment of hypercalcemia of malignancy,
osteolytic lesions of multiple myeloma, and osteolytic bone metastases associated with solid tumors.
Another new drug application (NDA) has been submitted requesting approval for use in the treatment of
Paget disease and the treatment of osteoporosis in postmenopausal women. The Food and Drug
Administration (FDA)-approved indications for the intravenous (IV) bisphosphonates are summarized in
Table 1. As of June 2008 the following inications was added: In patients at high risk of fracture, defined as
a recent low-trauma hip fracture, Reclast reduces the incidence of new clinical fractures. In Dec 2008
treatment to increase bone mass in men with osteoporosis and in March 2009 treatment and prevention
of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12
months. As of June 1, 2009 the FDA has approved Reclast in a single dose every two years to treat
ostopenia, or low bone mass, which can lead to osteoporosis.
Table 1. FDA-Approved Indications for IV Ibandronate, Pamidronate, and Zoledronic Acid
Indication Ibandronate Pamidronate Zoledronic
Acid
Treatment of osteoporosis in postmenopausal women X X
Treatment of osteopenia
X
Treatment of Paget disease of bone X X
Treatment/prevention of steroid induced osteoporosis
X
Treatment of hypercalcemia of malignancy X X
Treatment of osteolytic lesions of multiple myeloma X X
Treatment of osteolytic bone metastases from solid
X
tumors
Treatment of osteolytic bone metastases of breast cancer
X
CLINICAL PHARMACOLOGY: Zoledronic acid is a bisphosphonic acid. Like other bisphosphonates, it
inhibits osteoclast formation, osteoblast proliferation, and DNA synthesis. Zoledronic acid is a more
potent inhibitor of bone resorption than risedronate, alendronate, pamidronate, or etidronate. Zoledronic
acid is 100 to 850 times more potent than pamidronate. It has minimal effects on skeletal mineralization.
In long-term animal osteoporosis models, zoledronic acid prevented time- and dose-dependent bone loss
in the total body, lumbar spine, and femur, and was associated with increases in bone mass at those
sites. Trabecular deterioration was also prevented. When administered IV as single equipotent doses in
mice, the magnitude of effect and duration of action were comparable with alendronate, risedronate,
ibandronate, and zoledronic acid.
Zoledronic acid has also been demonstrated to decrease type II collagen degradation, suggesting it may
have chondroprotective effects. It also has the ability to preserve cortical bone integrity in inflammatory
arthritis and enhanced bone strength.
PHARMACOKINETICS: Changes in zoledronic acid plasma concentrations are dose proportional.
Although within 24 hours after the infusion plasma concentrations fall to less than 1% of the concentration
obtained at the end of the infusion, zoledronic acid remains detectable up to day 29 after IV
administration. Elimination is triphasic, with an alpha half-life of 0.23 hours, a beta half-life of 1.75 hours,
and a terminal elimination half-life of 167 hours observed in cancer patients with bone metastases.
Zoledronic acid is quickly taken up into the bone, then slowly released. The mean terminal elimination
half-life is 146 hours. It is only approximately 22% plasma protein bound.
Zoledronic acid does not undergo biotransformation in vivo; it is primarily eliminated intact via the kidney.
Clearance correlates with renal function in patients with healthy to moderately impaired renal function.
Clearance does not appear to be influenced by body weight, body mass index, gender, age, or race
(white, black, or Asian), and is independent of the dose. Pharmacokinetics have not been evaluated in
patients with hepatic impairment or severe renal function impairment.
Table 2 compares the pharmacokinetics of injectable ibandronate, pamidronate, and zoledronic acid.
41

Table 2. Comparison of the Pharmacokinetics of Ibandronate, Pamidronate and Zoledronic Acid
Pharmacokinetic Parameter Ibandronate Pamidronate Zoledronic Acid
Half-life 25.5 h 28 h 146 h
Renal clearance 60 mL/min 49 mL/min 62 mL/min
Renal elimination Extensive Extensive Extensive
COMPARATIVE EFFICACY: The phase 3 zoledronic acid clinical trial program is referred to as
HORIZON (Health Outcomes and Reduced Incidence with Zoledronic acid once yearly). Patients enrolled
in this trial are receiving an annual IV dose of the study medication. Approximately 13,000 patients have
been enrolled in studies assessing zoledronic acid in the treatment of Paget disease in comparison with
risedronate, treatment of postmenopausal osteoporosis, prevention of recurrent osteoporotic fractures,
prevention of osteoporosis in postmenopausal women with osteopenia, treatment of osteoporosis in men
in comparison with oral alendronate, treatment and prevention of corticosteroid-induced osteoporosis in
comparison with risedronate, and treatment of severe osteogenesis imperfecta in comparison with IV
pamidronate.
Paget disease
Zoledronic acid was evaluated in a double-blind, placebo-controlled, dose-ranging study enrolling 176
patients with Paget disease. Patients received a single 1-hour infusion of zoledronic acid 0.05, 0.1, 0.2, or
0.4 mg, or placebo. Median fasting urinary hydroxyproline and creatinine excretion were reduced in all 4
zoledronic acid groups, reaching a nadir by day 10. Reductions occurred sooner at the 0.2 and 0.4 mg
doses. Serum alkaline phosphatase activity also dropped, reaching a nadir by day 60 at the 0.05, 0.1, and
0.2 mg doses and continued to drop at day 90 at the 0.4 mg dose. All doses were more effective than
placebo at day 5. The 0.4 mg dose was more effective than the 0.05 and 0.1 mg doses. At the 0.4 mg
dose, a 50% decline in serum alkaline phosphatase from pretreatment was observed in 46% of patients
and normalization of serum alkaline phosphatase was achieved in 20%. 16 In another dose-finding study,
zoledronic acid was administered to 16 patients with Paget disease at doses of 0.024, 0.072, 0.216, or
0.4 mg as a single 1-hour infusion. Twenty-four-hour urinary hydroxyproline/creatinine excretion was
reduced by a mean of 16% to 19% from baseline on days 1, 3, 7, 10, and 14 at the 0.216 mg dose and by
55% to 71% at the 0.4 mg dose. Change in serum alkaline phosphatase was not observed within the 14-
day follow-up period. Calcif Tissue Int. 1997;60:415-418
Zoledronic acid was compared with oral risedronate and IV pamidronate in the therapy of Paget disease.
A single dose of zoledronic acid 5 mg has been shown to maintain response for at least 2 years. In 2
identical 6-month studies enrolling 357 patients with Paget disease, zoledronic acid 5 mg was
administered as a single 15-minute infusion and compared with treatment with oral risedronate 30 mg
daily for 60 days. N Engl J Med. 2005;353:898-908 and J Bone Miner Res. 2006; doi
10.1359/JBMR.061001. All patients received concomitant vitamin D 400 to 1,000 units/day and calcium 1
g/day. Approximately half of the enrolled patients had received previous bisphosphonate therapy for
Paget disease. The primary end point was the rate of therapeutic response at 6 months, defined as
normalization of alkaline phosphatase levels or a reduction of at least 75% in total alkaline phosphatase
excess above the midpoint of the reference range. At 6 months, a therapeutic response was achieved in
169 of 176 zoledronic acid–treated patients (96%) compared with 127 of 171 (74.3%) treated with
risedronate (P < 0.001). Alkaline phosphatase levels normalized in 88.6% of patients treated with
zoledronic acid compared with 57.9% in the risedronate group (P < 0.001). The median time to response
was shorter in the zoledronic acid group (64 days vs 89 days, P < 0.001). Quality of life (Medical
Outcomes Study 36-item Short-Form General Health Survey) and pain scores improved in both groups,
although quality of life scores were increased to a greater extent at 3 months in the zoledronic acid group.
Of the 296 patients achieving a therapeutic response, 267 were included in a study extension (152
treated with zoledronic acid and 115 treated with risedronate). No bisphosphonate therapy was
administered during the extension portion of the trial. Zoledronic acid maintained the mean level of total
alkaline phosphatase in the middle of the reference range throughout the 18 months follow-up, while
risedronate-treated patients exhibited a linear increase in total alkaline phosphatase from 6 months
posttreatment. Risedronate-treated patients lost therapeutic response more quickly and experienced a
higher rate of partial and complete disease relapse within the study follow-up period. A
pharmacoeconomic analysis of this study from the German payers’ perspective, which included only
42

direct health care costs, found zoledronic acid more effective and netting a cost-saving over oral
risedronate therapy. In a pharmacoeconomic assessment from the Hungarian societal perspective,
zoledronic acid 5 mg as a single dose was the most effective and least expensive therapy assessed,
dominating risedronate 30 mg/day orally for 2 months, alendronate 40 mg/day orally for 6 months,
tiludronate 400 mg/day orally for 3 months, and pamidronate 180 mg IV over 6 weeks. Value in Health.
2006;9:A380.
Osteoporosis
Several regimens of zoledronic acid were evaluated in the treatment of postmenopausal osteoporosis in a
randomized, double-blind, placebo-controlled study enrolling 351 postmenopausal women with T-scores
less than -2 and no more than 1 vertebral fracture at screening. Mean T-score at study entry was -2.9,
and none of the women had vertebral fractures. Zoledronic acid was administered IV at doses of 0.25,
0.5, and 1 mg every 3 months, 4 mg as a single dose, and 2 mg every 6 months. All women received
calcium 1 g/day. After 1 year, zoledronic therapy was associated with a 49% to 52% reduction in serum
C-telopeptide (compared with an 8% decrease with placebo) and a 54% to 65% reduction in the ratio of
urinary N-telopeptide to creatinine (compared with a 3% increase with placebo). Changes in spinal and
hip bone mineral density (BMD) from baseline relative to placebo at 1 year are summarized in Table 3.
Changes in BMD appeared comparable regardless of the dosage regimen. The study was not of sufficient
duration or size to detect differences in fracture incidence. N Engl J Med. 2002;346:653-661
Table 3. Increase in BMD With Zoledronic Acid Relative to Placebo in Postmenopausal
Osteoporosis
Regimen
Spine
BMD a
Hip
BMD a
0.25 mg every 3 months × 4 doses 5.1% 3.1%
0.5 mg every 3 months × 4 doses 4.9% 3.1%
1 mg every 3 months × 4 doses 4.3% 3.2%
2 mg every 6 months × 2 doses 4.3% 3.6%
4 mg single dose 4.6% 3.3%
a All values P < 0.001 vs placebo.
Subsequently, within the HORIZON Pivotal Fracture Trial, zoledronic acid 5 mg infused over 15 minutes
annually was compared with placebo in a double-blind study enrolling 7,736 postmenopausal women 55
to 89 years of age with osteoporosis. Mean age was 73.1 years. Enrolled patients had a femoral neck T-
score less than -2.5 or a T-score less than -1.5 with a vertebral fracture, and inability or unwillingness to
use oral bisphosphonates. A femoral neck T-score less than -2.5 was recorded for 71.9% of patients and
63.9% had prevalent vertebral fracture. Enrollment was stratified to include women with no current or
minimal prior osteoporosis therapy (6,084 patients) and women taking selective estrogen receptor
modulators, calcitonin, hormone therapy, or tibolone for osteoporosis. All patients received elemental
calcium 1,000 to 1,500 mg/day and vitamin D 400 to 1,200 units/day. The primary study end points were
the incidence of new vertebral and hip fractures. N Engl J Med 2007;356:1809-22. Treatment with
zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as
compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk,
0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the
zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83).
Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and
77%, respectively (P

alendronate (mean prior exposure, 4 years) were randomized to receive zoledronic acid 5 mg as a single
infusion plus 52 weeks of oral placebo (113 patients) or placebo infusion plus 52 weeks of oral
alendronate 70 mg (112 patients). Bone biopsy revealed nearly identical effects on static and dynamic
histomorphometric measures. BMD values did not differ between groups. Annual infusion was preferred
overall by 78.7% of patients; the once-a-week oral dosing was preferred by 9%. Substantially more
patients expressed the preference that the infusion was more convenient (79.2% vs 7.2%), the infusion
fits their lifestyle better (72.4% vs 8.1%), and they would be willing to take it for a longer period of time
(71.5% vs 9%). 28th Annual Meeting of the American Society for Bone and Mineral Research; September
15–19, 2006; Philadelphia, PA. Abstract SA357.and Abstract SU329.
The efficacy of zoledronic acid injection administered annually in the prevention of new clinical fracture is
also being assessed in a randomized, double-blind, placebo-controlled study enrolling 2,128 patients 50
years of age and older who have undergone surgical repair of a low-trauma hip fracture in the preceding
90 days (HORIZON-Recent Hip Fracture Trial RFT).N Engl J Med 2007;357: online 9/17/07.Mean age
was 74.4 years, and 76.1% were female. A prior osteoporotic fracture was reported for 45.3% of patents.
Patients received IV zoledronic acid 5 mg annually or placebo infusion annually. All patients received
vitamin D orally as a loading dose, followed by 800 units vitamin D3 and calcium carbonate 1,000 mg
daily. Concomitant therapy with calcitonin, hormone replacement therapy, selective estrogen receptor
modulators, tibolone, and external hip protectors was permitted. The primary study end point was
subsequent skeletal fractures; patients will be followed until 211 fractures have been reported. Secondary
outcomes included changes in BMD and health resource utilization. The rates of any new clinical fracture
were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with
zoledronic acid (P = 0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8%
(P = 0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P = 0.03). In the
safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the
placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P
= 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia,
and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse
effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events,
including atrial fibrillation and stroke, were similar in the two groups.
CONTRAINDICATIONS: The contraindications, warnings, and precautions for zoledronic acid are similar
to those of IV ibandronate and pamidronate. Zoledronic acid is contraindicated in patients with clinical
hypersensitivity to zoledronic acid monohydrate or other bisphosphonates, or any of the excipients in the
injectable formulation (mannitol, sodium citrate). When used in the treatment of osteoporosis and Paget
disease, zoledronic acid is also expected to be contraindicated in patients with uncorrected
hypocalcemia. Table 4 compares the contraindications associated with injectable ibandronate,
pamidronate, and zoledronic acid.
Table 4. Comparison of Contraindications Associated With Ibandronate, Pamidronate and
Zoledronic Acid Therapy
Contraindications Ibandronate Pamidronate Zoledronic Acid
Hypersensitivity to the product X X X
Hypersensitivity to other bisphosphonates X X
Uncorrected hypocalcemia
X
WARNINGS AND PRECAUTIONS: Because of the potential for renal toxicity, zoledronic acid should not
be administered at doses higher than the approved dosage, and the duration of infusion should be no
less than 15 minutes. In clinical trials, the risk of renal function deterioration was increased in patients
who received zoledronic acid over 5 minutes, compared with patients who received the same dose over
15 minutes. The risk of renal function deterioration and renal failure was also increased in patients
receiving an 8 mg dose, even when it was administered over 15 minutes.
The FDA reviewed spontaneous post-marketing reports of atrial fibrillation reported in association with
oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at
increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of onceyearly
Reclast for the treatment of postmenopausal osteoporosis, the FDA evaluated the possible
association between atrial fibrillation and the use of Reclast. Most cases of atrial fibrillation occurred more
44

than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the
11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation
between patients who received Reclast and patients who received placebo.
Atrial fibrillation is a heart rhythm disorder common in individuals 65 years old and older, the same age
range of many of the patients studied in the article published in The New England Journal of Medicine.
Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted.
Therefore, FDA does not believe that healthcare providers or patients should change either their
prescribing practices or their use of bisphosphonates at this time. Oct 1, 2007 FDA Early Communication
of an Ongoing Safety Review
Zoledronic acid should be administered with caution in patients with impaired renal function. In patients
with severe renal function impairment or with evidence of deterioration in renal function during zoledronic
acid therapy, zoledronic acid should be administered only if the potential benefits outweigh the possible
risks. Patients must be adequately rehydrated prior to the administration of zoledronic acid and
throughout therapy.
Osteonecrosis of the jaw has been reported in patients receiving injectable bisphosphonates. It is not
known if patients receiving injectable bisphosphonates for the treatment of osteoporosis are at different
risk for its development than patients receiving therapy for other indications.
Administration of other bisphosphonates has been associated with bronchoconstriction in aspirinsensitive
asthma patients; therefore, zoledronic acid should be used with caution in patients with aspirinsensitive
asthma.
Zoledronic acid is in Pregnancy Category D and should not be used during pregnancy. In animal studies,
administration of zoledronic acid was associated with increased pre- and postimplantation losses and
stillbirths; decreased neonatal survival; skeletal, visceral, and external malformations; and adverse
maternal effects, including periparturient mortality. Women of childbearing potential should be advised to
avoid becoming pregnant.
It is not known if zoledronic acid is excreted in human milk; therefore, caution is recommended when
zoledronic acid is administered to a breast-feeding woman.
The safety and efficacy of zoledronic acid have not been established in children.
Table 5 compares the warnings and precautions associated with injectable ibandronate, pamidronate,
and zoledronic acid.
Table 5. Comparison of Warnings and Precautions Associated With Ibandronate, Pamidronate and
Zoledronic Acid Therapy
Warnings/Precautions Ibandronate Pamidronate Zoledronic Acid
Renal toxicity X X X
Increased serum creatinine X X X
Hold therapy, if abnormal serum creatinine X X X
Caution with other nephrotoxic drugs X X
Transient hypocalcemia X X a
Adequate intake of calcium and vitamin D X X a
Hepatic insufficiency
X
Aspirin-sensitive asthma
X
Osteonecrosis of the jaw X X X
Musculoskeletal pain X X X
Pregnancy category C D D
Breast-feeding Caution Caution Not recommended
Safety and efficacy not established in children X X X
a Presumably will apply to new indications.
45

ADVERSE REACTIONS: Adverse reactions observed in clinical trials with the use of pamidronate in the
treatment of osteoporosis and Paget disease have included fatigue, fever, headache, hypocalcemia,
influenza-like symptoms, musculoskeletal pain, and nausea. Adverse reactions have generally occurred
with greater frequency than with comparator agents in the first days following administration but quickly
decline in frequency and occur with lower incidence with subsequent administration. Pain and fever have
been treated with acetaminophen.
DRUG INTERACTIONS: Drug interactions with zoledronic acid administered annually in the treatment of
osteoporosis and Paget disease have not been assessed.
Loop diuretics should be used with caution in combination with zoledronic acid therapy to avoid
hypocalcemia and should only be used after the patient has been adequately hydrated. Caution is
recommended when bisphosphonates are administered with aminoglycosides because these agents may
have an additive effect to lower serum calcium levels for a prolonged period. Caution is advised when
zoledronic acid is used in conjunction with other nephrotoxic drugs.
RECOMMENDED MONITORING: Serum creatinine and serum calcium should be assessed prior to
administration of each dose. Additional monitoring (serum electrolytes, serum phosphate, serum
magnesium, and hematocrit/hemoglobin) is recommended in patients receiving zoledronic acid in the
treatment of hypercalcemia of malignancy and osteolytic lesions.
(New 3/09) Renal toxicity may be greater in patients with underlying renal impairment or with other risk
factors such as dehydration that may occur in the post-dosing period. Patients with severe renal
impairment (creatinine clearance

Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced
osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial
Lancet 2009; 373: 1253–63
833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients
were stratifi ed by sex, and allocated to prevention or treatment subgroups dependent on duration of
glucocorticoid use immediately preceding the study Zoledronic acid was non-inferior and superior to
risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean
4·06% [SE 0·28] vs 2·71% [SE 0·28], mean diff erence 1·36% [95% CI 0·67–2·05], p=0·0001) and
prevention (2·60% [0·45] vs 0·64% [0·46], 1·96% [1·04–2·88], p

FEBUXOSTAT – ULORIC BY TAP Pharmaceuticals
INDICATIONS: Febuxostat has been approved for use in the chronic management of hyperuricemia in
patients with chronic gout. It is not recommended for the treatment of asymptomatic hyperuricemia. There
are no studies in patients with secondary hyperuricemia (patients treated for Lesch-Nyhan syndrome,
malignant disease or in organ transplant patients).
CLINICAL PHARMACOLOGY: Febuxostat is a nonpurine, selective inhibitor of xanthine
oxidase/xanthine dehydrogenase. The conversion of hypoxanthine to xanthine and uric acid is catalyzed
by xanthine oxidase/xanthine dehydrogenase. Like allopurinol, febuxostat reduces serum uric acid levels
through inhibition of this enzyme system, but febuxostat is more potent than allopurinol. Unlike allopurinol,
febuxostat inhibits both the oxidized and reduced forms of xanthine oxidase and does not inhibit other
enzymes involved in purine and pyrimidine metabolism. Febuxostat is chemically unique when compared
to allopurinol.
In healthy volunteers, the proportional reductions in mean serum urate with febuxostat doses of 10 to 120
mg was 25% to 70%. The percent reduction in 24-hour mean serum uric acid concentrations was
between 40 and 55% at the exposure levels of the 40 and 80 mg daily doses.
PHARMACOKINETICS: The time-to-peak concentration is about 1 to 2 hours following oral
administration. Administration with an antacid produces a delay in the time-to-peak concentration but no
change in the extent absorbed. Administration with food resulted in a delay in the time to peak and a
slight reduction in the extent absorbed; however, no reduction in pharmacodynamic effect was observed.
These data suggest febuxostat can be administered without regard to food or antacid intake.
Febuxostat plasma concentrations increase proportionally over a range of doses from 10 to 120 mg.
Febuxostat is highly bound to albumin (about 99%). The volume of distribution at steady state is
approximately 0.7 L/kg.
Febuxostat is metabolized in the liver to acyl-glucuronide metabolites, and, to a lesser extent, to oxidative
metabolites via cytochrome P-450 enzymes. Less than 6% of the administered dose is excreted in the
urine as unchanged drug. The mean half-life is about 4 to 8 hours.
Neither age nor gender affects the pharmacokinetics or pharmacodynamics of febuxostat.[8]
Concentrations of febuxostat and its metabolites were increased slightly in subjects with impaired renal
function; however, reductions in serum uric acid were similar regardless of the level of renal function
impairment. Dosage adjustments do not appear necessary in patients with mild to severe renal
impairment. Concentrations of febuxostat and its metabolites were increased slightly, and serum uric acid
declined to a slightly lesser extent in patients with mild or moderate hepatic function; however, the
differences were not judged to be clinically significant and dosage adjustments do not appear necessary.
COMPARATIVE EFFICACY: The New Drug Application (NDA) contains the results of a phase 3 study
enrolling 760 patients with gout treated with febuxostat 80 mg daily (255 patients), febuxostat 120 mg
daily (250 patients), or allopurinol 300 mg daily (251 patients) for 52 weeks. Enrolled patients had a
serum uric acid level of 8 mg/dL or greater at study entry. The primary end point of the study was a serum
uric acid level less than 6 mg/dL for 3 consecutive months. This was achieved in 53% of patients treated
with febuxostat 80 mg and 62% treated with febuxostat 120 mg, compared with 21% treated with
allopurinol. Similar reductions in gout flares and tophus area occurred in all treatment groups. The most
common adverse event leading to withdrawal was abnormal liver-function test results, which accounted
for the withdrawal of five patients receiving 80 mg of febuxostat, seven receiving 120 mg of febuxostat,
and one receiving allopurinol (P=0.04 for the comparison between the 120-mg febuxostat and the
allopurinol groups). Four subjects receiving 80 mg of febuxostat, four receiving 120 mg of febuxostat, and
one receiving allopurinol discontinued the study because of rashes. Most of these were localized and
transient maculopapular rashes that occurred during prophylactic treatment with either colchicine or
naproxen and resolved after topical treatment. (N Engl J Med 2005;353:2450-61)
Febuxostat was compared with allopurinol in a multicenter, randomized, double-blind, double-dummy
study enrolling 256 Japanese patients with gout or hyperuricemia (serum uric acid 8 mg/dL or greater).
48

Patients received either febuxostat (128 patients) or allopurinol (128 patients). Therapy was initiated with
febuxostat 10 mg once daily or allopurinol 100 mg once daily for 12 days and then continued with
febuxostat 40 mg once daily or allopurinol 100 mg twice daily for 44 days. Serum uric acid at the end of
the study was reduced 40.5% from baseline with febuxostat and 33.9% from baseline with allopurinol (P <
0.001 febuxostat vs allopurinol). Serum uric acid levels of 6 mg/dL or lower were achieved in 82% of
febuxostat-treated patients compared with 69% of allopurinol-treated patients (P = 0.019).[American
College of Rheumatology 2004 Annual Scientific Meeting. Arthritis Rheum. 2004;50(suppl 9):S336-S337]
Febuxostat was also evaluated in a randomized, double-blind, placebo-controlled, 28-day, dose-response
study enrolling 153 patients (23 to 80 years of age) with gout and hyperuricemia (serum urate 8 mg/dL or
greater). Patients received febuxostat 40, 80, or 120 mg, or placebo once daily for 28 days, with
prophylactic colchicine 0.6 mg twice daily for 14 days prior to and 14 days after randomization. The
primary end point was the proportion of patients with a serum urate concentration less than 6 mg/dL at
day 28. The mean serum urate reduction from baseline was 2% in the placebo group, 37% in the 40 mg
group, 44% in the 80 mg group, and 59% in the 120 mg group. The primary end point was achieved in
56% of patients treated with febuxostat 40 mg, 76% treated with febuxostat 80 mg, and 94% treated with
febuxostat 120 mg, compared with none of the placebo-treated patients (P < 0.001 for each dose in
comparison with placebo). (Arthritis Rheum. 2005;52:916-923)
A summary of the proportion of patients with a serum urate concentration less than 6 mg/dL treated with
placebo, febuxostat, or allopurinol in the clinical trials can be found in the following table.
Summary of the Proportion of Patients with a Serum Urate Concentration < 6 mg/dL Treated with
Placebo, Febuxostat, or Allopurinol in Clinical Trials
Proportion of Patients with a Serum Urate Concentration < 6 mg/dL
Reference
Number of Patients
Duration of
Treatment
Placebo
Febuxostat 20 mg
Febuxostat 40 mg
Febuxostat 80 mg a
Febuxostat 120
mg a
Allopurinol 200 mg
Allopurinol 300 mg
13 128 36 days 0% 31.5% 41.9% -- -- -- --
11 256 56 days -- -- 82% -- -- 69% --
12 103 42 days 0% 45.7% 91.2% -- -- -- --
14 153 28 days 0% -- 56% 76% 94% -- --
a Dose requested in the submitted NDA.
Results of an ongoing open-label study of febuxostat were presented in a meeting abstract. Patients with
gout and a serum uric acid level greater than 8 mg/dL who completed the 4-week, dose-response study
were eligible to participate in the long-term, open-label study. Patients initially received febuxostat 80 mg
daily, then at week 4 the dosage could be adjusted to 40 or 120 mg daily, if needed. Of the 116 patients
who continued in the open-label study, the febuxostat dose remained at 80 mg for 72% of patients, was
reduced to 40 mg in 9%, and increased to 120 mg in 20%. At each visit, 74% to 81% of febuxostattreated
patients had a serum uric acid level less than 6 mg/dL for up to 2 years.(American College of
Rheumatology 2004 Annual Scientific Meeting. Arthritis Rheum. 2004;50(suppl 9):S335)
Febuxostat was also assessed in 11 allopurinol-intolerant patients in the two 28-day and open-label
studies previously described. Intolerance was defined as a reaction precluding rechallenge and included
rash/hives in 8 patients, and drowsiness, nausea, and diarrhea in 1 patient each. Six patients continued
febuxostat therapy for 2 years or longer. All possibly related febuxostat adverse reactions observed were
transient and resolved with continued administration, except 1 case of abnormal liver function test results
in a patient with a history of alcohol abuse.(American College of Rheumatology 2004 Annual Scientific
Meeting. Arthritis Rheum. 2004;50(suppl 9):S336)
49

CONTRAINDICATIONS: Febuxostat will be contraindicated in patients with a history of hypersensitivity to
febuxostat and the other product ingredients. Febuxostat is also contraindicated in patients receiving
azathiaprine, mercaptopurine and theophylline, these agents are metabolized by xanthine oxidase and
thus levels would be significantly elevated..
WARNINGS AND PRECAUTIONS: As with allopurinol, periodic liver function tests may be advisable for
patients receiving febuxostat.
Febuxostat is not effective for the treatment of acute gouty attacks. Acute gouty attacks may be
precipitated at the start of treatment with febuxostat in new patients and these may continue even after
serum uric acid concentrations begin to fall, usually for the first 6 to 12 months. Colchicine has often been
coadministered during this time.
Cardiovascular events? A higher rate of CV and thromboembolic events was seen in the head to head
trials against allopurinol and patients should be monitored for signs of MI and stroke. A causal
relationship with febuxostat has not been established. Anti-Platelet Trialists’ Collaborative (APTC)
endpoints (CV death, non-fatal MI and non-fatal CVA) events per 100 patient-years of exposure were as
follows placebo 0, febuxostat 40mg 0, febuxostat 80 mg 1.09 and allopuriniol 0.60
ADVERSE REACTIONS: Adverse reactions reported during febuxostat therapy included liver function
test abnormalities, diarrhea, headache, nausea, flushing, dizziness, and gout flares. The concomitant use
of colchicine for acute gout flares may have influenced the overall nature of the adverse reactions.The
overall incidence of adverse reactions was similar in the febuxostat and allopurinol groups in the
comparative study.
Febuxostat 80 and 300 mg doses were not associated with a change in QT interval in a crossover
comparison with placebo and moxifloxacin enrolling 44 healthy subjects.
DRUG INTERACTIONS: Febuxostat is a significant xanthine oxidase inhibitor and would be expected to
significantly inhibit the metabolism of agents that are metabolized by this enzyme (IE azathioprine,
mercaptopurine and theophyllin).
In vitro, febuxostat exhibited no effect on CYP1A2, CYP2C9, CYP2C19, or CYP3A4, and weak inhibitory
activity on CYP2D6. When febuxostat was administered with desipramine (a CYP2D6 substrate) in 18
CYP2D6 extensive metabolizers, a slight increase in total exposure to desipramine was observed. The
effect did not appear clinically important; therefore, dose adjustments do not appear necessary when
CYP2D6 substrates are coadministered with febuxostat.
RECOMMENDED MONITORING: Periodic liver function tests may be advised in addition to monitoring of
serum uric acid.
DOSING: Febuxostat is administered orally once daily at a starting dose of 40 mg once a day. For
patients who do not achieve a serum uric acid of less than 6.0 mg/dl after 2 weeks the dose may be
increased o 80 mg once a day. Febuxostat can be administered without regard to food. No dosage
adjustment is need for mild to moderate renal or hepatic dysfunction.
PRODUCT AVAILABILITY/COST and STORAGE: An NDA for febuxostat 80 and 120 mg was submitted
to the Food and Drug Administration (FDA) in December 2004. The FDA approved the 40 and 80 mg
tablets. The cost of Uloric is $5.62 per 40 and 80 mg tablets AWP vs. $0.59 per allopurinol 300 mg
tablets.
CONCLUSION: Febuxostat offers an alternative to allopurinol. Additional studies are necessary to
compare febuxostat with recommended allopurinol doses, although serum uric acid levels were reduced
to a greater extent with febuxostat compared with low-dose allopurinol. Additional side effect information
is necessary to better determine the place of febuxostat in the treatment of hyperuricemia and gout.
Lijmited data suggest that with a different chemical structure that it may be safe to use in patients
intolerant to allopurinol.
50

NICE technology appraisal guidance 164 Febuxostat for the management of hyperuricaemia in
people with gout 12/2008
Febuxostat, within its marketing authorisation, is recommended as an option for the management of
chronic hyperuricaemia in gout only for people who are intolerant of allopurinol (as defined in section 1.2)
or for whom allopurinol is contraindicated.
1.2
For the purposes of this guidance, intolerance of allopurinol is defined as adverse effects that are
sufficiently severe to warrant its discontinuation, or to prevent full dose escalation for optimal
effectiveness as appropriate within its marketing authorisation
51

DEXLANSOPRAZOLE - Kapidex by Takeda 2S Now Dexilant
INDICATIONS: Dexlansoprazole is indicated for the healing of all grades of erosive esophagitis, the
maintenance of healing of erosive esophagitis, and the treatment of heartburn associated with nonerosive
gastroesophageal reflux disease (GERD).
The Food and Drug Administration (FDA)-approved indications for the oral proton pump inhibitors are
summarized in Table 1.
Table 1. FDA-Approved Indications for Oral Proton Pump Inhibitors
Dexlansoprazole
(Kapidex)
Esomeprazole
(Nexium)
Lansoprazole
(Prevacid)
Omeprazole
(Prilosec)
Pantoprazole
(Protonix)
Rabeprazole
(AcipHex)
Erosive esophagitis
Healing X X X X X
Maintenance X X X X X
Symptomatic
GERD
X X X X X
Duodenal ulcers
Healing X X X
Maintenance
Helicobacter
pylori eradication
to prevent
recurrence
X
X X X X
Gastric ulcers
Healing X X
Healing NSAIDassociated
a gastric
ulcers
Risk reduction of
NSAIDassociated
gastric
ulcer
X
X
X
Pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome)
Treatment X X X X X
a NSAID = nonsteroidal anti-inflammatory drug.
CLINICAL PHARMACOLOGY: Dexlansoprazole is the R-enantiomer of lansoprazole. It is formulated as
a dual delayed-release formulation for oral administration, with each capsule containing a mixture of
enteric-coated granules with different pH-dependent dissolution profiles that are designed to release drug
at different locations in the GI tract.
The proton pump inhibitors suppress gastric acid secretion at the final step of acid production by specific
inhibition of the (H+,K+)-ATPase in the gastric parietal cell.
The effects of dexlansoprazole 60 mg and lansoprazole 30 mg once daily for 5 days on 24-hour
intragastric pH have been assessed in healthy volunteers enrolled in a crossover study. On day 5, mean
intragastric pH was 4.55 after dexlansoprazole and 4.13 after lansoprazole. The percentage of time with
intragastric pH greater than 4 was 71% (17 hours) with dexlansoprazole and 60% (14 hours) with
52

lansoprazole. 1 In other pharmacodynamic studies, high doses of dexlansoprazole (60 to 120 mg)
produced greater 24-hour mean pH than lansoprazole 30 mg.
PHARMACOKINETICS: Following oral administration of the dexlansoprazole delayed-release capsules,
peak dexlansoprazole concentrations occur at 1 to 2 hours after administration and again 4 to 5 hours
after administration. In studies comparing the pharmacokinetics of dexlansoprazole 60 mg as the dual
delayed-release capsules and lansoprazole 60 mg administered as the conventional delayed-release
capsules, mean residence time was 5.5 hours for dexlansoprazole and 2.9 hours for lansoprazole. Dose
proportionality was observed over a range of doses from 60 to 120 mg. Plasma protein binding is more
than 96%.
The dexlansoprazole half-life is 1 to 2 hours. Dexlansoprazole is extensively metabolized in the liver to
inactive metabolites. Oxidative metabolites are formed via cytochrome P450 isozymes CYP2C19 and
CYP3A4. Dexlansoprazole systemic exposure was increased up to 2-fold in CYP2C19 intermediate
metabolizers and up to 12-fold in CYP2C19 poor metabolizers compared with CYP2C19 extensive
metabolizers. No unchanged dexlansoprazole is excreted in the urine following dexlansoprazole
administration.
In patients with moderate hepatic impairment, single doses of dexlansoprazole 60 mg were associated
with systemic exposure 2 times higher than in patients with healthy hepatic function. No adjustment in
dosing is necessary in patients with mild hepatic impairment (Child-Pugh class A); however, a 30 mg
doses is recommended for patients with moderate hepatic impairment (Child-Pugh class B). Studies have
not been conducted in patients with severe hepatic impairment (Child-Pugh class C). The
pharmacokinetics of dexlansoprazole are not likely to be altered in patients with renal impairment
because dexlansoprazole is extensively metabolized to inactive metabolites and no parent drug is
recovered in the urine following oral dexlansoprazole dosing. The half-life of dexlansoprazole is increased
in elderly subjects compared with younger subjects (2.23 h vs 1.5 h); however, the difference is not
clinically important. Systemic exposure was also increased 34.5% in elderly subjects. Dosage
adjustments are not necessary in elderly patients. Dexlansoprazole exposure was increased 42.8% in
women compared with men following a single 60 mg oral dose; however, dosage adjustments are not
necessary.
The pharmacokinetic parameters of the oral proton pump inhibitors are compared in Table 2.
Pharmacokinetic
parameter
Table 2. Pharmacokinetic Parameters of Oral Proton Pump Inhibitors
Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole
Rabeprazole
Bioavailability — 64% to 90% 80% to 85% 30% to 40% 77% 52%
Time to peak
plasma
concentration (h)
1 to 2; 4 to 5 1.5 1.7 0.5 to 3.5 2 to 3 2 to 5
Protein binding (%) 96% 97% 97% 95% 98% 96.3%
Half-life (h) 1 to 2 1 to 1.5 1.6 0.5 to 1 1 to 1.9 1 to 2
Primary route
excretion
Excreted unchanged
in urine
Hepatic CYP2C19
CYP3A4
Hepatic
CYP2C19
Hepatic CYP3A
CYP2C19
Hepatic
Hepatic
CYP2C19
CYP3A4
Hepatic
CYP3A
CYP2C19
0% < 1% 0% 0% 0% 0%
COMPARATIVE EFFICACY: Dexlansoprazole efficacy studies have not been published, but are
summarized in the prescribing information and meeting abstracts.
Dexlansoprazole was assessed in 2 randomized, double-blind, noninferiority studies enrolling a total of
4,092 patients 18 to 90 years of age (median age, 48 years) with endoscopically confirmed erosive
esophagitis. Patients received oral dexlansoprazole 60 mg daily, dexlansoprazole 90 mg daily, or
lansoprazole 30 mg daily. Patients who were H. pylori–positive, or had Barrett esophagus and/or definite
53

dysplastic changes at baseline were excluded. The majority of patients had mild erosive esophagitis (71%
with grade A or B and 29% with grade C or D). Noninferiority was exhibited in both studies; however,
superiority was only observed in one. Results are summarized in Table 3.
Table 3. Healing Rates in Erosive Esophagitis (All Grades) Treated With Dexlansoprazole and
Lansoprazole Therapy for 8 Weeks
Study 1 Study 2
% Healed
week 4
% Healed
week 8
Dexlansoprazole 60
mg (n = 657)
Lansoprazole 30
mg (n = 648)
Dexlansoprazole 60
mg (n = 639)
Lansoprazole 30
mg (n = 656)
70% 65% 66% 65%
87% 85% 85% 79%
Dexlansoprazole was also assessed for the maintenance of healed erosive esophagitis in a randomized,
double-blind, placebo-controlled study enrolling 445 patients who successfully completed an erosive
esophagitis study and showed endoscopically confirmed healed erosive esophagitis. Maintenance of
healing and resolution of symptoms were assessed following therapy with oral dexlansoprazole 30 or 60
mg once daily or placebo. Healing was maintained in 66.4% of patients treated with dexlansoprazole 30
mg, 66.4% of patients treated with dexlansoprazole 60 mg, and 14.3% treated with placebo. Patients
treated with dexlansoprazole 30 and 60 mg also had a higher median percent of 24-hour heartburn-free
days compared with placebo (96.1% and 90.9% vs 28.6%). Median nights without heartburn was 98.8%
with dexlansoprazole 30 mg, 96.3% with dexlansoprazole 60 mg, and 71.4% with placebo.
Dexlansoprazole was also assessed in a 4-week, randomized, double-blind, placebo-controlled study
enrolling 947 patients with symptomatic nonerosive GERD. Patients had heartburn identified as their
primary symptom, had a history of heartburn for at least 6 months, had heartburn on at least 4 of 7 days
immediately prior to randomization, and had no esophageal erosions confirmed by endoscopy. Patients
received oral dexlansoprazole 30 mg daily, dexlansoprazole 60 mg daily, or placebo. The median
percentage of 24-hour heartburn-free periods during the 4-week treatment period were 54.9% with
dexlansoprazole 30 mg and 18.5% with placebo.
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS:
CONTRAINDICATIONS
Dexlansoprazole is contraindicated in patients with known hypersensitivity to any component of the
formulation (magnesium carbonate, sucrose, hydroxypropyl cellulose, titanium dioxide, hydroxypropyl
cellulose, hypromellose 2910, talc, methacrylic acid copolymer, polyethylene glycol 8000, triethyl citrate,
polysorbate 80, colloidal silicon dioxide). Hypersensitivity and anaphylaxis have been reported with
dexlansoprazole use. The contraindications, warnings, and precautions associated with the proton pump
inhibitors, as well as use in special populations, are summarized in Table 4.
WARNINGS AND PRECAUTIONS
Symptomatic response to therapy with any proton pump inhibitor, including dexlansoprazole, does not
preclude the presence of gastric malignancy.
The safety and effectiveness of dexlansoprazole have not been established in children.
Dexlansoprazole is in Pregnancy Category B. No adverse fetal effects were observed in animal studies.
Dexlansoprazole should be used in pregnancy only if clearly needed.
It is not known whether dexlansoprazole is excreted in human milk; however, lansoprazole and its
metabolites are present in rat milk following administration of lansoprazole. Because of the potential for
tumorigenicity shown for lansoprazole in rat carcinogenicity studies, the dexlansoprazole prescribing
54

information recommends discontinuing the drug or breast-feeding, taking into consideration the
importance of the drug to the mother.
Table 4. Contraindications, Warnings, and Precautions Associated With Proton Pump Inhibitor Therapy
Contraindications
Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Hypersensitivity to
drug
Hypersensitivity to
substituted
benzimidazole
agents
X X X X X X
X
Warnings and precautions
Atrophic gastritis X X X
Symptomatic relief
does not rule out
gastric malignancy
X X X X X X
Special populations
Elderly
No unique
precautions
No unique
precautions
No unique
precautions
No unique
precautions
No unique
precautions
Children Not established > 1 y of age > 1 y of age > 1 y of age Not
established
Pregnancy
Category
Lactation
No unique
precautions
≥ 12 y of age
B B B C B B
Not
recommended
Excreted in
small amounts
Not
recommended
Not
recommended
Not
recommended
Not
recommended
ADVERSE REACTIONS: The most commonly reported adverse reactions to dexlansoprazole, occurring
in at least 2% of patients in clinical trials, include diarrhea, abdominal pain, nausea, upper respiratory
tract infection, vomiting, and flatulence. The incidence of these adverse reactions from studies comparing
dexlansoprazole with placebo and lansoprazole are summarized in Table 5.
Table 5. Most Frequent Adverse Reactions Reported in the Dexlansoprazole Clinical Trials
Adverse
Reactions
Dexlansoprazole
30 mg
(n = 455)
Dexlansoprazole
60 mg
(n = 2,218)
Dexlansoprazole
Total
(n = 2,621)
Lansoprazole
30 mg
(n = 1,363)
Placebo
(n =
896)
Diarrhea 5.1% 4.7% 4.8% 3.2% 2.9%
Abdominal pain 3.5% 4% 4% 2.6% 3.5%
Nausea 3.3% 2.8% 2.9% 1.8% 2.6%
Upper respiratory
tract infection
2.9% 1.7% 1.9% 0.8% 0.8%
Vomiting 2.2% 1.4% 1.6% 1.1% 0.8%
Flatulence 2.6% 1.4% 1.6% 1.2% 0.6%
55

DRUG INTERACTIONS: Dexlansoprazole is metabolized by CYP2C19 and CYP3A4. Dexlansoprazole is
not likely to inhibit cytochrome isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. In
CYP2C19 extensive and intermediate metabolizers, dexlansoprazole did not affect the pharmacokinetics
of diazepam, phenytoin, or theophylline.
Atazanavir should not be coadministered with dexlansoprazole, because atazanavir absorption is
dependent upon the presence of gastric acid and systemic concentrations may be substantially reduced.
Dexlansoprazole may also interfere with the absorption of other drugs with pH-dependent absorption,
including ampicillin esters, digoxin, iron salts, and ketoconazole.
A pharmacokinetic interaction or change in international normalized ration (INR) was not observed with
coadministration of dexlansoprazole 90 mg and warfarin 25 mg; however, increased INR has been
observed in patients receiving proton pump inhibitors and warfarin concomitantly. Patients receiving
warfarin and dexlansoprazole concomitantly should be monitored for increased INR and prothrombin
time.
Table 6. Drug Interactions Associated With Proton Pump Inhibitors
Drug Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Effects on absorption
Atazanavir X X X X X X
Gastric pH
determines
bioavailability
(ketoconazole,
iron salts,
digoxin,
ampicillin)
X X X X X X
CYP mediated
Cyclosporine X X
Diazepam
Phenytoin
Propranolol
Tacrolimus
Theophylline X X
Voriconazole X X
Other
Warfarin X X X X X X
RECOMMENDED MONITORING: No specific laboratory monitoring is necessary. Patients should be
monitored for esophageal healing and symptomatic improvement.
DOSING: Dexlansoprazole can be taken without regard to food. The capsules should be swallowed
whole. If necessary, the capsules may be opened, the intact granules sprinkled on 1 tablespoon of
applesauce and swallowed immediately.
For the healing of erosive esophagitis, the recommended dosage is 60 mg once daily for up to 8 weeks.
For the maintenance of healing of erosive esophagitis, the recommended dosage is 30 mg once daily.
Studies for this indication did not extend beyond 6 months. For the treatment of symptomatic nonerosive
X
X
X
X
56

GERD, the recommended dosage is 30 mg once daily for 4 weeks.
A maximum dosage of 30 mg once daily is recommended for patients with moderate hepatic impairment
(Child-Pugh class B). Dexlansoprazole has not been studied in patients with severe hepatic impairment
(Child-Pugh class C). Dosage adjustments are not necessary in elderly patients, patients with impaired
renal function, or patients with mild hepatic impairment (Child-Pugh class A).
Table 7. FDA-Approved Dosages for Oral Proton Pump Inhibitors in Erosive Esophagitis
Agent
Dexlansoprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Healing
Dosage
60 mg
daily × 8
wk
30 mg
daily × 8
wk
20 mg
daily × 4
to 8 wk
40 mg
daily × 8
wk
20 mg
daily × 4
to 8 wk
Maintenance
Dosage
30 mg once
daily
15 mg once
daily
Renal
Adjustment
None
None
Hepatic
Adjustment
30 mg maximum
daily dose for
moderate
impairment
Consider dose
reduction in
severe
impairment
20 mg daily None Consider dose
reduction in
hepatic
impairment
Administration
With or without food
Taken before eating
Taken before eating
40 mg daily None None With or without food
20 mg daily None Caution in severe
hepatic
impairment
With or without food
PRODUCT AVAILABILITY/COST and STORAGE: Dexlansoprazole received FDA approval January 30,
2009. It is available as 30 and 60 mg delayed-release capsules supplied in bottles of 30, 90, and 1,000,
and unit-dose packages of 100. Dexlansoprazole delayed-release capsules should be stored at controlled
room temperature (25°C; 77°F), with excursions permitted between 15° and 30°C (59° and 86°F). The
cost is $136.88/30 caps AWP for both the 30 and 60 mg capsules. Vs $167.98/30 x 30mg Prevacid caps
Vs. $63.97/90 x 20 mg generic omeprazole caps and $26.99/42 x 20 mg Prilosec OTC tabs
Table 8. Commercial Dosage Forms for Proton Pump Inhibitors
Agent Dosage Forms Generic Available? Rx/OTC
Dexlansoprazole Capsules, delayed-release: 30, 60 mg N Rx
Esomeprazole Capsules, delayed-release: 20, 40 mg N Rx
Powder for suspension, delayed-release: 10, 20, 40 mg N Rx
Injection, powder for solution: 20, 40 mg N Rx
Lansoprazole Tablets, orally disintegrating delayed-release: 15, 30 mg N Rx
Capsules, delayed-release: 15, 30 mg N Rx
Granules for suspension, delayed-release: 15, 30 mg N Rx
Injection, powder for solution: 30 mg N Rx
57

Omeprazole Capsules, delayed-release: 10, 20, 40 mg Y Rx
Tablets, delayed-release: 20 mg Y OTC
Suspension, delayed-release granules: 2.5, 10 mg Y Rx
Pantoprazole Tablets, delayed-release: 20, 40 mg Y Rx
Granules for suspension, delayed-release: 40 mg N Rx
Injection, powder for solution: 40 mg N Rx
Rabeprazole Tablets, delayed-release: 20 mg N Rx
CONCLUSION: Dexlansoprazole is another proton pump inhibitor. Although present with a longer
residence time because of the dual delayed-release formulation, neither longer acid suppression nor a
clinical advantage has been demonstrated relative to lansoprazole or other proton pump inhibitors.
The Medical Letter (3/23/09) concluded “It is not surprising that dexlansoprazole (Kapidex) is an effective
PPI, because it was approved for use in a dose that is twice the dose of lansoprazole, which will soon be
available generically. PPIs appear to have little dose-related toxicity in the short term, but their long-term
safety is unclear.”
Name Change
March 4, 2010 The U.S. Food and Drug Administration has approved a name change for the heartburn
drug Kapidex (dexlansoprazole) to avoid confusion with two other medications – Casodex and Kadian.
Effective in late April 2010, Takeda Pharmaceuticals North America Inc. will market Kapidex under the
new name Dexilant.
Since Kapidex was approved in January 2009, there have been reports of dispensing errors because of
confusion with the drugs Casodex (bicalutamide) to treat men with advanced prostate cancer and Kadian
(morphine sulfate),
58

MILNACIPRAN - Savella by Forest/Cypress
1S
INDICATIONS: Milnacipran is indicated for the management of fibromyalgia.
The Food and Drug Administration (FDA)-approved indications for the serotonin and norepinephrine
reuptake inhibitors (SNRIs) are summarized in Table 1.
Table 1. FDA-Approved Indications for SNRIs
Indication Duloxetine Desvenlafaxine Milnacipran Venlafaxine
Diabetic peripheral neuropathic pain
Fibromyalgia X X
X
Generalized anxiety disorder X X
Major depressive disorder X X X
Panic disorder
Social anxiety disorder
CLINICAL PHARMACOLOGY: Milnacipran is an SNRI. It does not affect postsynaptic cholinergic,
adrenergic, histaminergic, dopaminergic, or serotonergic receptor sites. Milnacipran binds to both
serotonin and norepinephrine transporters with high affinity, but preferentially blocks norepinephrine
reuptake compared with serotonin reuptake by an approximately 3:1 ratio. The exact mechanism of the
central pain inhibitory action and fibromyalgia symptom improvement effects are unknown.
In healthy young subjects, milnacipran at dosages of up to 100 mg daily or 50 mg twice daily for 7 days
did not affect cognitive function or psychomotor performance. In elderly volunteers, milnacipran at single
doses of up to 75 mg did not affect cognitive function and had no detrimental effects on psychomotor
performance.
PHARMACOKINETICS: Peak concentrations are reached about 2 to 4 hours after oral administration.
Steady-state levels are reached within 36 to 487 hours. Absolute oral bioavailability is 85% to 90%.
Absorption is not affected by food. Milnacipran exposure increases dose proportionately over the
therapeutic dosage range. Plasma protein binding is low (less than 13%).
The milnacipran half-life is 6 to 8 hours; the active d-milnacipran enantiomer has a longer half-life (8 to 10
hours) than the l-milnacipran enantiomer (4 to 6 hours). Approximately 55% of the dose is excreted in the
urine as unchanged drug, with another 14% to 30% excreted as the glucuroconjugate and the remainder
as inactive metabolites.
Milnacipran pharmacokinetics were not substantially altered in patients with mild to moderate hepatic
function impairment. In patients with severe hepatic impairment, mean exposure (area under the curve
[AUC]) was increased by 31% and the half-life was increased by 55%.
Renal clearance of milnacipran is reduced in patients with renal function impairment; pharmacokinetic
changes are proportional to the degree of renal failure. In patients with severe renal function impairment,
the half-life was increased approximately 3-fold. Mean exposure (AUC) was increased by 16%, 52%, and
199%, and half-life was increased by 38%, 41%, and 122% in patients with mild (creatinine clearance
[CrCl], 50 to 80 mL/min), moderate (CrCl, 30 to 49 mL/min), and severe (CrCl, 5 to 29 mL/min) renal
impairment, respectively.
In elderly patients, the peak concentration and AUC were about 30% higher than in younger patients
because of age-related reductions in renal function. The peak concentration and AUC were about 20%
higher in women than in men.
Table 2 compares the pharmacokinetics of duloxetine and milnacipran, the 2 SNRIs indicated for the
management of fibromyalgia. The primary pharmacokinetic difference between these agents is in the
X
X
59

primary route of elimination.
Table 2. Comparison of the Pharmacokinetic Parameters for Duloxetine and Milnacipran
Parameter Duloxetine Milnacipran
T max
a
6 h 2 to 4 h
Bioavailability — 85% to 90%
Protein binding > 90% < 13%
Half-life 12 h 6 to 8 h
Elimination primary route Hepatic (CYP1A2, CYP2D6) Renal (55% as unchanged drug in the urine)
a T max = time to maximal plasma concentration.
COMPARATIVE EFFICACY:
Fibromyalgia
Milnacipran was assessed in a randomized, double-blind, placebo-controlled study enrolling 1,196
patients meeting the American College of Rheumatology criteria for fibromyalgia. The majority of patients
were women (96.2%) and white (93.5%), with a mean age of 50.2 years. Patients received milnacipran
100 mg/day (399 patients), milnacipran 200 mg/day (396 patients), or placebo (401 patients) for 15
weeks. Patients were required to discontinue all centrally acting fibromyalgia therapies, including
antidepressants, sedative-hypnotics, anticonvulsants, muscle relaxants, and centrally acting analgesics,
as well as transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point injections,
acupuncture, and anesthetic or narcotic patches. Limited rescue doses of hydrocodone were permitted.
The primary efficacy end point for the “treatment of fibromyalgia” was a composite defining responders as
patients with at least 30% pain improvement as assessed by the change from baseline in 24-hour
morning recall pain collected from daily e-diary scores, a rating of “very much improved” or “much
improved” on the Patient Global Impression of Change (PGIC), and an at least 6-point improvement from
baseline in physical function (SF-36 Physical Component Summary score). The primary end point
measure for “treatment of pain of fibromyalgia” was a composite defining responders as patients
achieving at least 30% improvement in pain in 24-hour morning recall pain and rating themselves as “very
much improved” or “much improved” on the PGIC scale. Results were analyzed using baseline
observation carried forward (BOCF), for which any patients missing any primary end point data were
classified as nonresponders, as well as a last observation carried forward (LOCF) and a completer
analysis. Odds ratios for response compared with placebo are summarized in Table 3. At 15 weeks, there
were more “treatment of fibromyalgia” responders in the milnacipran groups than in the placebo group
(15% [P = 0.011] and 14% [P = 0.015] for 100 and 200 mg/day groups, respectively vs 9% for placebo).
Response rates for “treatment of pain of fibromyalgia” were also greater in the milnacipran groups (23%
[P = 0.0252] and 25% [P = 0.0037] for 100 and 200 mg/day groups, respectively, compared with 16% for
placebo). Pain improvements were reported to be evident as early as 1 week after initiation of
milnacipran. At 3 months, milnacipran was also reported to be associated with improvements in additional
pain measures (morning recall pain, weekly recall pain, real-time pain, paper visual analog scale [VAS]
measures), as well as the PGIC (both doses, P < 0.001). Discontinuation rates were 28% in the placebo
group, 34% in the milnacipran 100 mg/day group, and 35% in the milnacipran 200 mg/day group (Clin
Ther. 2008;30(11):1988-2004).
Table 3. Odds Ratios for Composite Response in Adults With Fibromyalgia Treated for 15 Weeks
With Placebo or Milnacipran
Parameter Milnacipran 100 mg/day Milnacipran 200 mg/day
Fibromyalgia treatment
BOCF 1.79 (95% CI, 1.14 to 2.8) a,b 1.75 (95% CI, 1.11 to 2.75) b
LOCF 1.82 (95% CI, 1.18 to 2.78) c 1.9 (95% CI, 1.24 to 2.91) c
60

Observed cases 2.12 (95% CI, 1.33 to 3.38) c 2.32 (95% CI, 1.44 to 3.73) d
Fibromyalgia pain treatment
BOCF 1.5 (95% CI, 1.05 to 2.13) b 1.68 (95% CI, 1.18 to 2.38) c
LOCF 1.56 (95% CI, 1.11 to 2.19) c 1.9 (95% CI, 1.36 to 2.65) d
Observed cases 1.86 (95% CI, 1.27 to 2.73) d 2.49 (95% CI, 1.69 to 3.66) d
a CI = confidence interval; b P < 0.05 vs placebo.; c P ≤ 0.01 vs placebo.; d P ≤ 0.001 vs placebo.
Milnacipran was also assessed in a randomized, double-blind, placebo-controlled study enrolling 888
patients with fibromyalgia. The majority of patients were women (95.6%) and white (93.6%), with a mean
age of about 49 years and a mean duration of fibromyalgia of 5.6 years. Patients received placebo (223
patients), milnacipran 100 mg/day (224 patients), or milnacipran 200 mg/day (441 patients) for 27 weeks.
Patients were required to discontinue all centrally acting fibromyalgia therapies, including
antidepressants, sedative-hypnotics, muscle relaxants, and centrally acting analgesics, as well as
transcutaneous electrical nerve stimulation, biofeedback, tender and trigger point injections, acupuncture,
and anesthetic or narcotic patches. All analgesics were prohibited except acetaminophen, aspirin, stable
doses of NSAIDs, and limited doses of rescue hydrocodone. The primary efficacy end point for the
“treatment of fibromyalgia” was a composite defining responders as patients with at least 30% pain
improvement as assessed by the change from baseline in 24-hour morning recall pain collected from
daily e-diary scores, a rating of “very much improved” or “much improved” on the PGIC, and an at least 6-
point improvement from baseline in physical function (SF-36 Physical Component Summary score). The
primary end point measure for “treatment of pain of fibromyalgia” was a composite defining responders as
patients achieving at least 30% improvement in pain in 24-hour morning recall pain and rating themselves
as “very much improved” or “much improved” on the PGIC scale. Missing data were analyzed using
BOCF for the week-15 evaluation. At the week-27 assessment, BOCF was utilized for patients
prematurely discontinuing the study before week 15, and LOCF was used for patients who completed
week 15 but discontinued prior to week 27. Results for patients completing the study and those with
partial data are summarized in Table 4. Overall, in the modified intent-to-treat analysis, composite
responses were not consistently achieved in more milnacipran-treated patients at 3 months or at 6
months. Improvements were observed with milnacipran on the secondary end points of morning recall
pain scores (P = 0.01), real-time pain scores (P = 0.01), weekly recall pain scores (P = 0.018), PGIC (P <
0.001), multidimensional Fatigue Inventory total score (P = 0.016), the Multiple Ability Selfreport
Questionnaire (MASQ) cognition total score (P = 0.025), and multiple domains of the SF-36.
Improvements were not observed in sleep quality or quantity. Among subjects completing the study, the
composite pain response rate was 27.2% for placebo, 45.2% for milnacipran 100 mg/day, and 45.4% for
milnacipran 200 mg/day; however, dropout rates were 35% in the placebo group, 43% in the 100 mg/day
group, and 46% in the 200 mg/day group (J Rheumatol. 2009;36(2):398-409).
A randomized, blinded extension to this study enrolled 449 patients who were either maintained on
milnacipran 200 mg/day (209 patients) or re-randomized from placebo or milnacipran 100 mg/day to
milnacipran 100 mg/day (48 patients) or 200 mg/day (192 patients) for an additional 6 months of therapy.
Among patients re-randomized from placebo to milnacipran 200 mg/day, pain scores improved 47%
(mean pain score declined from 53.9 to 39.4). Among those continuing milnacipran, VAS pain scores
remained consistent (42 mm at week 27, 39.2 mm at week 38, 39.5 mm at week 44, and 38.6 mm at
week 52) and improvements on the PGIC and pain, stiffness, tiredness, and depressed mood times of the
Fibromyalgia Impact Questionnaire (FIQ) were maintained over 12 months. Sixty-seven percent of
patients completed the extension study (Arthritis Rheum. 2008;58(9)(suppl):S383).
Table 4. Composite Response Rates With Milnacipran in Patients With Fibromyalgia
Parameter Placebo (n =
223)
Milnacipran 100 mg/day (n =
224)
Milnacipran 200 mg/day (n =
441)
Fibromyalgia treatment (>/=30% pain decrease, a reduction in PGIC and SF 36)
Week 15
BOCF 12.1% 19.6% (P = 0.028) 19.3% (P = 0.017)
61

Observed
cases
17.3% 32.8% (P = 0.003) 32.8% (P < 0.001)
Week 27
BOCF/LOCF 13% 18.3% (P = 0.245) 18.1% (P = 0.105)
Observed
cases
19.4% 33.3% (P = 0.056) 31.9% (P = 0.017)
Fibromyalgia pain treatment (>/= 30% reduction in pain scores)
Week 15
BOCF 19.3% 27.2% (P = 0.056) 26.8% (P = 0.032)
Observed
cases
27.2% 45.2% (P = 0.003) 45.4% (P < 0.001)
Week 27
BOCF/LOCF 18.4% 25.9% (P = 0.072) 25.6% (P = 0.034)
Observed
cases
27.9% 43.8% (P = 0.021) 45.2% (P = 0.001)
Another randomized, double-blind, phase 3 study that assessed milnacipran 200 mg/day compared with
placebo in 884 patients with fibromyalgia was reported in a meeting abstract. The majority of patients
were women (94.3%), with a mean age of 48.8 years. Patients received placebo (449 patients) or
milnacipran 200 mg/day (435 patients) for 12 weeks. The primary end point, fibromyalgia composite
response, was defined as patients with at least 30% improvement in 24-hour recall pain and a rating of
“very much improved” or “much improved” on the PGIC scale. Overall impact on symptomatology was
assessed with the FIQ total score. Milnacipran exhibited greater improvement relative to placebo in the
composite response (P = 0.0003; results not provided) and in the FIQ total score (P = 0.015). Greater
improvement with milnacipran than placebo was also observed for secondary end points, including
weekly pain on e-diary, Brief Pain Inventory (BPI), SF-36 Mental and Physical components,
Multidimensional Fatigue Inventory total score, FIQ physical function subscale score, and the MASQ
cognition total score (Eur Neuropsychopharmacol. 2008;18(suppl 4):S574-S575).
Milnacipran was also evaluated in a randomized, double-blind, dose-escalation study enrolling 125
patients with fibromyalgia. Mean age was 46.2 to 48 years; 96% to 98% of patients in each treatment
group were women, and 79% to 89% were white. The mean duration of fibromyalgia ranged from 3.8 to
4.3 years, and most patients had used multiple nondrug treatment modalities (eg, acupuncture,
antiepileptics, chiropractic, diet, exercise, hot-cold packs, massage, physical therapy). Patients were
assigned to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months using a3:3:2
ratio. All previous antidepressants, centrally acting muscle relaxants, hypnotics, and opioids and their
derivations had to be discontinued over a period of 1 to 4 weeks. Stable doses of NSAIDs, aspirin, and
acetaminophen were allowed during the study. Following a 2-week baseline observation period, patients
were randomized to therapy with placebo (28 patients), milnacipran 25 mg once daily (46 patients), or
milnacipran 12.5 mg twice daily (51 patients). If doses were tolerated, dose escalation was completed
weekly to 50, 100, and then 200 mg once daily, or 25, 50, and then 100 mg twice daily over a 4-week
period. Patients were then continued at a stable dose for an additional 8 weeks. There was no difference
in the rate of discontinuation of drug therapy (30.4% with milnacipran once daily, 27.5% with milnacipran
twice daily, and 25% with placebo). Dose escalation to the target dose of 200 mg was achieved in 92% of
patients assigned twice-daily administration and 81% of those assigned once-daily administration. The
mean daily dose of milnacipran was 174 mg in the once-daily group and 191 mg in the twice-daily group.
The primary end point was the change in pain recorded on e-diary during the final 2 weeks of the trial
compared with the average pain scores during the 2-week baseline period. All analysis was intent-to-treat
with LOCF. Improvements in pain, global well-being, and fatigue were observed in both active-treatment
groups; however, twice-daily administration was associated with more improvements compared with
placebo. Pain scores are summarized in Table 5. Response was defined as a 30% or 50% reduction in
62

pain score. On patient global assessment, patients in either milnacipran group were more likely to rate
themselves as improved (73% in the twice-daily group [P = 0.013] and 77% in the once-daily group [P =
0.008] vs 38% in the placebo group). No difference between groups was observed on FIQ total scores or
sleep scores (J Rheumatol. 2005;32(10):1975-1985).
Table 5. Changes in Pain Parameters With Milnacipran vs Placebo
Parameter
Milnacipran Twice
Daily (n = 51)
Milnacipran Once
Daily (n = 46)
Placebo (n = 28)
Daily e-diary pain scores
(range, 0 to 20) from baseline
−3 −2.2 −1.86
Daily e-diary responders
30% pain reduction (> −3.3 units) 35% 22% 18%
50% pain reduction (> −4 units) 35% 22% 14%
Weekly e-diary pain scores
(range, 0 to 20) from baseline
−3.1 (P = 0.025) −2.5 −1.14
Weekly e-diary responders
30% pain reduction (> −3.3 units) 39% (P = 0.023) 28% 14%
50% pain reduction (> −4 units) 37% (P = 0.04) 22% 14%
Paper Gracely pain scores
(range, 0 to 20) from baseline
−4.7 (P = 0.01) −2.9 −1.7
Paper Gracely pain scores
30% pain reduction (> −3.3 units) 45% (P = 0.007) 35% 18%
50% pain reduction (> −4 units) 37% (P = 0.04) 28% 14%
Paper VAS pain scores
(range, 0 to 10) from baseline
−2.5 (P = 0.03) −2 −0.9
Paper VAS pain scores
30% pain reduction (−3.3 units) 39% 35% 21%
50% pain reduction (−4 units) 29% 26% 21%
McGill present-pain intensity
(range, 0 to 10) from baseline
a P > 0.05 unless provided.
−2.2 (P = 0.023) −1.4 −0.6
Milnacipran was also assessed in a smaller open-label, 12-week study enrolling 20 Japanese patients (3
men and 17 women) with fibromyalgia and comorbid depressive symptoms. Mean age was 54.1 years
and mean duration of fibromyalgia was 21.4 months. Patients initially received milnacipran 15 mg twice
daily, with titration as needed and tolerated to a maximum dose of 100 mg/day. The final daily dose at the
end of the study was 50 mg in 13 patients, 75 mg in 3 patients, and 100 mg in 2 patients; 2 additional
patients discontinued therapy because of nausea. Five patients had a reduction in pain of more than 50%
as assessed on a VAS; 9 had a reduction of 30% or more. Post-hoc analysis suggested that the 11
patients who were no longer depressed at the end of the study had the greatest improvement in pain and
overall fibromyalgia symptoms (
. Int J Psych Clin Pract. 2004;8(1):47-51)
Major depressive disorder (OFF Label – NOT FDA Approved)
Milnacipran was also assessed in numerous studies enrolling patients with major depressive disorder. In
a meta-analysis of 6 studies comparing milnacipran with a selective serotonin reuptake inhibitor (SSRI)
63

for the treatment of major depressive disorder, patients treated with milnacipran were as likely to
experience clinical response as patients randomized to treatment with an SSRI. Outcome assessments in
these studies were either the Montgomery-Asberg Depression Rating Scale (MADRS) (relative risk [RR] =
1.04; 95% confidence interval [CI], 0.88 to 1.23; P = 0.533) or the Hamilton Depression Rating Scale
(HDRS) (RR = 1.06; 95% CI, 0.9 to 1.24; P = 0.456). MADRS response rates were 58.9% with
milnacipran and 58.3% with SSRIs; HDRS response rates were 59.7% with milnacipran and 57.5% with
SSRIs. Overall discontinuation rates and rates of discontinuation because of adverse reactions or lack of
efficacy did not differ between therapies. In another meta-analysis of 16 studies comparing milnacipran
with any other antidepressant, no differences in clinical response were observed in comparison with
tricyclic antidepressants or SSRIs. Compared with tricyclic antidepressants, milnacipran-treated patients
experienced fewer adverse effects and were less likely to withdraw early because of adverse effects.
Additional studies comparing milnacipran with imipramine have demonstrated equivalent efficacy with
better tolerability with milnacipran. Milnacipran also demonstrated efficacy in small studies enrolling
patients with poststroke depression and depression associated with Alzheimer disease.
Pilot studies also suggested potential activity of milnacipran in bulimia nervosa and panic disorders.
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS:
CONTRAINDICATIONS
Milnacipran is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) concomitantly
or in close temporal proximity, and in patients with uncontrolled narrow-angle glaucoma.
WARNINGS AND PRECAUTIONS
The milnacipran package insert includes required antidepressant class black box warning regarding the
increased risk of suicidal ideation observed in children and young adults taking antidepressants for major
depressive disorder and other psychiatric disorders. Milnacipran is not FDA-approved for the treatment of
major depressive disorder or for use in children. All patients receiving milnacipran should be monitored for
worsening of depressive symptoms and suicide risk.
Serotonin syndrome has been reported with the SNRIs. Concomitant use of serotonergic drugs is not
recommended.
Elevated blood pressure and heart rate have been observed with milnacipran. Blood pressure and heart
rate should be determined prior to initiating milnacipran and periodically throughout treatment.
Milnacipran should be used with caution in patients with hypertension or cardiac disease; preexisting
hypertension, tachyarrhythmias, or other cardiovascular disease should be treated before initiating
therapy. In fibromyalgia studies, milnacipran was associated with a mean increase of up to 3.1 mm Hg in
systolic and diastolic blood pressure, and mean increases in heart rate of approximately 7 to 8 beats per
minute. Among patients who were not hypertensive at baseline, approximately twice as many treated with
milnacipran became hypertensive at study end compared with those treated with placebo (7.2% vs 19.5%
treated with milnacipran 100 mg/day; 16.6% treated with milnacipran 200 mg/day). Among patients who
were hypertensive at baseline, more patients treated with milnacipran had a more than 15 mm Hg
increase in systolic blood pressure (1% on placebo vs 7% in the milnacipran 100 mg/day group; 2% in the
milnacipran 200 mg/day group) and/or a more than 10 mm Hg increase in diastolic blood pressure (3%
with placebo vs 8% with milnacipran 100 mg/day and 6% with milnacipran 200 mg/day). In patients
experiencing a sustained increase in blood pressure or heart rate while receiving milnacipran, the dose
should be reduced or therapy discontinued.
Seizures have been reported in patients receiving milnacipran. Milnacipran should be used with caution in
patients with a history of seizure disorder.
Elevations in hepatic transaminases and fulminant hepatitis have been reported in patients treated with
milnacipran. Avoid use of milnacipran in patients with substantial alcohol use or chronic liver disease.
Milnacipran should be discontinued in patients who develop jaundice or other evidence of liver
dysfunction.
Withdrawal symptoms have been observed upon discontinuation of milnacipran therapy. A gradual dose
64

eduction is recommended.
Hyponatremia, often associated with the syndrome of inappropriate antidiuretic hormone secretion, has
been reported during milnacipran therapy. Elderly patients, patients taking diuretics, and patients who are
volume depleted are at increased risk. Milnacipran should be discontinued in patients developing
symptomatic hyponatremia.
The risk of bleeding events may be increased during milnacipran therapy. Caution is advised with the
concomitant use of NSAIDs, aspirin, or other drugs affecting coagulation.
Although not observed in fibromyalgia studies with milnacipran, activation of mania and hypomania has
occurred in patients with major depressive disorder receiving other SNRIs. Milnacipran should be used
cautiously in patients with a history of mania.
Men with a history of obstructive uropathies may experience higher rates of genitourinary adverse events,
such as dysuria or urinary retention.
Milnacipran has been associated with mydriasis and, therefore, should be used cautiously in patients with
controlled narrow-angle glaucoma. Use in uncontrolled narrow-angle glaucoma is contraindicated.
The 50 mg tablets contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions in
susceptible persons.
Milnacipran should be used with caution in patients with moderate renal impairment or severe hepatic
impairment; dosage adjustment is necessary in patients with severe renal impairment.
The safety and effectiveness of milnacipran have not been established in children. Use is not
recommended in this population. 1 Two studies of milnacipran in patients 13 to 17 years of age with
juvenile primary fibromyalgia syndrome have been proposed, but have not been initiated.
Milnacipran is in Pregnancy Category C. In animal studies, milnacipran increased the incidence of death
in utero and skeletal variations. Neonates exposed to SNRIs or SSRIs late in the third trimester have
developed complications resulting in prolonged hospitalization, respiratory support, and tube feeding.
Milnacipran should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
It is not known whether milnacipran is excreted in human milk; however, either milnacipran or its
metabolites were observed in be excreted in breast milk in animal studies. Because of the risk of adverse
effects in the infant, breast-feeding while receiving milnacipran is not recommended.
Contraindications
Table 6. Contraindications, Warnings, and Precautions Associated
With Duloxetine and Milnacipran Therapy
Duloxetine
Milnacipran
Concomitant MAOIs X X
Uncontrolled narrow-angle glaucoma X X
Black box warnings
Suicidal risk X X
Warnings and precautions
Serotonin syndrome X X
Hepatotoxicity X X
Orthostatic hypotension
X
65

Increased blood pressure and heart rate X X
Bipolar disorder
Mania/Hypomania X X
Hyponatremia X X
Controlled narrow-angle glaucoma X X
Withdrawal symptoms X X
Seizures X X
Diabetes and glycemic control
Abnormal bleeding X X
Urinary hesitation and retention X X
Renal function impairment X X
Hepatic function impairment X X
Pregnancy Category C C
Lactation Not recommended Not recommended
Children Not established Not recommended
ADVERSE REACTIONS: The most frequently occurring adverse events during milnacipran therapy have
included nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting,
palpitations, heart rate increased, dry mouth, and hypertension. Elevations in ALT and AST have also
been observed.
Milnacipran appeared weight-neutral in the 2 large studies of milnacipran in fibromyalgia. In both studies,
a slight weight loss was observed with milnacipran compared with placebo. In both studies, the majority of
patients were overweight or obese at baseline (mean body mass index [BMI], 30.5 and 30.7; patients with
BMI more than 25, 78.2% in 1 study and 76.9% in the other). Mean weight loss ranged from 0.67 to 0.85
kg in the milnacipran groups compared with a gain of 0.43 kg in 1 placebo group and a weight loss of
0.11 kg in the other (P < 0.001).
In comparison, the most frequently reported adverse effects with duloxetine include nausea, dry mouth,
constipation, somnolence, hyperhidrosis, and decreased appetite.
Table 7. Adverse Reactions Reported in 3 Placebo-Controlled Clinical Trials of Milnacipran
in the Treatment of Fibromyalgia 1
Adverse Reactions
Placebo
(n = 652)
Milnacipran
100 mg/day
(n = 623)
X
X
Milnacipran
200 mg/day
(n = 934)
All Milnacipran
(n = 1,557)
Nausea 20% 35% 39% 37%
Headache 14% 19% 17% 18%
Constipation 4% 16% 15% 16%
Insomnia 10% 12% 12% 12%
Hot flush 2% 11% 12% 12%
Dizziness 6% 11% 10% 10%
Hyperhidrosis 2% 8% 9% 9%
66

Palpitations 2% 8% 7% 7%
Upper respiratory
tract infection
6% 7% 6% 6%
Hypertension 1% 7% 4% 5%
Vomiting 2% 6% 7% 7%
Migraine 3% 6% 4% 5%
Heart rate increased 1% 5% 6% 6%
Dry mouth 2% 5% 5% 5%
Anxiety 4% 5% 3% 4%
DRUG INTERACTIONS: Milnacipran pharmacokinetics are not affected by inducement or inhibition of
CYP2D6 or 2C19. Milnacipran does not appear to be metabolized by CYP1A2, CYP2A6, CYP2B6,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Milnacipran does not induce CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5 or inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, or CYP3A4.
No pharmacokinetic interaction was observed when switching immediately from fluoxetine to milnacipran,
or from clomipramine to milnacipran. No pharmacokinetic interaction was observed with coadministration
of milnacipran and digoxin, warfarin, lorazepam, lithium, carbamazepine, or levomepromazine.
Potential pharmacodynamic interactions include those with MAOIs, other serotonergic medications, other
medications that affect blood pressure or heart rate, and other CNS-active medications.
Concomitant use of milnacipran with an MAOI is contraindicated. At least 14 days should elapse between
discontinuation of an MAOI and initiation of milnacipran therapy. In addition, at least 5 days should be
allowed after stopping milnacipran before starting an MAOI.
The risk of serotonin syndrome is increased when milnacipran is administered with other drugs that are
serotonergic or that impair the metabolism of serotonin. Caution is advised if milnacipran is administered
with such agents (eg, linezolid, lithium, tramadol, triptans).
Concomitant use of milnacipran with epinephrine and norepinephrine may be associated with paroxysmal
hypertension and possible arrhythmia. Use with digoxin may result in potentiation of hemodynamic
effects. Coadministration with intravenous (IV) digoxin has been associated with postural hypotension
and tachycardia; therefore, coadministration with IV digoxin should be avoided. Coadministration with
clonidine may inhibit clonidines antihypertensive effect.
Milnacipran should be used with caution in combination with other CNS-active agents. An increase in
euphoria and postural hypotension was observed in patients switched from clomipramine to milnacipran.
Drug interactions associated with duloxetine and milnacipran are summarized in Table 8.
Table 8. Drug Interactions Associated With Duloxetine and Milnacipran Therapy
Interacting Agent
Duloxetine Milnacipran
CNS-acting agents X X
Alcohol X X
MAOIs X X
Serotonergic agents X X
Epinephrine and norepinephrine
X
67

Drugs that interfere with hemostasis (eg, aspirin, NSAIDs, warfarin) X X
CYP1A2 inhibitors (eg, cimetidine, ciprofloxacin, fluvoxamine)
CYP2D6 inhibitors (eg, fluoxetine, paroxetine, sertraline, quinidine)
CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines,
propafenone, flecainide)
Clomipramine
Digoxin
Clonidine
X
X
X
X
X
X
RECOMMENDED MONITORING: In addition to monitoring for therapeutic response and general adverse
reaction monitoring, blood pressure monitoring is advised. Blood pressure and heart rate should be
determined prior to initiating therapy and periodically throughout therapy.
DOSING: The milnacipran dose should be titrated over 1 week to the recommended dosage of 50 mg
twice daily. Therapy should be initiated with a single 12.5 mg dose on the first day, 12.5 mg twice daily on
days 2 and 3, 25 mg twice daily on days 4 through 7, and 50 mg twice daily thereafter. The dose may be
subsequently increased to 100 mg twice daily based on individual response. Milnacipran may be taken
with or without food; however, administration with food may improve tolerability.
No dosage adjustments are necessary in patients with mild renal impairment. Milnacipran should be used
with caution in patients with moderate renal impairment. In patients with severe renal impairment (CrCl
less than 30 mL/min), the usual maintenance dosage should be reduced 50% to 25 mg twice daily, with
increase to 50 mg twice daily based on individual patient response. Use is not recommended in patients
with end-stage renal disease. 1,8 Dosage adjustments are not necessary in patients with hepatic function
impairment; however, caution is advised with the use of milnacipran in patients with severe hepatic
impairment.
Table 9. Comparative Dosing Regimens in Fibromyalgia
Normal Dose
Duloxetine Initiate at 30 mg once daily. May increase to 60
mg once daily after 1 week.
Milnacipran Initiate at 12.5 mg on the first day. Increase to
50 mg twice daily over the first week. May
further increase to 100 mg twice daily.
Special Populations
Avoid use in patients with severe renal
impairment (CrCl < 30 mL/min) or any
hepatic function impairment
Reduce dose by 50% in severe renal
impairment. Avoid use in end-stage renal
disease.
PRODUCT AVAILABILITY/COST and STORAGE: Milnacipran was originally developed as an
antidepressant in France, and has been available in that country since 1997. 12 Milnacipran received FDA
approval January 14, 2009. It is available as 12.5, 25, 50, and 100 mg film-coated tablets. Milnacipran
should be stored at room temperature (25°C; 77°F), with excursions permitted between 15°C and 30°C
(59°F and 86°F). The cost of Savella AWP is $127.00/60 tabs (all strengths) Vs. Cymbalta (duloxetine)
60mg $140.27/30; 30mg $139.13/30 and 20mg $129.00/30 enteric coated capsules Vs. Lyrica
(pregabalin) $80.10 per 30 capsules of all strengths 25,50,75,100, 150, 200,225 and 300mg
68

Agent
Table 10. Dosage Forms for the Available SNRIs
Desvenlafaxine Tablets, extended-release: 50 mg, 100 mg
Duloxetine
Milnacipran
Venlafaxine
Dosage Forms
Capsules, delayed-release: 20 mg, 30 mg, 60 mg
Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg
Tablets: 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg
Capsules, extended-release: 37.5 mg, 75 mg, 150 mg
CONCLUSION: Milnacipran appears to have activity in fibromyalgia; however, studies directly comparing
milnacipran with duloxetine would be useful to determine its place in therapy. Duloxetine has more
approved indications and is administered once daily and requires fewer dosage adjustments to achieve
the recommended target dose; however, milnacipran may have fewer drug interactions. Both duloxetine
and milnacipran require careful monitoring of BP and heart rate as they both increase norepinephrine and
it appears that milnacipran is the most likely to do so of these two agents.
69

TAPENTADOL IMMEDIATE-RELEASE TABLETS – NUCYNTA C-II by PriCara, Ortho-McNeil-Janssen
1S
INDICATIONS: Tapentadol immediate-release tablets are indicated for the relief of moderate to severe
acute pain in patients 18 years of age and older. An extended-release formulation is currently in
development for the treatment of chronic pain.
CLINICAL PHARMACOLOGY: Tapentadol is a mu opioid receptor agonist and norepinephrine reuptake
inhibitor.
Tapentadol has a 18- to 50-fold lower affinity for mu opioid receptors than morphine, but is only 2- to 3-
fold less potent than morphine in analgesic activity, which indicates its analgesic activity not exclusively
based on its binding affinity to an opioid receptor. Norepinephrine reuptake potency is similar to that of
venlafaxine. In an animal model, the analgesic effects of tapentadol is antagonized by yohimbine, an
alpha 2 -norepinephrine receptor antagonist, and only weakly antagonized by naloxone. This has led
investigators to believe that the inhibition of the reuptake of norepinephrine is an important part of the
analgesic pharmacology of this compound.
Tapentadol has displayed activity in a wide variety of animal pain models, demonstrating antinociceptive,
antihyperalgesic, and antiallodynic effects in models of acute antinociception, acute and chronic
neuropathic pain, visceral pain, and inflammatory pain. In visceral pain models, the analgesic effects
observed with tapentadol are comparable with morphine.
PHARMACOKINETICS: Tapentadol is rapidly absorbed following oral administration, with a mean time to
peak concentration of less than 1.5 hours. Oral bioavailability is 32%. Tapentadol is not absorbed
following buccal administration. Tapentadol is 20% plasma protein bound.
The mean elimination half-life of tapentadol is about 4 hours. Tapentadol is metabolized predominantly by
hepatic glucuronidation via the UDP-glucuronosyltransferase (UGT) pathways by UGT1A9 and UGT2B7
enzymes. To a minor extent, it is also metabolized by CYP2C9, CYP2C19, and CYP2D6. The major
metabolite, tapentadol-glucuronide, and the minor metabolites are inactive. Tapentadol metabolites are
renally eliminated. About 3% of the administered dose is excreted unchanged in the urine.
Pharmacokinetic parameters of tapentadol are not altered in elderly subjects. The area under the curve
(AUC) of tapentadol is unchanged in subjects with renal impairment; however, the level of the major
metabolite (tapentadol-glucuronide) is increased 1.5-, 2.5-, and 5.5-fold in subjects with mild, moderate,
and severe renal impairment. Tapentadol serum levels were increased in subjects with hepatic
impairment. The AUC was increased 1.7- and 4.2-fold in subjects with mild and moderate hepatic
impairment. Peak concentrations were increased 1.4- and 2.5-fold, respectively. Half-life was increased
1.2- and 1.4-fold.
Table 1. Pharmacology and Pharmacokinetics of Oxycodone, Tapentadol, and Tramadol
Oxycodone Tapentadol Tramadol
Pharmacology Mu opioid agonist Mu opioid agonist
Norepinephrine
reuptake inhibitor
Mu opioid agonist
Norepinephrine
and 5-HT reuptake
inhibitor
Time to peak 1 to 2 h < 1.5 h 2 h
Half-life 3.5 to 4 h 4 h 6.3 h
Metabolism
Active
metabolites
Elimination
CYP2D6,
glucuronidation
Glucuronidation
CYP2D6, CYP3A4
Weak No Yes
Metabolites renally
eliminated
Metabolites renally
eliminated
Metabolites renally
eliminated
70

19% unchanged in urine 3% unchanged in urine 30% unchanged in
urine
COMPARATIVE EFFICACY: Tapentadol efficacy as an analgesic was established in several pain
conditions, including postoperative bunionectomy pain, dental extraction pain, and osteoarthritis. The
extended-release formulation (NOT FDA approved) has been studied in osteoarthritis, chronic low back
pain, and diabetic neuropathic pain.
Tapentadol immediate-release was assessed in a randomized, double-blind study enrolling 269 patients
with moderate to severe pain following bunionectomy surgery. Eligible patients had a postoperative pain
score of at least 4 on an 11-point numerical-rating scale and an increase in pain of at least 1 point on the
11-point scale within 9 hours after regional anesthesia was discontinued on the first postoperative day.
Patients received tapentadol 50 or 100 mg, oxycodone immediate-release 10 mg, or placebo, with study
drug taken every 4 to 6 hours over a 72-hour period starting 1 day after surgery. Oxycodone was included
to demonstrate model sensitivity; the study was not powered for comparison of tapentadol with
oxycodone. Rescue medication was available for patients requiring pain medication within 4 hours after
the second or subsequent dose of study drug. The primary end point was the sum of pain intensity over
24 hours (SPI-24) on the second day after randomization (study day 3). Mean SPI-24 values on the day 3
were 33.6 for tapentadol 50 mg (P = 0.0133 vs placebo), 29.2 for tapentadol 100 mg (P = 0.0001 vs
placebo), and 35.7 for oxycodone 10 mg (P = 0.0365 vs placebo) compared with 41.9 for placebo.
Results from this study are summarized in Table 2. Tapentadol 50 mg was associated with a lower
incidence of dizziness than oxycodone (32.8% vs 56.7%), but a similar incidence of somnolence (28.4%
vs 26.9%). Tapentadol 100 mg was associated with higher rates of dizziness (64.7%) and somnolence
(36.8%). GI side effects also appeared less frequently with tapentadol; however, the study was not
powered for these comparisons (Curr Med Res Opin. 2008;24(11):3185-3196).
Table 2. Efficacy of Tapentadol Immediate-Release Formulation in the
Treatment of Postsurgical Bunionectomy Pain
Tapentadol 50
mg
(n = 67)
Tapentadol 100
mg
(n = 68)
Oxycodone 10
mg
(n = 67)
Mean SPI-24 on day 2 41.2 a 36.9 a 43.3 a 53.9
Mean SPI-24 on day 3 33.6 b 29.2 a 35.7 b 41.9
Mean SPI-24 on day 4 24.9 23.4 b 25 30.1
Median time to
perceptible pain
relief
Median time to
50% pain relief
Percentage rating
study drug “good,”
“very good,” or
“excellent” on day 3
Percentage receiving
rescue medication
Placebo
(n = 67)
43 min 31 min 31 min 2 h 40 min
2 h 1 h 1.5 h 3.5 h
64.1% 86.5% 74.2% 45.4%
80.6% 76.5% 80.6% 98.5%
Tapentadol immediate-release was also assessed in a subsequent randomized, double-blind, placebocontrolled
study enrolling 603 patients with moderate to severe pain following bunionectomy. Patients
received tapentadol 50, 75, or 100 mg, oxycodone 15 mg, or placebo every 4 to 6 hours over a 72-hour
period following bunionectomy. Patients receiving rescue medication were withdrawn from the study. The
primary end point was the sum of pain intensity difference (SPID) over 48 hours in the modified intent-totreat
population. Mean SPID48 values were higher for all tapentadol doses and oxycodone compared
71

with placebo. Results are summarized in Table 3. A prespecified noninferiority comparison of tapentadol
75 mg with oxycodone 15 mg was also conducted; however, the 75 mg dose was not found to be
noninferior to oxycodone 15 mg as the lower boundary of the 2-sided 95% confidence interval exceeded
the prespecified noninferiority margin. A post hoc demonstrated noninferiority of tapentadol 100 mg with
oxycodone 15 mg (Curr Med Res Opin. 2009;25(3):765-776).
Table 3. Tapentadol vs Oxycodone in the Treatment of Postsurgical Bunionectomy Pain
Tapentadol
50 mg
(n = 119)
Tapentadol
75 mg
(n = 120)
Tapentadol
100 mg
(n = 118)
Oxycodone
15 mg
(n = 125)
Placebo
(n = 121)
Mean SPID12 23.2 a 30 a 35.5 a 35.6 a 4.7
Mean SPID24 46.6 a 60.5 a 73.3 a 73. 3a 5.2
Mean SPID48 119.1 a 139.1 a 167.2 a 172.3 a 24.5
Mean SPID72 207.9 a 230.5 a 271.1 a 288.3 a 55.7
Median time to perceptible
pain relief
Median time to meaningful
pain relief
≥ 50% reduction in
pain intensity at 48 h
Percentage rating overall
status “much improved” or
“very much improved”
Percentage receiving
rescue medication
Percentage reporting
adverse reactions
a P < 0.001.
46 min 31 min 36 min 30 min 34 min
2 h 1.75 h 1.5 h 1.3 h 4 h
58% 56.7% 70.3% 72.8% 30%
67% 77% 89% 88% 41%
19% 14% 10% 9% 49%
70% 75% 85% 87% 41%
Single-dose tapentadol immediate-release was also evaluated in a randomized, double-blind, placebocontrolled
study in patients with moderate to severe pain following mandibular third molar extraction. The
study enrolled 400 patients who were randomized to treatment with tapentadol 25, 50, 75, 100, or 200
mg, morphine sulfate 60 mg, ibuprofen 400 mg, or placebo. TOTPAR-8 was the primary end point.
TOTPAR-8 scores were greater for tapentadol 50, 75, 100, and 200 mg; morphine; and ibuprofen
compared with placebo; the greater effect with ibuprofen established the sensitivity of the model. The
study was not powered to detect differences between tapentadol and morphine. Results from this study
are summarized in Table 4 (Anesth Analg. 2008;107(6):2048-2055.)
Table 4. Single-Dose Study Using Tapentadol Immediate-Release to Treat Molar Extraction Pain
Tapentadol
25 mg
Tapentadol
50 mg
Tapentadol
75 mg
Tapentadol
100 mg
Tapentadol
200 mg
Morphine
60 mg
Ibuprofen
400 mg
Placebo
TOTPAR-8 6.3 7.9a 9.7a 11.6a 15.3a 13.8a 17.9a 4.7
Median time to
meaningful pain relief
8 h 8 h 8 h 3.9 ha 1.5 ha 2.6 ha 1.5 ha 8 h
≥ 50% pain relief 32.7% 46% 46% 64.6% a 87.8% a 64.7% a 76.5% a 25.5%
72

Percentage rating study
drug “good,” “very
good,” or “excellent”
22% 28% 35% 50% 68% 55% 64% 12%
a P ≤ 0.001
Tapentadol immediate-release was compared with oxycodone immediate-release in a randomized,
double-blind, placebo-controlled study enrolling 674 patients with uncontrolled hip or knee osteoarthritis
pain awaiting primary joint replacement surgery. The 659 patients with a valid baseline pain assessment
were included in the efficacy analysis. Mean age was 61.2 years; mean weight was 97 kg; 51% were
men, 91% white. Patients received tapentadol 50 or 75 mg, oxycodone 10 mg, or placebo every 4 to 6
hours during waking hours for 10 days. Patients were permitted to continue their stable nonopioid
analgesics during the study. Patients requiring rescue medication beyond the study medication and their
previous stable nonopioid analgesic regimen were withdrawn from the study. The primary end point was
the SPID over the first 5 days. The least squares mean difference from placebo in 5-day SPID was 101.2
with tapentadol 50 mg (P < 0.001), 97.5 with tapentadol 75 mg (P < 0.001), and 111.9 with oxycodone (P
< 0.001). Additional study results are summarized in Table 5. Prespecified noninferiority comparisons
were made between tapentadol and oxycodone with respect to the primary end point, as well as the
incidence of nausea, vomiting, and constipation. The efficacy of both tapentadol doses for the primary
end point was classified as noninferior to oxycodone 10 mg immediate-release. The odds ratios for the
incidence of nausea, vomiting, or constipation were lower for both doses of tapentadol compared with
oxycodone (Clin Ther. 2009;31(2):260-271)
Table 5. Treatment of Uncontrolled Osteoarthritis Pain with Tapentadol
Tapentadol
50 mg
(n = 151)
Tapentadol
75 mg
(n = 164)
Oxycodone
10 mg
(n = 164)
Placebo
(n = 168)
2-day TOTPAR 82 a 80.3 a 86.7 a 54.5
5-day TOTPAR 202.2 a 207.6 a 216 a 142.9
10-day TOTPAR 376.6 a 384.5 a 391.9 a 259
≥ 50% decrease in pain
intensity
Overall status “very much
improved” or “much
improved”
a P < 0.001.
27% 26% 25% 13%
49% 42% 41% 21%
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: The contraindications, warnings, and
precautions for tapentadol, tramadol, and oxycodone are compared in Table 6.
CONTRAINDICATIONS
Tapentadol is contraindicated in patients with paralytic ileus or impaired pulmonary function (including
significant respiratory depression, acute or severe bronchial asthma, or hypercapnia in unmonitored
settings or in the absence of resuscitative equipment). Concomitant use of tapentadol with monoamine
oxidase inhibitors (MAOIs) or use within 14 days of MAOIs is also contraindicated. Unknown
hypersensitivity reactions to tapentadol or its ingredients (microcrystalline cellulose, lactose monohydrate,
croscarmellose sodium, povidone, magnesium stearate, Opadryl II, polyvinyl alcohol, titanium dioxide,
polyethylene glycol, talc, aluminum lake coloring) should be considered a contraindication to the use of
tapentadol.
WARNINGS AND PRECAUTIONS
As with all mu opioid agonists, tapentadol is associated with a risk of respiratory depression. Respiratory
depression risk is increased in elderly patients, debilitated patients, and patients suffering from conditions
accompanied by hypoxia, hypercapnia, or upper airway obstruction, such as asthma, chronic obstructive
pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis,
CNS depression, or coma.
73

Additive CNS-depressive effects have been noted when tapentadol is used in conjunction with alcohol,
other opioids, illicit drugs, general anesthetics, phenothiazines, sedatives, hypnotics, or other CNS
depressants. Dose reductions of 1 or both agents should be considered.
Tapentadol has not been evaluated in patients with seizure disorders because this type of patient was
excluded from clinical trials. Caution is advised with tapentadol use in patients with a history of seizures.
Serotonin syndrome risk may be increased with concomitant use of serotonergic drugs.
Opioid analgesics can raise cerebrospinal fluid pressure. Tapentadol should not be used in patients
susceptible to the effects of raised cerebrospinal fluid pressure, such as those with evidence of head
injury and increased intracranial pressure.
Patients should be advised that tapentadol may impair mental and physical abilities; caution is advised if
the patient is going to be involved with potentially hazardous activities (eg, driving, operating machinery).
Tapentadol is a mu opioid agonist and has been proposed for inclusion into schedule II of the Controlled
Substances Act. It has an abuse potential similar to hydromorphone. Monitor patients closely for signs of
abuse and addiction. Tapentadol may be abused by crushing, chewing, snorting, or injecting the product.
Withdrawal symptoms may occur if tapentadol is discontinued abruptly; such symptoms may be reduced
by tapering tapentadol.
Tapentadol should be used with caution in patients with moderate hepatic impairment, as serum
concentrations of tapentadol were increased compared with patients with healthy hepatic function.
Dosage reductions are recommended in this population. Tapentadol has not been studied in patients with
severe hepatic impairment; therefore, use in this population is not recommended.
Tapentadol has not been studied in patients with severe renal impairment; therefore, use in this
population is not recommended. No dosage adjustments are necessary in patients with mild to moderate
renal impairment.
Caution is advised in patients with biliary tract disease, including acute pancreatitis, because of the
potential for tapentadol to cause spasm of the sphincter of Oddi.
The safety and effectiveness of tapentadol have not been established in patients younger than 18 years
of age.
Tapentadol is classified as Pregnancy Category C. Embryofetal toxicity was observed in animal studies
(eg, rats, rabbits). It should be used in pregnancy only if the potential benefit justifies the potential risk to
the fetus. Tapentadol should not be used immediately prior to labor and delivery. Neonates born to
mothers using tapentadol should be monitored for respiratory depression.
It is not known if tapentadol is excreted in breast milk. Use during breast-feeding is not recommended.
Table 6. Contraindications, Warnings, and Precautions Associated With Oxycodone, Tapentadol,
and Tramadol Therapy
Contraindications
Oxycodone Tapentadol Tramadol
Impaired pulmonary
function
X
X
Paralytic ileus X X
MAOIs X See below
Hypersensitivity X X
74

Acute intoxication
Warnings and Precautions
Respiratory
depression
Hypotensive effects
X X X
X
CNS effects X X X
Elevated intracranial
pressure
X X X
Abuse potential X X X
Withdrawal X X
Impaired mental/
physical abilities
X X X
Seizures X X X
Serotonin syndrome X X
MAOIs See above X
Pancreatic/biliary
tract disease
Anaphylactoid
reactions
Hepatic impairment
Renal impairment
X
Caution in severe
impairment
Caution in severe
impairment
X
Not recommended in severe
impairment; caution in moderate
impairment
Not recommended in severe
impairment
Elderly Caution Caution in selecting
initial dose
Children
Not recommended
< 18 y of age
Not recommended
< 18 y of age
Pregnancy Category B C C
Breast-feeding
mothers
Adverse Effects:
X
X
Dose reduction in
cirrhosis
Dose reduction in
severe impairment
Caution in
selecting
initial dose
Not recommended
< 16 y of age
Not recommended Not recommended Not recommended
Table 8. Adverse Reactions Reported in the Tapentadol vs Oxycodone in Bunionectomy Pain
Study
Tapentadol
50 mg
(n = 119)
Tapentadol
75 mg
(n = 120)
Tapentadol
100 mg
(n = 118)
Oxycodone
15 mg
(n = 125)
Placebo
(n = 121)
Nausea 35% 38% 49% 67% 13%
Vomiting 18% 21% 32% 42% 3%
Constipation 7% 1% 10% 15% 1%
75

Dizziness 16% 22% 31% 30% 5%
Somnolence 12% 13% 21% 10% 1%
Headache 12% 11% 12% 14% 7%
Pruritus 3% 9% 17% 12% 1%
Hyperhidrosis 0% 5% 4% 6% 1%
Pyrexia 1% 6% 0% 2% 3%
Table 9. Adverse Reactions Reported in the Tapentadol vs Oxycodone in the 10-Day
Uncontrolled Osteoarthritis Pain Study 22
Tapentadol
50 mg
(n = 157)
Tapentadol
75 mg
(n = 168)
Oxycodone
10 mg
(n = 172)
Dizziness 18% 26% 23% 5%
Nausea 18% 21% 41% 5%
Vomiting 7% 14% 34% 4%
Somnolence 6% 10% 12% 1%
Headache 6% 8% 3% 6%
Constipation 4% 7% 26% 2%
Pruritus 2% 5% 15% 1%
Diarrhea 1% 5% 1% 3%
Fatigue 1% 7% 10% 1%
Placebo
(n = 169)
Table 10. Tapentadol and Oxycodone Tolerability Over 90 Days in
Patients With Lower Back Pain or Osteoarthritis 24
Tapentadol
Oxycodone
Nausea 18.4% 29.4%
Dizziness 18.1% 17.1%
Vomiting 16.9% 30%
Constipation 12.8% 27.1%
Headache 11.5% 10%
Somnolence 10.2% 9.4%
Pruritus 4.3% 11.8%
DRUG INTERACTIONS: Tapentadol use is contraindicated with or within 14 days of using an MAOI.
Tapentadol should be used with caution in patients using other centrally acting agents or alcohol.
Tapentadol does not inhibit or induce cytochrome P450 enzymes; therefore, CYP-mediated interactions
are unlikely. Drug interactions were not observed with coadministration with acetaminophen,
acetylsalicylic acid, metoclopramide, naproxen, omeprazole, or probenecid.
RECOMMENDED MONITORING: Patients should be monitored for analgesic response, respiratory
depression, and impaired CNS function during tapentadol therapy.
76

DOSING: Tapentadol may be taken orally with or without food. Therapy should be initiated with a dosage
of 50, 75, or 100 mg every 4 to 6 hours depending on pain intensity. The dose should be individualized
based on the severity of pain being treated, previous experience with similar drugs, and the ability to
monitor the patient. On the first day of dosing, the second dose may be administered as soon as 1 hour
after the first dose if adequate pain relief is not attained with the first dose. The dose should be adjusted
to maintain adequate analgesia with acceptable tolerability. Daily doses of more than 700 mg on the first
day of therapy and 600 mg on subsequent days have not been studied and are not recommended.
No dosage adjustment is recommended in patients with mild to moderate renal impairment. Use is not
recommended in patients with severe renal impairment.
No dosage adjustment is recommended in patients with mild hepatic impairment. Tapentadol should be
used with caution in moderate hepatic impairment, with the dose initiated at 50 mg and the interval
between doses no less than every 8 hours for a maximum of 3 doses in 24 hours. The interval may be
adjusted to achieve maintenance of analgesia with acceptable tolerability. Tapentadol use is not
recommended in patients with severe hepatic impairment.
PRODUCT AVAILABILITY/COSE and STORAGE: Tapentadol received Food and Drug Administration
approval November 20, 2008. It is available as 50, 75, and 100 mg tablets supplied in bottles of 100 and
hospital unit-dose blister pack of 10.
Tapentadol tablets should be stored at controlled room temperature (25°C; 77°F), with excursions
permitted between 15° and 30°C (59° and 86°F); protect from moisture.
Tapentadol is only available as immediate-release tablets at this time. The Drug Enforcement
Administration has proposed inclusion of tapentadol in schedule II and that is how it is available.
50 mg tablets $51.99/20 tabs drugstore.com
75 mg tablets $59.99/20 tabs
100 mg tablets $69.99/20 tabs
CONCLUSION: Tapentadol is an opioid agonist analgesic that shares some properties with tramadol but
has exhibited an abuse liability similar to hydromorphone. In vivo pain studies have demonstrated activity
similar to other opioid analgesics, with a slightly different adverse event profile (less GI side effects but
similar rates of somnolence and dizziness). Additional studies in pain conditions that have not been FDA
approved (eg, neuropathic pain) that might benefit from the added norepinephrine reuptake inhibition
mechanism will further define the role of this agent as will additional studies with the extended-release
formulation for the treatment of various chronic pain conditions.
77

ASENAPINE – Saphris by Schering-Plough
1S
INDICATIONS:
Asenapione is an atypical antipsychotic indicated for: acute treatment of schizophrenia in adults and
acute treatment of manic or mixed episodes associated with bipolar I disorder in adults
CLINICAL PHARMACOLOGY: Asenapine has exhibited antagonist activity at dopamine D2 receptors as
well as at serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors; dopamine
D1, D3, and D4 receptors; alpha-adrenergic and histamine receptor subtypes; and glutamate receptors. It
has minimal activity at the muscarinic receptors. Asenapine has higher affinity for serotonergic (5-HT2A,
5-HT2C, 5-HT6, and 5-HT7), noradrenergic (alpha-2A, alpha-2B, and alpha-2C), and dopamine D3 and
D4 receptors than the D2 receptor. 3,6 Asenapine has shown partial agonist activity at the 5-HT1A receptor
in some assessments, but not others. It is a potent antagonist at the alpha-2A receptor.
Compared with other antipsychotic agents, asenapine has greater affinity for the 5-HT2A receptor than
risperidone, ziprasidone, clozapine, olanzapine, or quetiapine. It also has greater affinity at 5-HT1A, 5-
HT1B, 5-HT2C, 5-HT6, and 5-HT7 receptors than olanzapine and risperidone. It has greater D2 affinity
than risperidone, ziprasidone, olanzapine, quetiapine, and clozapine. It has also has high affinity for 5-
HT2C receptors. Asenapine has a lower affinity for histamine receptors relative to its D2 affinity, unlike
olanzapine, clozapine, and quetiapine.
In animal models, asenapine has exhibited activity in the conditioned avoidance response model
predictive of antipsychotic activity and in stress-induced anhedonia without acute stimulation predictive of
activity in bipolar disorder.
PHARMACOKINETICS: Following a single 5-mg dose of SAPHRIS, the mean Cmax was approximately
4 ng/mL and was observed at a mean tmax of 1 hr. Elimination of asenapine is primarily through direct
glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly
CYP1A2). Following an initial more rapid distribution phase, the mean terminal half-life is approximately
24 hrs. With multiple-dose twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state
asenapine pharmacokinetics are similar to single-dose
Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations
occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%.
Increasing the dose from 5 to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times)
increases in both the extent of exposure and maximum concentration. The absolute bioavailability of
asenapine when swallowed is low (

In elderly patients with psychosis (65-85 years of age), asenapine concentrations were on average 30 to
40% higher compared to younger adults.
COMPARATIVE EFFICACY: Bipolar disorder
Asenapine was assessed in the treatment of acute mania in a double-blind, placebo- and olanzapinecontrolled
study enrolling patients with a manic or mixed episode of bipolar I disorder and a Young Mania
Rating Scale (YMRS) score of at least 20. Following a 7-day washout period, patients were randomized
to 3 weeks of treatment with asenapine 5 to 10 mg twice daily, olanzapine 5 to 20 mg once daily, or
placebo. Mean doses were 18.4 mg/day for asenapine and 15.9 mg/day for olanzapine. A total of 488
patients who received at least 1 dose of study medication were included in the assessment. The primary
end point was the least-squares mean change from baseline in YMRS total score. At day 21,
improvement in YMRS score was −11.5 with asenapine (P = 0.0065 vs placebo), −14.6 with olanzapine
(P < 0.0001 vs placebo), and −7.8 with placebo. Both agents were more effective than placebo from day
2 through day 21 (Biol Psychiatry. 2007;61:222S-223S)
Asenapine was also assessed in a 9-week, double-blind, noninferiority extension study enrolling 504
patients. Patients receiving active medication continued the same medication regimen; those in the
placebo group were assigned therapy with asenapine in a safety analysis. The primary efficacy end point
was the change from baseline to day 84 in YMRS total score. At day 84, mean change in YMRS total
score was −24.4 for asenapine and −23.9 for olanzapine (not inferior; P < 0.0001). The incidence of
treatment-related adverse reactions was similar for asenapine and olanzapine, although olanzapine was
associated with a greater incidence of weight gain. A further 40-week extension of this study is ongoing
(http://www.clinicaltrials.gov/ct2/show/NCT00159783)
An additional ongoing study is assessing asenapine when added to lithium or valproate in patients with
acute manic or mixed episodes of bipolar I disorder.
Schizophrenia
Asenapine was assessed in a double-blind, double-dummy, placebo- and risperidone-controlled 6-week
study enrolling patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) diagnosis of schizophrenia with symptoms of disorganized, paranoid, catatonic, or
undifferentiated subtypes. Current antipsychotic medications were discontinued at least 3 days before
baseline assessment and mood stabilizers were discontinued at least 5 days before the baseline
assessment. Following a single-blind placebo phase, patients who were 75% adherent were randomized
to treatment with asenapine, placebo, or risperidone. Patients were treated as inpatients during the
placebo washout and the first 1 to 3 weeks of the study, then as outpatients if they had improved.
Sublingual asenapine was titrated as 1 mg twice daily on day 1, 2 mg twice daily on day 2, 3 mg twice
daily on day 3, 4 mg twice daily on day 4, and 5 mg twice daily on days 5 through 42. Oral risperidone
was titrated from 1 mg twice daily on day 1, 2 mg twice day on day 2, and 3 mg twice daily on days 3
through 42. Asenapine-treated patients also received an oral placebo twice daily. Risperidone-treated
patients also received a sublingual placebo twice daily. Those in the placebo group received an oral and
sublingual placebo twice daily. Asenapine was more effective than placebo as judged by the primary
efficacy assessment, change from baseline in Positive and Negative Syndrome Scale (PANSS) total
score at end point, as well as changes in Clinical Global Impression Severity (CGI-S) scores, PANSS
positive and negative subscale scores, and the PANSS general psychopathology subscale score.
Changes in PANSS total scores were greater with asenapine than placebo from week 2 onward. The
study was not powered to directly compare asenapine with risperidone. Weight gain (at least 7% increase
from baseline) occurred in 17% treated with risperidone, 4.3% treated with asenapine, and 1.9% treated
with placebo. Mean weight gain was 1.6 kg with risperidone compared with 0.47 kg with asenapine and
0.15 kg with placebo. Increases in prolactin from a healthy level to 2 or more times the upper limit of
normal (ULN) occurred in 79% of risperidone-treated patients compared with 9% in the asenapine group
and 2% in the placebo group. Fasting glucose levels at least 20% above the ULN occurred in 14% treated
with asenapine, 20% treated with risperidone, and 12% treated with placebo. 2 In cognitive assessments
performed during this study, asenapine-treated patients demonstrated improvement on tests of verbal
learning and memory (immediate and delayed recall and delayed recognition) and speed of processing
(trails A, digit symbol substitution test, and verbal fluency), but decreased performance in other
79

processing assessments (trails B errors). Risperidone-treated patients exhibited improvement in speed of
processing (trails A, digit symbol substitution test, and verbal fluency), but worsening in the domain of
reasoning and problem solving (Wisconsin card sorting test percentage of perseverative errors and total
number correct)( Neuropsychopharmacol. 2006;31(suppl 1):S251 & Biol Psychiatry. 2007;61:241S).
Table 1. Efficacy Outcomes from a 6-Week Placebo- and Risperidone-
Controlled Study Changes From Baseline
Efficacy Measures Asenapine Risperidone Placebo
PANSS total score −15.9 (P < 0.005) −10.9 −5.3
CGI-S scores −0.74 (P < 0.01) −0.75 (P < 0.005) −0.28
PANSS positive subscale scores −5.5 (P = 0.01) −5.1 (P < 0.05) −2.5
PANSS negative subscale scores −3.2 (P = 0.01) −1.05 −0.6
PANSS general psychopathology subscale score −7.2 (P < 0.005) −4.8 −2.2
(Biol Psychiatry. 2007;61:241S)
Additional ongoing studies are assessing asenapine in comparison with olanzapine, haloperidol, and
placebo in the treatment of patients with an acute exacerbation of schizophrenia and in the long-term
therapy of patients with schizophrenia. Asenapine is also undergoing evaluation in the treatment of
psychosis in elderly patients.
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: The contraindications, warnings, and
precautions for asenapine are similar to the other atypical antipsychotic agents and include warnings
regarding the potential for orthostatic hypotension and syncopy, weight gain, hyperglycemia and diabetes
mellitus, increased mortality in dementia-related psychosis, suicide risk, neuroleptic malignant syndrome,
tardive dyskinesia, seizures, leucopenia, neutrapenia, and agranulocytosis, QT prolongation,
hyperprolactinemia, potential for cognitive motor impairment and dysphagia..
BLACK BOX WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA
RELATED PSYCHOSIS
Asenapine may be associated with less weight gain than olanzapine and risperidone; however, additional
study results are necessary to fully characterize its impact on blood glucose and weight gain.
ADVERSE REACTIONS: The most frequently observed adverse reactions with asenapine included
insomnia, somnolence, nausea, anxiety, and agitatio
Adverse Events reported in the Schizophrenia Trials
Placebo N= 378
Asenapine 5
mg twice daily
N= 274
Asenapine 10
mg twice daily
N= 208
All Asenapine§ 5
or 10 mg twice
daily N=572
System Organ Class /
Preferred Term
Gastrointestinal
disorders
Constipation 6% 7% 4% 5%
Dry mouth 1% 3% 1% 2%
Oral hypoesthesia 1% 6% 7% 5%
Salivary hypersecretion 0%

Investigations
Weight increased

DRUG INTERACTIONS:
Summary of Effect of
Coadministered Drugs on
Exposure to Asenapine in
Healthy Volunteers
Coadministered drug
(Postulated effect on
CYP450/UGT)
Fluvoxamine (CYP1A2
inhibitor)
Paroxetine (CYP2D6 inhibitor)
Imipramine (CYP1A2/2C19/3A4
inhibitor)
Cimetidine (CYP3A4/2D6/1A2
inhibitor)
Carbamazepine (CYP3A4
inducer)
Valproate (UGT1A4 inhibitor)
Dose schedules
Coadministered drug
25 mg twice daily for 8
days
20 mg once daily for 9
days
75 mg Single Dose
800 mg twice daily for
8 days
400 mg twice daily for
15 days
500 mg twice daily for
9 days
Asenapine
5 mg
Single
Dose
5 mg
Single
Dose
5 mg
Single
Dose
5 mg
Single
Dose
5 mg
Single
Dose
5 mg
Single
Dose
Effect on asenapine
pharmacokinetics
+13% +29%
–13% –9%
+17% +10%
–13% +1%
–16% –16%
2% –1%
Recommendation
Coadminister with
caution
No asenapine dose
adjustment required
No asenapine dose
adjustment required
No asenapine dose
adjustment required
No asenapine dose
adjustment required
No asenapine dose
adjustment required
Asenapine appears to be at most a weak inhibitor of CYP2D6. Coadministration of a single 20-mg dose of
paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg SAPHRIS twice daily in 15
healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. Asenapine may
enhance the inhibitory effects of paroxetine on its own metabolism.
Senapine should be coadministered cautiously with drugs that are both substrates and inhibitors for
CYP2D6.
RECOMMENDED MONITORING: Patients should be monitored for response and adverse reactions. The
need for specific laboratory monitoring has not been described at this time.
DOSING: Asenapine is administered sublingually twice daily. In clinical trials, it has been rapidly titrated
to daily doses of 5 to 10 mg. Asenapine is a sublingual tablet. To ensure optimal absorption, patients
should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet
will dissolve in saliva within seconds. SAPHRIS sublingual tablets should not be crushed, chewed, or
swallowed.. Patients should be instructed to not eat or drink for 10 minutes after administration
Schizophrenia Usual Dose for Acute Treatment in Adults: The recommended starting and target dose of
SAPHRIS is 5 mg given twice daily. In controlled trials, there was no suggestion of added benefit with the
higher dose, but there was a clear increase in certain adverse reactions. The safety of doses above 10
mg twice daily has not been evaluated in clinical studies
Bipolar Disorder - Usual Dose for Acute Treatment in Adults: The recommended starting dose of
SAPHRIS, and the dose maintained by 90% of the patients studied, is 10 mg twice daily. The dose can
be decreased to 5 mg twice daily if there are adverse effects. In controlled trials, the starting dose for
SAPHRIS was 10 mg twice daily. On the second and subsequent days of the trials, the dose could be
lowered to 5 mg twice daily, based on tolerability, but less than 10% of patients had their dose reduced.
The safety of doses above 10 mg twice daily has not been evaluated in clinical trials.
PRODUCT AVAILABILITY/COST and STORAGE: A new drug application (NDA) for asenapine fastdissolving
sublingual tablets was accepted for FDA review in November 2007 and approved in the
summer of 2009..The cost is $575.94 for 60 sublingual tablets on drugstore.com.
82

3 mg tablets of repspiridone are $299.99/60 tabs and brand Respirdal 3 mg tabs are $637.40/60 tabs on
drugstore.com.
CONCLUSION: Asenapine will offer yet another alternative for the treatment of schizophrenia and bipolar
disorder. It appears effective and well tolerated, although insufficient study results are available to fully
assess this agent relative to the other atypical antipsychotic agents. Most of the trial data has yet to be
published.
83

ILOPERIDONE - FANAPT by Vanda/Novartis 1S
INDICATIONS: Iloperidone is indicated for the acute treatment of schizophrenia in adults. Because of its
potential to prolong the QT interval, it is recommended that other agents be considered for use first. The
Food and Drug Administration (FDA)-approved labeling also advises that because slow dose titration is
necessary with this agent, effectiveness may be delayed during the first 1 to 2 weeks of treatment
compared with other agents that do not require dosage titration.
Table 1. FDA-Approved Indications for the Benzisoxazole Derivative Atypical Antipsychotics
Indications
Iloperidone
Paliperidone
Risperidone
Oral
Risperidone
Injection
Ziprasidone
Oral
Ziprasidone
Injection
Treatment of schizophrenia X X X X X
Acute agitation in patients with schizophrenia
Bipolar mania X X
Irritability associated with autistic disorder
X
X
CLINICAL PHARMACOLOGY: Iloperidone is a dopamine and serotonin receptor antagonist exhibiting
antipsychotic activity. Structurally, it is a piperidinyl-benzisoxazole derivative, sharing with risperidone a
piperidine ring structure. It is an antagonist of dopamine D 2 , D 3 , and D 4 receptors; serotonin 5-HT 1A , 5-
HT 2A , 5-HT 6 , 5-HT 7 , and 5-HT 2C receptors; and the alpha 1 and alpha 2C receptors. It has a high affinity for
alpha 1 and 5-HT 2 receptors; moderate affinity for alpha 2 , D 2 , and 5-HT 1A ; and lower affinity for D 1 , D 5 , and
5-HT 3 receptors. It also has high affinity for 5-HT 6 and 5-HT 7 .No appreciable binding was observed at the
muscarinic receptor or the N-methyl-D-asparate receptor channel. It is a more potent antagonist at 5-HT 2
than D 2 . It has higher affinity for the dopamine D 3 receptor than the dopamine D 4 receptors. It has higher
affinity for 5-HT 2A than for 5-HT 2C . Its binding affinities for dopamine and serotonin receptors are similar to
those of risperidone. Two primary metabolites have also displayed activity. The P88 metabolite has
demonstrated affinity equal to or less than that of iloperidone. The P95 metabolite shows affinity only for
5-HT 2A and alpha 1A , alpha 1B , alpha 1D , and alpha 2C receptors.
Iloperidone has exhibited activity in numerous animal models suggestive of antipsychotic activity, activity
on anxiety and negative symptoms, as well as limited activity in models of extrapyramidal side effect
liability. In an animal model, iloperidone improved working memory but impaired task performance.
PHARMACOKINETICS: Peak iloperidone concentrations are reached within 2 to 4 hours after oral
iloperidone administration. Administration with food slowed the rate, but not the extent, of absorption.
With food, peak concentrations were reached within 4 to 5 hours.
Iloperidone is metabolized by CYP2D6 and CYP3A4. Increased iloperidone concentrations have been
observed in CYP2D6 intermediate and poor metabolizers. The mean elimination half-lives for iloperidone,
P88, and P95 in CYP2D6 extensive metabolizers are 18, 26, and 23 hours, respectively, and in poor
metabolizers are 33, 37, and 31 hours, respectively. Steady-state concentrations are reached within 3 to
4 days. Less than 1% of the dose is excreted unchanged in the urine. Iloperidone pharmacokinetics are
dose-proportional over the range of dosages from 2 to 12 mg twice daily. Iloperidone and its metabolites
are approximately 95% bound to serum proteins.
The pharmacokinetics of iloperidone were not significantly impacted in patients with severe renal
impairment. Iloperidone has not been studied in patients with mild or moderate hepatic impairment.
84

Table 2. Pharmacokinetics of the Benzisoxazole Antipsychotics
Iloperidone Paliperidone Risperidone Oral Ziprasidone Oral
Time to peak 2 to 4 h 24 h 1 h 6 to 8 h
Half-life 18 h/33 h a 23 h 3 h/20 h a 7 h
Metabolism
Extensive
CYP2D6
CYP3A4
Limited
CYP2D6
CYP3A4
Extensive
CYP2D6
Extensive
aldehyde
oxidase
CYP3A4
CYP1A2
Active
metabolites
Yes No Yes No
Elimination
Metabolites primarily
excreted in urine;
< 1% unchanged in
urine
Renally as
unchanged drug
(59%) and
metabolites
Metabolites
primarily
excreted in urine
Metabolites
primarily
excreted in feces
a Extensive/Poor CYP2D6 metabolizers.
COMPARATIVE EFFICACY: Iloperidone was assessed in a multicenter, randomized, double-blind,
placebo-controlled study enrolling 593 patients with acute exacerbations of schizophrenia. Eligible
patients were 18 to 65 years of age, had a Clinical Global Impression of Severity (CGI-S) score of 4 or
more, overall Positive and Negative Syndrome Scale Total (PANSS-T) score of 70 or more, and a rating
of 4 (moderate) or more on at least 2 of the PANSS Positive (PANSS-P) symptoms (delusions,
conceptual disorganization, hallucinations, and suspiciousness/persecution). Patients were assigned
treatment with iloperidone 24 mg/day, ziprasidone 160 mg/day, or placebo. The study design included a
1-week titration period followed by a 3-week, double-blind maintenance period. During the titration phase,
patients received placebo twice daily, iloperidone twice daily at doses escalating from 1 to 12 mg, or
ziprasidone twice daily at doses escalating from 20 to 80 mg. Twice-daily dosing of the assigned dose
with food was continued through the maintenance phase. The primary efficacy end point was the change
from baseline in the PANSS-T score. PANSS-T score was reduced in the iloperidone group (−12)
compared with the placebo group (−7.1; P < 0.01), and also in the ziprasidone group (−12.3) compared
with placebo (−7.1; P < 0.05) at 4 weeks. Both the iloperidone and ziprasidone groups showed
improvement from baseline versus placebo in the Brief Psychiatric Rating Scale (BPRS), PANSS-P, and
PANSS Negative (PANSS-N) scores. A 20% or more reduction from baseline in the PANSS-P scores was
achieved in 143 of 200 (72%) patients in the iloperidone group compared with 48 of 93 (52%) in the
placebo group (P = 0.005). CGI-S scores were reduced in both active-treatment groups compared with
placebo (placebo, −0.39; iloperidone, −0.65 [P = 0.007]; ziprasidone, −0.67 [P = 0.013]). Clinical Global
Impression of Change(CGI-C) improvement was achieved in 65% of iloperidone-treated patients
compared with 52% in the placebo group (P < 0.05). Compared with ziprasidone, iloperidone was
associated with a lower rate of sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and
restlessness, but a higher rate of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal
congestion. Weight gain during the 4-week study was 2.8 kg in the iloperidone group, 1.1 kg in the
ziprasidone group, and 0.5 kg in the placebo group. A 7% or more weight gain occurred in 21% of
iloperidone-treated patients, 7% of ziprasidone-treated patients, and 3% of placebo recipients. QT
prolongation was similar with iloperidone (11.4 msec; P < 0.001 vs placebo) and ziprasidone (11.3 msec;
P < 0.001 vs placebo); no patient had a postbaseline QTc interval of 500 msec or more. During the study,
mean changes in total cholesterol were 8.1, 4.1, and −0.5 mg/dL for iloperidone, ziprasidone, and
placebo, respectively. Mean change in glucose was 7.9, 4.7, and 3.2 mg/dL, respectively (. J Clin
Psychopharmacol. 2008;28(2)(suppl 1):S20-S28)
The results from 3 studies of iloperidone using haloperidol or risperidone as active comparator were
combined. The three 6-week, randomized, double-blind, placebo- and active-controlled studies enrolled a
total of 1,943 patients with schizophrenia or schizoaffective disorder. Each study consisted of a 7-day,
fixed-titration phase followed by 5 weeks of maintenance therapy. Patients in study 1 (N = 573) received
iloperidone 4, 8, or 12 mg/day; haloperidol 15 mg/day; or placebo. Patients in study 2 received
85

iloperidone 4 to 8 mg/day, iloperidone 10 to 16 mg/day, risperidone 4 to 8 mg/day, or placebo. Patients in
study 3 received iloperidone 12 to 16 mg/day, iloperidone 20 to 24 mg/day, risperidone 6 to 8 mg/day, or
placebo. In each study, mean age was approximately 39 years, and the majority of subjects were men
(59% to 75%) and white (39% to 76%) or black (17% to 46%). In study 1, mean change from baseline in
PANSS-T (the primary study end point) was −9 with iloperidone 4 mg/day (P = 0.097), −7.8 with
iloperidone 8 mg/day (P = 0.227), −9.9 with iloperidone 12 mg/day (P = 0.047), −13.9 with haloperidol 15
mg/day (P < 0.001), and −4.6 with placebo. In study 1, only the iloperidone 12 mg/day dose was more
effective than placebo for any primary or secondary end points. In study 2, mean change in BPRS scores
(the primary study end point) was −6.2 with iloperidone 4 to 8 mg/day (P = 0.012), −7.2 with iloperidone
10 to 16 mg/day (P = 0.001), −10.3 with risperidone 4 to 8 mg/day (P < 0.001), and −2.5 with placebo. In
study 2, both iloperidone dose ranges were more effective than placebo, as assessed by the PANSS-T,
PANSS-P, BPRS, and CGI-S. In study 3, mean change in BPRS scores (the primary study end point) was
−7.1 for iloperidone 12 to 16 mg/day (P = 0.09), −8.6 with iloperidone 20 to 24 mg/day (P = 0.01), −11.5
with risperidone 6 to 8 mg/day (P < 0.001), and −5 with placebo. Only the higher-dose iloperidone and
risperidone were consistently more effective than placebo in study 3. The combined results for patients
receiving treatment for at least 2 weeks are summarized in Table 3 (J Clin Psychopharmacol.
2008;28(2)(suppl 1):S4-S11).
Table 3. Combined Efficacy Results (Mean Change From Baseline to End Point) for Patients
Receiving
Treatment for ≥ 2 Weeks Using a Modified Intent-to-Treat Analysis and LOCF for Missing Data a,16
End Point
Iloperidone
4 to 8 mg/day
(n = 316)
Iloperidone
10 to 16
mg/day
(n = 417)
Iloperidone
20 to 24
mg/day
(n = 118)
Haloperidol
15 mg/day
(n = 87)
Risperidone
4 to 8 mg/day
(n = 265) Placebo
(n = 350)
BPRS −7.9
(P < 0.05)
−9.2
(P < 0.05)
−10
(P < 0.05)
−11.4
(P < 0.05)
−11.9
(P < 0.05)
−5.4
PANSS-T −11.6
(P = 0.014)
−14.1
(P < 0.001)
−16.5
(P < 0.001)
−18.8
(P < 0.001)
−18.9
(P < 0.001)
−7.7
PANSS-P −4.1
(P = 0.031)
−5.1
(P < 0.001)
−5.8
(P < 0.001)
−6.3
(P < 0.001)
−7.1
(P < 0.001)
−3
PANSS-N −1.9
(P = 0.638)
−2.8
(P = 0.006)
−3.6
(P = 0.001)
−3.7
(P = 0.003)
−3.6
(P < 0.001)
−1.7
a LOCF = last observation carried forward.
A combined analysis of 3 multicenter, randomized, double-blind studies of iloperidone compared with
haloperidol in patients with schizophrenia was also published. Mean patient age was 34.7 years; 63.5% of
subjects were men, 45.6% were white and 38.9% were Asian, and the most common diagnosis was
paranoid schizophrenia (56.6%). Patients were titrated over a 6-week, double-blind phase, with patients
receiving iloperidone 2 to 8 mg/day or haloperidol 2 to 10 mg/day over week 1, and iloperidone 4 to 16
mg/day or haloperidol 5 to 20 mg/day from weeks 2 through 4. Doses titrated through week 4 were then
maintained through week 6. Patients completing the 6-week, double-blind phase and exhibiting a
treatment response were eligible to continue into a 46-week, double-blind maintenance phase. The initial
6-week phase included 1,239 patients randomized to iloperidone and 405 randomized to haloperidol.
Mean dosages at the end of the 6-week phase were 11.8 mg/day for iloperidone and 13.2 mg/day for
haloperidol. The second phase included 359 iloperidone-treated patients and 114 haloperidol-treated
patients, of whom 236 in the iloperidone group and 75 in the haloperidol group completed the long-term
phase. At the end of the long-term phase, the mean dosages were 12.5 mg/day for both agents. Relapse
rates did not differ between groups (iloperidone, 43.5%; haloperidol, 41.2%). Mean time to relapse also
did not differ (P = 0.8411). The mean time to relapse was 89.8 days with iloperidone (median, 50 days)
and 101.8 days with haloperidol (median, 78 days). The mean change in PANSS-T was −16.1 for
iloperidone and −17.4 for haloperidol (P = 0.338). Adjusted mean change in PANSS-N scores was −4.7
for each group (P = 0.981). PANSS-P scores were reduced by 4.2 with iloperidone and by 5.3 with
86

haloperidol (P = 0.006). No difference between groups was observed in change in BPRS or CGI-C scores
(. J Clin Psychopharmacol. 2008;28(2)(suppl 1):S29-S35)
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: The labeled contraindications, warnings,
and precautions for the benzisoxazole antipsychotic agents are compared in Table 4.
CONTRAINDICATIONS
Iloperidone is contraindicated in patients with hypersensitivity to iloperidone or any components of the
formulation (eg, lactose monohydrate, microcrystalline cellulose, hydroxypropylmethylcellulose,
crospovidone, magnesium stearate, colloidal silicon dioxide).
WARNINGS AND PRECAUTIONS
Iloperidone labeling contains a class black box warning regarding increased mortality in elderly patients
with dementia-related psychosis.
Iloperidone has been associated with QTc prolongation and may be associated with arrhythmia and
sudden death. In a combined analysis of three 6-week iloperidone studies, mean changes in QTc from
baseline to end point were 2.9 msec with iloperidone 4 to 8 mg/day, 3.9 msec with iloperidone 10 to 16
mg/day, and 9.1 msec with iloperidone 20 to 24 mg/day (all P < 0.05), which compares with 5 msec
observed with haloperidol 15 mg/day (P < 0.05) and 0.6 msec with risperidone. No deaths or serious
arrhythmias attributable to QTc prolongation occurred in those studies. Iloperidone use should be avoided
in combination with other drugs known to prolong the QTc (eg, quinidine, procainamide, amiodarone,
sotalol, chlorpromazine, thioridazine, gatifloxacin, moxifloxacin, pentamidine, levomethadyl acetate,
methadone); use should also be avoided in patients with congenital long QT syndrome, patients with a
history of cardiac arrhythmias, patients with recent acute myocardial infarction, patients with
uncompensated heart failure, or a patients with persistent QTc measurement of more than 500 msec.
Caution is advised and dosage modification should be considered when iloperidone is used with other
drugs that inhibit iloperidone metabolism and in patients with reduced activity of CYP2D6. Serum
potassium and magnesium should be monitored in patients at risk for electrolyte disturbances.
Hyperglycemia and an increased incidence of diabetes mellitus have been associated with the use of
atypical antipsychotics. Monitor glucose in all patients at risk for diabetes. 1 Weight gain of 7% of body
weight or more was observed in 12% of patients receiving iloperidone 10 to 16 mg/day in clinical trials
and 18% receiving iloperidone 20 to 24 mg/day, compared with 4% receiving placebo. The overall mean
weight change from baseline to end point in 4- to 6-week studies was 2.1 kg.
Use with caution in patients with a history of seizures or with conditions that lower seizure threshold.
Orthostatic hypotension associated with the alpha-adrenergic–blocking properties of iloperidone
necessitates slow dosage titration. Dizziness, tachycardia, and syncope may occur with standing. With
dosage titration, orthostatic hypotension was reported in 5% of patients receiving iloperidone 20 to 24
mg/day, 3% receiving iloperidone 10 to 16 mg/day, and 1% receiving placebo.
Iloperidone elevated prolactin levels and may cause hyperprolactinemia. In short-term clinical trials,
iloperidone 24 mg/day was associated with an increase in prolactin of 2.6 ng/mL compared with a
decrease of 6.3 ng/mL with placebo. Elevated prolactin levels were observed in 26% of iloperidonetreated
patients compared with 12% in the placebo group. Gynecomastia and galactorrhea occurred
infrequently.
Three cases of priapism have been reported in association with iloperidone therapy.
Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics. Patients with a
preexisting low white blood cell count or history of leukopenia or neutropenia should have their completed
blood count monitored frequently during the first few months of therapy. Therapy should be discontinued
at the first sign of a decline in white blood cell count in the absence of other causative factors.
87

Other warnings and precautions are typical for the class and include suicide risk, neuroleptic malignant
syndrome, tardive dyskinesia, disruption of body temperature regulation, dysphagia, and the potential for
cognitive and motor impairment.
The safety and effectiveness of iloperidone have not been established in children.
Iloperidone is in Pregnancy Category C. In animal models, iloperidone caused developmental toxicity but
was not teratogenic. It should be used in pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Iloperidone was excreted in milk of rats during lactation. It is not known whether iloperidone or its
metabolites are excreted in human milk. It is recommended that women receiving iloperidone not breastfeed.
Table 4. Contraindications, Warnings, and Precautions of the Benzisoxazole Antipsychotics
Contraindications
Iloperidone Paliperidone Risperidone Ziprasidone
Hypersensitivity X X X X
QT prolongation
Black Box Warnings
Increased mortality
in elderly patients
with dementiarelated
psychoses
Warnings and Precautions
Cerebrovascular
events in elderly
patients with
dementia- related
psychoses
X X X X
X X X X
QT prolongation X X X
Neuroleptic
malignant
syndrome
X X X X
Tardive dyskinesia X X X X
Hyperglycemia/
diabetes mellitus
Weight gain
X X X X
X
Seizures X X X X
Orthostatic
hypotension
X X X X
Hyperprolactinemia X X X X
Body temperature
regulation
X X X X
Dysphagia X X X X
Suicide X X X X
X
88

Priapism X X X X
Cognitive and
motor impairment
Potential for GI
obstruction
X X X X
X
Antiemetic effects X X
Leukopenia,
neutropenia,
agranulocytosis
X
Thrombotic
thrombocytopenic
purpura
X
X
Rash
Special Populations
Hepatic impairment Not
recommended
Renal impairment
Pharmacokinetics
not affected
Not affected in mild
to moderate
impairment; not
studied in severe
impairment
Reduced dose
in moderate to
severe impairment
Reduced dose
in severe
impairment
Reduced dose
in severe
impairment
X
Dosage
adjustments
not necessary
Elderly Caution Caution Caution Caution
Pharmacokinetics
not affected
Children Not established Not established 5 y and older Not established
Pregnancy Category C;
use only if
clearly needed
Breast-feeding
mothers
Not
recommended
Category C;
use only if
clearly needed
Caution
Category C;
use only if
clearly needed
Not
recommended
Category C;
use only if clearly
needed
Not
recommended
ADVERSE REACTIONS: The most common adverse effects have included dizziness, dry mouth, fatigue,
nasal congestion, orthostatic hypotension, somnolence, tachycardia, and increased weight.Other
common adverse effects have included nausea, headache, anxiety, and insomnia. Administration with
food reduced the incidence of many common adverse events, including orthostatic hypotension,
dizziness, and nausea.
Iloperidone has been associated with an increase in heart rate and reduction in blood pressure.
Reductions in blood pressure were most commonly observed during the first week of therapy and were
generally not sustained. The incidence of sustained orthostatic hypotension was 2.4% of patients treated
with iloperidone, compared with 0.8% treated with haloperidol and no patients treated with placebo or
risperidone in 3 of the clinical trials. Sustained orthostatic hypotension was observed in 4.8% of patients
treated with iloperidone 20 to 24 mg/day.
89

Table 5. Adverse Reactions Occurring in ≥ 5% of Patients With Acute Exacerbations of
Schizophrenia Receiving Iloperidone or Ziprasidone.
Adverse Reactions Iloperidone (n = 300) Ziprasidone (n = 150) Placebo (n = 147)
Dizziness 17% 13% 8%
Sedation 13% 27% 8%
Weight gain 11% 5% 2%
Dry mouth 9% 7% 0.7%
Tachycardia 9% 2% 0.7%
Heart rate increase 8% 6% 0.7%
Nasal congestion 8% 3% 3%
Orthostatic
hypotension
7% 0% 2%
Somnolence 4% 6% 1%
Restlessness 4% 5% 2%
Extrapyramidal
symptoms
3% 9% 2%
Agitation 3% 7% 3%
Anxiety 3% 5% 0.7%
Akathisia 1% 7% 0%
Adverse events from 3 iloperidone studies are summarized in Table 6.
Table 6. Adverse Reactions Occurring in ≥ 5% of Patients in any Active Treatment Group and at Least
Twice the Rate of Placebo From 3 Clinical Studies With Iloperidone, Haloperidol, and Risperidone vs
Placebo
Adverse Reactions
Iloperidone
4 to 8
mg/day
(n = 463)
Iloperidone
10 to 16
mg/day
(n = 456)
Iloperidone
20 to 24
mg/day
(n = 125)
Haloperidol
15 mg/day
(n = 118)
Risperidone
4 to 8 mg/day
(n = 306) Placebo
(n = 440)
Dizziness 12.1% 10.3% 23.2% 5.1% 7.2% 6.8%
Weight gain (≥ 7%) 10.9% 12.8% 15.2% 5.1% 11.9% 5.1%
Dry mouth 5.2% 7.9% 10.4% 2.5% 2.9% 1.4%
Somnolence 5% 5.7% 8% 6.8% 5.9% 2.7%
Fatigue 4.3% 4.6% 6.4% 7.6% 1.6% 2.7%
Nasal congestion 4.8% 5% 5.6% 1.7% 2.6% 2.3%
Dyspepsia 7.8% 5.5% 4.8% 11% 5.9% 5.5%
Tremor 2.8% 2.6% 4.8% 22% 6.9% 1.8%
Akathisia 3.7% 1.5% 4.8% 13.6% 6.9% 3.6%
Extrapyramidal
disorder
5.4% 4.8% 4% 20.3% 9.5% 4.8%
90

Flatulence 1.9% 1.3% 1.6% 5.1% 2.3% 1.1%
Dystonia 0.9% 0.9% 0.8% 11.9% 2.6% 0.7%
The comparative metabolic effects and rates of extrapyramidal effects with iloperidone from phase 3
clinical trials including 2,505 patients (iloperidone, 1,344 patients; haloperidol, 118 patients; risperidone,
306 patients; ziprasidone, 150 patients; placebo, 587 patients) are summarized in Table 7. In these
studies, iloperidone was associated with minimal effects on total cholesterol, triglycerides, and prolactin;
modest weight gain; and a low incidence of extrapyramidal side effects. Among 371 patients receiving
iloperidone in a comparative study with haloperidol, mean weight gain was 2.6 kg at 6 weeks and 3.8 kg
at 52 weeks.
Table 7. Effects From Baseline to End Point in 4 Phase 3 Clinical Efficacy Studies With
Iloperidone, Haloperidol, Risperidone, and Ziprasidone vs Placebo
Iloperidone
(n = 1,344)
Haloperidol
(n = 118)
Risperidone
(n = 306)
Ziprasidone
(n = 150)
Placebo
(n = 587)
Metabolic Effects
Mean weight change +2 kg −0.1 kg +1.5 kg +1.1 kg −0.1 kg
% patients with 7% or
more weight gain
Mean change blood
glucose
Mean change total
cholesterol
Mean change
triglycerides
13.5% 5.1% 11.9% 5.4% 4.3%
+9 mg/dL +14.4 mg/dL +1.8 mg/dL +9 mg/dL 0 mg/dL
0 mg/dL +3.9 mg/dL −3.9 mg/dL +3.9 mg/dL −7.7 mg/dL
−17.7 mg/dL −8.8 mg/dL −26.5 mg/dL +8.8 mg/dL −26.5
mg/dL
Mean change prolactin −19.2 mcg/L +133 mcg/L +203.5
mcg/L
+2 mcg/L −40.9
mcg/L
Extrapyramidal Effects
EPS reported as TAER 4.6% 20.3% 9.5% 9.3% 4.1%
Mean change in ESRS −0.3 +1.8 −0.3 +0.2 −0.3
Akathisia reported as
TAER
2.5% 13.6% 6.9% 7.3% 2.7%
% patients with
worsening of akathisia
(BAS scores)
7.8% — 15.5% 15.6% 11.4%
a EPS = extrapyramidal symptoms; TAER = treatment-emergent adverse event; ESRS = Extrapyramidal
Symptoms Rating Scale; BAS = Barnes Akathisia Scale.
DRUG INTERACTIONS: Iloperidone should not be used with other drugs that prolong the QT interval.
The dose of iloperidone should be reduced in patients receiving a strong CYP2D6 or CYP3A4 inhibitor.
Coadministration with ketoconazole, a potent CYP3A4 inhibitor, increased the area under the curve
(AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively.
Coadministration with fluoxetine, a potent CYP2D6 inhibitor, increased the AUC of iloperidone and its P88
metabolite by 2- to 3-fold. Coadministration with paroxetine, another potent CYP2D6 inhibitor, increased
the mean steady-state peak concentrations of iloperidone and its metabolite P88 by about 1.6-fold.
Administration of iloperidone with both ketoconazole and paroxetine resulted in increases in iloperidone
concentrations similar to those observed with administration with either inhibitor alone
91

Iloperidone does not inhibit or induce CYP enzymes.
Combined use with other alpha antagonist should be done with caution and the patients monitored for
orthostatic changes in their blood pressure. Caution should also be used when combining iloperidone
therapy with antihypertensive medications. The combination of these 2 agents may enhance the effect of
the antihypertensive medication.
Caution should be used if iloperidone is combined with other centrally acting drugs or alcohol.
RECOMMENDED MONITORING: Patients should be monitored for response and adverse events,
particularly orthostatic hypotension and changes in blood glucose.
A complete blood cell count should be obtained prior to starting therapy and checked frequently during
the first few months of therapy to determine if leukopenia, neutropenia, or agranulocytosis is occurring.
Therapy should be discontinued if the white blood cell count declines in the absence of other causative
factors.
Weight should also be monitored throughout therapy.
Serum potassium and magnesium should be checked in patients at risk for electrolyte disturbances.
DOSING: The recommended iloperidone target dosage is 12 to 24 mg/day administered twice daily.
Iloperidone therapy should be initiated with a dosage of 1 mg twice daily and titrated with daily dosage
adjustments as tolerated to 2, 4, 6, 8, 10, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively,
to reach the target dosage. The maximum recommended dosage is 12 mg twice daily, or 24 mg/day.
Iloperidone can be administered without regard to meals.
If therapy is interrupted at any time for more than 3 days, the initial titration should be repeated.
In patients taking strong CYP2D6 inhibitors (eg, fluoxetine, paroxetine) or strong CYP3A4 inhibitors (eg,
clarithromycin, ketoconazole), the iloperidone dose should be reduced by one-half. When the CYP
inhibitor is withdrawn from combination therapy, the iloperidone dose should be increased to where it was
before.
Dosage adjustments are not routinely recommended on the basis of age, gender, race, or renal
impairment. Use is not recommended in patients with hepatic impairment.
Table 8. Comparative Oral Dosing of the Benzisoxazole Atypical Antipsychotics for the
Treatment of Schizophrenia in Adults
Dosing
frequency
Iloperidone Paliperidone Risperidone Ziprasidone
Twice daily Once daily Once or twice
daily
Twice daily
Initial dose 2 mg/day 6 mg/day 2 mg/day 40 mg/day
Titration 2 mg/day 3 mg/day at
intervals of at
least 5 days
1 to 2 mg/day At intervals of at
least 2 days
Target dose 12 to 24 mg/day 3 to 12 mg/day 4 to 8 mg/day 40 to 160
mg/day
Dosage
adjustment in
renal impairment
No dosage
adjustment
Reduced
maximum dose
in mild to severe
impairment
Reduce dose in
severe
impairment
No dosage
adjustment
Dosage Use not No dosage Reduce dose in No dosage
92

adjustment in
hepatic
impairment
recommended
adjustment in
mild to moderate
impairment; not
studied in severe
impairment
severe
impairment
adjustment
Dosage
adjustments in
other special
populations
CYP2D6 and
CYP3A4 strong
inhibitors: reduce
iloperidone dose by
one-half
None
Reduce dose i
n elderly,
debilitated, and
those
predisposed to
hypotension
None
PRODUCT AVAILABILITY/COST and STORAGE: Iloperidone received FDA approval in May 2009. It is
available in 1, 2, 4, 6, 8, 10, and 12 mg tablets supplied in bottles of 60, and in a titration pack containing
8 tablets (two 1 mg, two 2 mg, two 4 mg, and two 6 mg tablets). Drugstore.com 1 and 2 mg tablets
$599.95/60 tabs
Iloperidone tablets should be stored at controlled room temperature (25°C; 77°F), with excursions
permitted to between 15° and 30°C (59° and 86°F), and protected from light and moisture.
Table 9. Available Dosage Forms of the Various Benzisoxazole Atypical Antipsychotics
Agent
Iloperidone
Paliperidone
Risperidone
Ziprasidone
Dosage Forms
Tablets: 1, 2, 4, 6, 8, 10, and 12 mg
Extended-release tablets: 3, 6, and 9 mg
Tablets: 0.25, 0.5, 1, 2, 3, and 4 mg
Oral solution: 1 mg/mL
Orally disintegrating tablets: 0.5, 1, 2, 3, and 4 mg
Injection: 12.5, 25, 37.5, and 50 mg
Capsules: 20, 40, 60, and 80 mg Injection: 20 mg
CONCLUSION: Iloperidone offers another but NOT first line alternative for the treatment of
schizophrenia. Additional adverse effect data, particularly as they relate to QT prolongation, weight gain,
and diabetes risk, are necessary, particularly at the higher doses, which appear more effective than the
lower doses in the treatment of schizophrenia. The dosage must be started low and gradually increased
and patients need to be monitored for dizziness and orthostatic changes. At this time, advantages over
other atypical antipsychotics have not been demonstrated.
7/23/09 "Vanda Pharmaceuticals Inc. won approval in May to sell Fanapt [iloperidone], a schizophrenia
drug that had been abandoned by three companies and rejected initially by US regulators," but now the
company "can't afford to market the product." The company "has no product on the market, has run up
losses of $231.5 million in six years and may have trouble raising funds needed beyond this year,"
according to a May 11, 2009 filing. Now, "Vanda is 'open to every option,' including a buyout," Chief
Executive Officer Mihael Polymeropoulos said. Novartis has now agreed to market the product.
93

PRASUGREL - Effient by Daiichi Sankyo and Lilly 1-P
INDICATIONS: Prasugrel has been approved by the Food and Drug Administration (FDA) for use in
combination with low dose aspirin (75-325mg/day) in the treatment of patients with acute coronary
syndrome (IE unstable angina or MI) who have received a percutaneous coronary intervention including
coronary stenting. But the FDA approved label contains a BLACK BOX WARNING about bleeding risks
(three subgroups have been identified with an increased risk of significant bleeding: the elderly age 75
and greater, underweight less than 60 Kg (consider 5mg/day dose vs. 10mg) and those with a history of
previous CVA or TIA. It is also recommended that presugrel be avoided in favor of clopidogrel is patients
who CABG is anticipated as in the Triton-TIMI 38 trial these patients had a much higher risk of bleeding
13.4% vs. 3.2% and CV surgeons will be reluctant to operate on these patients. Patients will likely need to
be evaluated prior to selecting one of these two agents, it appears that until we get more data from
ongoing trials in the acute management of ACS patients that it may be premature to recommend routine
use of this new agent. For use in patients with PCI and stenting it appears to be of some benefit but even
here we need more experience to delineate its appropriate use. The FDA has instituted a REMS for
appropriate prescribing and a patient medication Guide for Effient.
CLINICAL PHARMACOLOGY: Prasugrel is an antiplatelet agent. It is a thienopyridine prodrug like
clopidogrel and ticlopidine. Once it is metabolically transformed to its sulfhydryl-containing active
metabolite (R-138727), it binds platelet PY 12 receptors selectively and irreversibly and is a potent inhibitor
of adenosine 5’diphosphate-induced platelet activation and aggregation.
Conversion of prasugrel to the active component requires rapid hydrolysis by esterases followed by a
single CYP-450–dependent oxidative step. In contrast, clopidogrel requires 2 consecutive CYP-450–
dependent steps. CYPs contributing to prasugrel conversion to the active metabolite are CYP3A4,
CYP3A5, CYP2B6, CYP2C9, and CYP2C19. Because of the more efficient transformation to the active
metabolite, prasugrel has approximately 10-times greater potency than clopidogrel and 100- to 300-times
greater potency than ticlopidine.
Onset of inhibition of platelet aggregation occurs within 30 minutes to 1 hour of oral prasugrel
administration, peaks within 2 hours, and is maintained for 24 hours. Full recovery of platelet aggregation
occurs between 48 hours and 7 days after the last dose. In another study, the maximum inhibition of
platelet aggregation 24 hours after the last dose of drug administration was 42% to 71% with prasugrel 10
mg, 0% to 38% with clopidogrel 75 mg, and 0% to 25% with placebo. With repeated maintenance doses
of 7.5 or 15 mg following an initial 40 or 60 mg loading dose, inhibition of platelet aggregation reached
steady state between 7 and 14 days. In another study, the inhibition of platelet aggregation reached
steady state by day 3 with prasugrel 10 and 20 mg daily doses, compared with 5 days to reach steady
state with clopidogrel 75 mg daily and prasugrel 5 mg daily.
In comparison with a clopidogrel 300 mg loading dose, a prasugrel 60 mg loading dose is associated with
more rapid onset, less variability, and greater magnitude of platelet inhibition. Inhibition of platelet
aggregation after prasugrel 60 mg was greater than after clopidogrel 300 mg from 15 minutes through 24
hours after administration in a crossover study enrolling healthy subjects. For 20 mcmol/L adenosine
diphosphate (ADP), the median time to reach at least 20% inhibition of platelet aggregation was 30
minutes for prasugrel compared with 1.5 hours for clopidogrel (P < 0.001). Peak inhibition of platelet
aggregation was 84.1% with prasugrel compared with 48.9% with clopidogrel with 5 mcmol/L ADP and
78.8% with prasugrel compared with 35% with clopidogrel with 20 mcmol/L ADP (P < 0.001). Consistency
of response between subjects was greater with prasugrel than with clopidogrel (P < 0.001). At 24 hours
after dosing, inhibition of platelet aggregation in response to 20 mcmol/L ADP could not be distinguished
from background variability in 27 of 64 patients during clopidogrel administration, but was greater than
background variability in all subjects during prasugrel administration.
Loading plus maintenance dose prasugrel 60 mg/10 mg has also been compared with clopidogrel 600
mg/75 mg and clopidogrel 300 mg/75 mg in a crossover study in healthy subjects. Inhibition of platelet
aggregation was 54% 30 minutes after prasugrel 60 mg, compared with 3% 30 minutes after the 300 mg
clopidogrel dose and 6% after the clopidogrel 600 mg dose (P < 0.001). At 1 hour and 2 hours after
prasugrel 60 mg dosing, inhibition of platelet aggregation was 82% and 91% compared with 51% and
69% at 6 hours after dosing of clopidogrel 300 and 600 mg, respectively (P < 0.01). With maintenance
94

dosing, inhibition of platelet aggregation was 78% with prasugrel compared with 56% with clopidogrel 300
mg/75 mg and 52% with clopidogrel 600 mg/75 mg (P < 0.001).
Mean bleeding times at 4 hours after administration of prasugrel 30 and 75 mg were increased
approximately 3- and 4-fold, respectively, compared with placebo (P < 0.05). Mean bleeding times
remained elevated at 24-hours postdosing. Bleeding time was also prolonged at 4-hours postdose with
daily prasugrel 10 mg for 10 days, but not with clopidogrel 75 mg daily; 706 s with prasugrel (P =0.05),
201 s with placebo, and 283 s with clopidogrel. Bleeding times remained 30% to 50% greater than
baseline with daily prasugrel 7.5 to 15 mg maintenance doses.
Prasugrel plus aspirin resulted in greater inhibition of platelet aggregation than aspirin alone and additive
inhibition of collagen-induced and thrombin-receptor–activating peptide (TRAP)–induced platelet
aggregation.
PHARMACOKINETICS: Numerous metabolites have been identified in the circulation following oral
prasugrel administration. R-138727 is the most active metabolite. It is detectable within the plasma within
15 minutes of oral prasugrel administration, and peak levels of the active metabolite are reached in 30
minutes. The most abundant metabolite (R-106583) is the S-methylated derivative of the active
metabolite, which reaches peak concentrations about 2 to 3 hours after prasugrel administration.
Peak concentrations of the other metabolites are reached within approximately 2 hours after prasugrel
administration. The terminal elimination half-life of the prasugrel active metabolite is 8 to 9 hours. Linear
pharmacokinetics have been observed at doses up to 75 mg. Approximately 70% of the dose is excreted
in the urine and 25% in the feces.
COMPARATIVE EFFICACY: The effects of prasugrel and clopidogrel on inhibition of platelet aggregation
were compared in a randomized study enrolling 101 aspirin-treated patients with stable coronary artery
disease. Patients received a loading dose/maintenance dose regimen of prasugrel 40 mg/5 mg, 40
mg/7.5 mg, 60 mg/10 mg, or 60 mg/15 mg, or clopidogrel 300 mg/75 mg for 28 days. At 4 hours after
dosing, with 20 mcmol/L ADP, both prasugrel loading doses achieved higher mean inhibition of platelet
aggregation (60.6% and 68.4% vs 30%; P < 0.0001) and lower percentage of pharmacodynamic
nonresponders than clopidogrel (defined as inhibition of platelet aggregation less than 20%; 3% vs 52%,
P < 0.0001). Prasugrel 10 and 15 mg maintenance doses achieved higher mean inhibition of platelet
aggregation than clopidogrel 75 mg at day 28 (P < 0.0001). On day 28, there were no nonresponders in
the prasugrel 10 and 15 mg groups compared with 45% in the clopidogrel group (P = 0.0007) (Eur Heart
J. 2008;29(1):21-30).
A prasugrel 60 mg loading dose followed by 10 mg maintenance dose was compared with clopidogrel
600 mg loading dose followed by a 75 mg maintenance dose in a 28-day study enrolling 110 aspirintreated
patients with stable coronary artery disease. Platelet aggregation to 20 mcM ADP was reported as
maximal platelet aggregation. Prasugrel was associated with faster onset and greater inhibition of platelet
aggregation than clopidogrel. At 2 hours post–loading dose, mean maximal platelet aggregation was 31%
for prasugrel and 55% for clopidogrel, and mean platelet reactivity index was 8.3% for prasugrel and
55.9% for clopidogrel (P < 0.001). During maintenance dosing, mean maximal platelet aggregation was
42% for prasugrel and 54% for clopidogrel, and mean platelet reactivity index was 25% for prasugrel and
51% for clopidogrel (P < 0.001). Bleeding-related events occurred more frequently in the prasugrel group
(32 bleeding and bruising events in the prasugrel group vs 13 in the clopidogrel group) (Eur Heart J.
2008;29(1):21-30).
Prasugrel was also compared with clopidogrel in a phase 2, randomized, dose-ranging, double-blind,
double-dummy study enrolling 904 patients undergoing elective or urgent percutaneous coronary
intervention. Patients received a clopidogrel 300 mg loading dose followed by 75 mg daily (254 patients),
a prasugrel 40 mg loading dose followed by 7.5 mg daily (199 patients), prasugrel 60 mg followed by 10
mg daily (200 patients), or prasugrel 60 mg daily followed by 15 mg daily (251 patients) and were
monitored for 30 days for bleeding and clinical events. Median patient age was 60 years; 77% were male,
27% had diabetes, and approximately 70% received Gp IIB/IIIA inhibitors. The primary end point was
clinically significant noncoronary artery bypass graft (CABG)–related thrombolysis in myocardial infarction
(TIMI) major or minor bleeding. There was no difference in the rates of significant bleeding between the
95

prasugrel (1.7%) and clopidogrel (1.2%) groups (hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.4
to 5.08). Major bleeding occurred in 0.5% in the prasugrel group and 0.8% in the clopidogrel group. Rates
of primary composite end point events (30-day major adverse cardiac events) and secondary end points
of myocardial infarction, recurrent ischemia, and clinical target vessel thrombosis did not differ between
groups. Major adverse cardiac events occurred in 47 (7.2%) prasugrel-treated patients and 24
clopidogrel-treated patients (9.4%; HR, 0.76; 95% CI, 0.45 to 1.24; P = 0.26) (Circulation.
2005;111(25):3366-3373).
Prasugrel was also compared with clopidogrel in a phase 3, randomized, double-blind study enrolling
13,608 patients with moderate- to high-risk acute coronary syndromes (10,074 with unstable angina or
non–ST-elevation myocardial infarction and 3,534 with ST-elevation myocardial infarction) undergoing
percutaneous coronary intervention. Patients received a prasugrel 60 mg loading dose followed by 10 mg
daily or clopidogrel 300 mg loading dose followed by 75 mg daily for 6 to 15 months. The loading dose
was given anytime after randomization up to 1 hour after the patient left the cardiac catheterization
laboratory. The median duration of therapy was 14.5 months. Concomitant use of aspirin was required;
concomitant heparin, low-molecular weight heparin, direct thrombin inhibitors, and/or GP IIb/IIIa inhibitors
were at the discretion of the treating physician. The primary study end point was the time to first event of
cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The primary efficacy end point
occurred in 12.1% of patients in the clopidogrel group compared with 9.9% of patients in the prasugrel
group (HR, 0.81; 95% CI, 0.73 to 0.9; P < 0.001; number needed to treat, 45.5 patients). Prasugrel was
also associated with reduced rates of myocardial infarction (9.7% for clopidogrel vs 7.4% for prasugrel; P
< 0.001), urgent target-vessel revascularization (3.7% vs 2.5%; P < 0.001), and stent thrombosis (2.4%
vs 1.1%; P < 0.001). Major bleeding occurred in 2.4% of patients in the prasugrel group compared with
1.8% of patients in the clopidogrel group (HR, 1.32; 95% CI, 1.03 to 1.68; P = 0.03; number needed to
harm, 166.7 patients). Rates of life-threatening bleeding were also greater in the prasugrel group (1.4%
vs 0.9%; P = 0.01), including rates of nonfatal bleeding (1.1% vs 0.9%; HR, 1.25; P = 0.23) and fatal
bleeding (0.4% vs 0.1%; P = 0.002). In subgroup analysis, patients with a history of stroke or transient
ischemic attack had net harm from prasugrel (HR, 1.54; 95% CI, 1.02 to 2.32; P = 0.04), patients 75 years
of age or older had no net benefit from prasugrel (HR, 0.99; 95% CI, 0.81 to 1.21; P = 0.92), and patients
weighing less than 60 kg had no net benefit from prasugrel (HR, 1.03; 95% CI, 0.69 to 1.53; P = 0.89).
Patients with at least one of these risk factors had higher rates of bleeding than those without these risk
factors (TRITON-TIMI 38 - Am Heart J. 2006;152(4):627-635 and N Engl J Med. 2007;357(20):2001-
2015).
Prasugrel was also compared with clopidogrel in a randomized, double-blind, crossover study enrolling
patients undergoing cardiac catheterization for planned percutaneous coronary intervention. Patients
received prasugrel 60 mg or clopidogrel 600 mg as a loading dose before the time catheterization was
expected to begin. The primary end point of the loading dose phase was the inhibition of platelet
aggregation with 20 mcmol/L ADP at 6 hours. Patients undergoing percutaneous coronary intervention
entered the maintenance dose phase, a 28-day crossover comparison of prasugrel 10 mg daily and
clopidogrel 150 mg daily, with a primary end point of inhibition of platelet aggregation after 14 days. The
loading dose phase randomized 201 patients. The inhibition of platelet aggregation at 6 hours was
greater with prasugrel therapy (74.8% vs 31.8%; P < 0.0001). During the maintenance phase, which
included 197 patients, inhibition of platelet aggregation was also greater with prasugrel (61.3% vs 46.1%;
P < 0.0001). No TIMI major bleeds occurred in either arm of the study. A total of 19 patients (18.6%) had
a bleeding event while receiving prasugrel compared with 14 subjects receiving clopidogrel (14.1%; P =
not significant) (Circulation. 2007;116(25):2923-2932).
CONTRAINDICATIONS
The contraindications for prasugrel will likely be similar to those of clopidogrel. Clopidogrel is
contraindicated in patients with hypersensitivity to any of the product ingredients and in patients with
active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
WARNINGS AND PRECAUTIONS
The warnings and precautions for prasugrel will likely be similar to those of clopidogrel. Thrombotic
96

thrombocytopenic purpura has been reported rarely following exposure to clopidogrel. It is not known if it
is also associated with prasugrel therapy.
Prasugrel and clopidogrel both prolong bleeding time and should be used with caution in patients who
may be at risk of increased bleeding from trauma, surgery, or other pathological condition. Platelet
transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by
dialysis.
.
BLACK BOX WARNING/ REMS and Patient Medication Guide
Effient can cause significant, sometimes fatal, bleeding.
Do not use Effient in patients with active pathological bleeding or a history of transient ischemic
attack or stroke.
In patients ≥ 75 years of age, Effient is generally not recommended because of the increased risk
of fatal and intracranial bleeding and uncertain benefit, except in high-risk patients (diabetes or
prior MI), where its effect appears to be greater and its use may be considered.
Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery
(CABG). When possible, discontinue Effient at least 7 days prior to any surgery.
Additional risk factors for bleeding include:
• body weight < 60 kg
• propensity to bleed
• concomitant use of medications that increase the risk of bleeding
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary
angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in
the setting of Effient.
If possible, manage bleeding without discontinuing Effient. Stopping Effient, particularly in the
first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular
events).
Discontinue thienopyridines, including Effient, for active bleeding, elective surgery, stroke, or TIA. The
optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent
placement, premature discontinuation of any antiplatelet medication, including thienopyridines, conveys
an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature
discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should
be avoided, and if thienopyridines must be temporarily discontinued because of an adverse event(s), they
should be restarted as soon as possible
ADVERSE REACTIONS: Adverse reactions occurring more frequently with prasugrel than placebo have
included dizziness and hematoma. 3 Other adverse reactions that have been associated with prasugrel
include headache, increased ALT, positive fecal occult blood, and bleeding.
Non-Hemorrhagic Treatment Emergent
Adverse Events Reported by at Least Effient (%) (N=6741 Clopidogrel (%) (N=6716)
2.5% of Patients in Either Group)
Hypertension 7.5 7.1
Hypercholesterolemia/Hyperlipidemia 7.0 7.4
Headache 5.5 5.3
Back pain 5.0 4.5
Dyspnea 4.9 4.5
Nausea 4.6 4.3
Dizziness 4.1 4.6
Cough 3.9 4.1
Hypotension 3.9 3.8
Fatigue 3.7 4.8
Non-cardiac chest pain 3.1 3.5
Atrial fibrillation 2.9 3.1
Bradycardia 2.9 2.4
Leukopenia (< 4 x 109 WBC/L) 2.8 3.5
97

Rash 2.8 2.4
Pyrexia 2.7 2.2
Peripheral edema 2.7 3.0
Pain in extremity 2.6 2.6
Diarrhea 2.3 2.6
DRUG INTERACTIONS: Coadministration of prasugrel with the CYP3A4 inhibitor ketoconazole did not
affect exposure to the prasugrel active metabolite or prasugrels inhibition of platelet aggregation. In
contrast, coadministration of clopidogrel and ketoconazole resulted in reduced exposure to the
clopidogrel active metabolite 22% to 29% and reduced inhibition of platelet aggregation 28% to 33%.
Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes.
Effient can be administered with aspirin (75 mg to 325 mg per day), heparin, GPIIb/IIIa inhibitors, statins,
digoxin, and drugs 188 that elevate gastric pH, including proton pump inhibitors and H2 blockers
Coadministration of prasugrel and warfarin or NSAIDs should be undertaken with caution because
increased risk for bleeding occurs when clopidogrel is used concurrently with warfarin.
RECOMMENDED MONITORING: Blood cell count determination should be considered if bleeding or
related clinical symptoms occur during prasugrel therapy.
DOSING: The most extensively studied dosing regimen has been a 60 mg loading dose followed by a 10
mg daily maintenance dose. The FDA has also approved a 5mg dose for patients weighing less than 60
Kg but it is not based on any clinical data
The FDA approved label states:
Initiate Effient treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily.
Patients taking Effient should also take aspirin (75 mg to 325 mg) daily Effient may be administered with
or without food.
Dosing in Low Weight Patients
Compared to patients weighing ≥ 60 kg, patients weighing < 60 kg have an increased exposure to the
active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance
dose. Consider lowering the maintenance dose to 5 mg in patients < 60 kg. The effectiveness and safety
of the 5 mg dose have not been prospectively studied.
PRODUCT AVAILABILITY/COST and STORAGE: A new drug application (NDA) for prasugrel was
submitted to the FDA in January 2008.and approved in July 2009. It is projected to have a cost that is
about 18% above the cost of clopidogrel – Plavix according to a Lilly press release.. Effient is available in
both 5 and 10 mg tablets AWP $204.05 per 30 5 and 10 mg tablets.
CONCLUSION: Prasugrel shows greater platelet inhibitory effect with more rapid onset than clopidogrel.
It has been associated with a lower risk of major cardiovascular events than clopidogrel following
percutaneous coronary intervention; however, it was associated with increased risk of major bleeding.
Further data are necessary to establish which patients are more likely to benefit and which are at greater
risk for bleeding.. For now, prasugrel use should not be recommended for those in the risk groups
identified in the TRITON-TIMI 38 study (patients with a history of stroke or transient ischemic attack,
patients 75 years of age or older, and patients weighing less than 60 kg).as well as in patients who will
need CABG surgery. It is also not FDA approved for patients with A Fib, , PVD, or post CVA where
clopidogrel is FDA approved.
Red flags raised over FDA advisory-panel hearing on prasugrel
February 13, 2009 | Michael O'Riordan
“Ten days ago prasugrel (Lilly/Daiichi Sankyo) cleared a major regulatory hurdle when a US Food and
Drug Administration advisory panel voted unanimously to recommend approval of the novel antiplatelet
agent for the treatment of acute coronary syndromes.
The vote, by the nine panel members of the Cardiovascular and Renal Drugs Advisory Committee, was
based largely on the premise that the antiplatelet agent provides greater cardiovascular-event protection
compared with clopidogrel, but at a cost of increased bleeding.”
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“Despite the thumbs-up, the panel's decision has not been without controversy. Specifically, questions
arose when Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), an expert in the field of
vascular physiology who has been critical of prasugrel in the past, was asked not to participate in the FDA
advisory panel. Some cardiologists were critical of the decision and openly questioned why the FDA
excluded a member who was likely to bring a critical eye to the proceedings.”
“This raises some obvious red flags.” Dr William Boden (Buffalo General Hospital, NY), who was not part
of the panel, told heartwire he was mystified by the decision. "This raises some obvious red flags," he
said. "You know, regarding the unanimous vote, if you don't have anybody there who is going to be
speaking critically about the drug, and you've maneuvered the committee to be that way, then I'm not
shocked there was a nine-to-zero vote."
“Also, one panel member publicly questioned why the Drug Safety and Risk Management subcommittee
wasn't involved, while another antiplatelet expert criticized the TRITON-TIMI-38 findings and what he
called a "family-picnic" atmosphere of the FDA hearing, telling heartwire that the decision to approve
prasugrel appeared predetermined from the start.”
The FDA has agreed that ti acting in haste and should not have excluded the one panel member, they
have reviewed and changed the way that this process will happen in the future.
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Aug 2009
Final appraisal determination Prasugrel for the treatment of acute coronary syndromes with
percutaneous coronary intervention
Guidance
1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic
events in people with acute coronary syndromes having percutaneous coronary intervention, only when:
• immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is
necessary or
• stent thrombosis has occurred during clopidogrel treatment or
• the patient has diabetes mellitus.
Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and
planned percutaneous coronary intervention. Circulation 2010; 121:71-79. Data is from the Trial to
Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel
(TRITON-TIMI 38),
Prasugrel, approved in 2009, costs more than clopidogrel. In the current analysis, which included data
prospectively collected from 6705 patients in eight countries, researchers used net wholesale prices—
clopidogrel at $4.62/day and prasugrel at $5.45/day—to calculate the cost-effectiveness of the treatment
strategies. Data related to hospitalizations for cardiovascular and bleeding events were obtained from
adverse-event reporting.
During the index hospitalization, the incidence of periprocedural-MI events was higher with clopidogrel,
but bleeding events were greater with prasugrel. The costs of these events offset each other and did not
translate into a difference in mean index hospitalization costs between treatments.
Total hospitalization costs, excluding the cost of the drug, were $517-per-patient lower with prasugrel, the
result of reduced rates of rehospitalization for PCI. With the increased costs of the drug, this difference
still resulted in cumulative medical care costs, including study drug and initial and follow-up
hospitalization, that were $221 lower with prasugrel than with clopidogrel.
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DRONEDARONE – MULTAQ by Sanofi Aventis 1-P
Indications: Dronedarone is indicated to reduce the risk of cardiovascular hospitalization in patients with
paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and
associated cardiovascular risk factors (i.e., age greater than 70, hypertension, diabetes, prior
cerebrovascular accident, left atrial diameter greater than or equal to 50 mm or left ventricular ejection
fraction [LVEF] less than 40%), who are in sinus rhythm or who will be cardioverted. Approved by the
FDA:July 2, 2009.
Pharmacology:
Dronedarone (also known as N[2butyl3[4(3dibutylaminopropoxy) benzoyl] methanesulfonamide,
hydrochloride]) is a noniodinated benzofuran derivative of amiodarone with a sulfonamide group on the
benzofuran ring
The mechanism of action of dronedarone is unknown. Dronedarone has antiarrhythmic properties
belonging to all 4 Vaughan-Williams classes, but the contribution of each of these activities to the clinical
effect is unknown. The electrophysiological properties of dronedarone are very similar to those of
amiodarone; both agents belong to all 4 Vaughan Williams classes. Consequently, amiodarone like
antiarrhythmic actions, including sodium channel blocking at rapid pacing
rates (class I effect), prolonged cardiac action potentials and refractoriness (class III effect), calcium
channel antagonism (class IV effect), and noncompetitive antiadrenergic effects (class II effect), have
been demonstrated with dronedarone in dog, rat, and human hearts.
As a result of these channel blocking effects, there is a dose related increase in the PR and QT intervals
with dronedarone doses up to 1,600 mg/d. With the 400mg twice daily dose typically used in clinical trials,
the PR interval increased by 13.4 milliseconds, and the incidence of any QTc interval >500 milliseconds
was 7.7%.
Pharmacodynamics:
Electrophysiological effects: Dronedarone exhibits properties of all 4 Vaughn-Williams antiarrhythmic
classes, although it is unclear which of these are important in producing dronedarone's clinical effects.
The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in
healthy subjects following repeated oral doses up to 1,600 mg once daily or 800 mg twice daily for 14
days and 1,600 mg twice daily for 10 days. In the dronedarone 400 mg twice daily group, there was no
apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg
twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg
twice daily and up to +50 ms at 1,600 mg twice daily. There was a moderate dose-related effect on the
QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1,600 mg twice
daily.
DAFNE study: DAFNE was a dose-response study in patients with recurrent AF, evaluating the effect of
dronedarone in comparison with placebo in maintaining sinus rhythm. The doses of dronedarone in this
study were 400, 600, and 800 mg twice a day. In this small study, doses above 400 mg were not more
effective and were less well tolerated.
Pharmacokinetics:
Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is
increased by meals. Its elimination half life is 13 to 19 hours.
Absorption:
Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is
low, about 4%. It increases to approximately 15% when dronedarone is administered with a high-fat meal.
After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main
circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated
administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment, and the
mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady-state Cmax and exposure of
the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of
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dronedarone and its N-debutyl metabolite deviate moderately from dose proportionality: a 2-fold increase
in dose results in an approximate 2.5- to 3-fold increase with respect to Cmax and AUC.
Distribution:
The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is greater than 98% and
not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume
of distribution at steady state is about 1,400 L.
Metabolism:
Dronedarone is extensively metabolized, mainly by CYP 3A. The initial metabolic pathway includes N-
debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic
acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30
uncharacterized metabolites. The N-debutyl metabolite exhibits pharmacodynamic activity but is 1/10 to
1/3 as potent as dronedarone.
Excretion:
In a mass balance study with orally administered dronedarone (14C-labeled) approximately 6% of the
labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine),
and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite
accounted for less than 15% of the resultant radioactivity in the plasma.
After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination
half-life of dronedarone ranges from 13 to 19 hours.
Special Populations:
Renal Function Impairment - Consistent with the low renal excretion of dronedarone, no pharmacokinetic
difference was observed in subjects with mild or moderate renal impairment compared with subjects with
normal renal function. No pharmacokinetic difference was observed in patients with mild to severe renal
impairment in comparison with patients with normal renal function.
Hepatic Function Impairment - In subjects with moderate hepatic impairment, the mean dronedarone
exposure increased by 1.3-fold relative to subjects with normal hepatic function, and the mean exposure
of the N-debutyl metabolite decreased by about 50%. Pharmacokinetic data were significantly more
variable in subjects with moderate hepatic impairment.
The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed.
Elderly - Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and
older and 34% were 75 years of age and older. In patients 65 years of age and older, dronedarone
exposures are 23% higher than in patients younger than 65 years of age.
Gender - Dronedarone exposures are on average 30% higher in females than in males.
Race - Pharmacokinetic differences related to race were not formally assessed. However, based on a
cross study comparison, following single dose administration (400 mg), Asian males (Japanese) have
about a 2-fold higher exposure than white males. The pharmacokinetics of dronedarone in other races
has not been assessed.
CLINICAL STUDIES:
ATHENA Study
ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of
dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be
converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay
death from any cause or hospitalization for cardiovascular reasons.
Initially patients were to be ≥70 years old, or

6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but
patients not in sinus rhythm were expected to be either electrically or chemically converted to normal
sinus rhythm after anticoagulation.
Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either
MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional
therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II
receptor blockers (ARBs)(69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral
anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).
The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death
from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons,
and time to cardiovascular death and time to all causes of death were also explored.
Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%)
of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of
those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent
(29%) of patients had heart failure, mostly NYHA class II (17%) The majority had hypertension (86%) and
structural heart disease (60%).
Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization
or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to
its effect on cardiovascular hospitalization, principally hospitalization related to AF.
Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown
below. Secondary endpoints count all first events of a particular type, whether or not they were preceded
by a different type of event.
Results:
Primary endpoint
Cardiovascular hospitalization or death from any cause 913 (39.2%) placebo vs 727 (31.6%)
dronedarone HR 0.76 or 24% RRR, 7.6% ARR, NNT=14, p

ANDROMEDA Study (Increased Mortality in Patients with Severe Heart Failure)
Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic
dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching
placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. After
enrollment of 627 of 1000 planned patients (310 and 317 in the dronedarone and placebo groups,
respectively), and a median follow-up of 63 days, the trial was terminated because of excess mortality in
the dronedarone group. Twenty-five (25) patients in the dronedarone group (8.1%) versus 12 patients in
the placebo group (3.8%) had died, hazard ratio 2.13; 95% CI: 1.07 to 4.25; p=0.027. ARI 4.3%, NNH =
26. The main reason for death was worsening heart failure. There were also excess hospitalizations for
cardiovascular reasons in the dronedarone group (71 versus 51 for placebo)
The populations enrolled in the ANDROMEDA and ATHENA studies were significantly different. The
patients enrolled in ANDROMEDA had relatively severe heart failure and had been hospitalized, or
referred to a specialty heart failure clinic, for worsening symptoms of heart failure, notably shortness of
breath. Note that these patients may have been clinically improved at the time of enrollment and it is the
history of decompensation that characterized them. Patients enrolled into ANDROMEDA were
predominantly NYHA Class II (40%) and III (57%), and only 38% had a history of AF/AFL (25% had AF at
randomization). In contrast, in ATHENA, 71% of patients had no heart failure, 25% were NYHA Class I or
II, and only 4% were Class III. All patients had a history of AF/AFL.
BLACK BOX WARNING: HEART FAILURE
MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II
- III heart failure with a recent decompensation requiring hospitalization or referral to a
specialized heart failure clinic [see Contraindications.
In a placebo-controlled study in patients with severe heart failure requiring recent
hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the
ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in
mortality. Such patients should not be given dronedarone
This study is the reason for the Black Box Warning, the REMS and Patient Medication Guide
Contraindications:
Dronedarone is contraindicated in patients with:NYHA Class IV heart failure or NYHA Class II - III heart
failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure
clinic
Second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in
conjunction with a functioning pacemaker)
Bradycardia less than 50 bpm
Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole,
cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir
Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of
Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral
macrolide antibiotics, and Class I and III antiarrhythmics
QTc Bazett interval greater than or equal to 500 ms or PR interval greater than 280 ms
Severe hepatic impairment
Pregnancy (Category X): dronedarone may cause fetal harm when administered to a pregnant woman.
Dronedarone is contraindicated in women who are or may become pregnant. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the
potential hazard to a fetus
Nursing mothers
Warnings/Precautions:
Patients with new or worsening heart failure during treatment: Advise patients to consult a health care
provider if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or
increasing shortness of breath. There are limited data available for AF/AFL patients who develop
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worsening heart failure during treatment with dronedarone. If heart failure develops or worsens, consider
the suspension or discontinuation of dronedarone.
Hypokalemia and hypomagnesemia with potassium-depleting diuretics: Hypokalemia or
hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium
levels should be within the normal range prior to administration of dronedarone and maintained in the
normal range during administration of dronedarone.
QT interval prolongation: Dronedarone induces a moderate (average of about 10 ms but much greater
effects have been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is greater than or equal
to 500 ms, stop dronedarone.
Increase in creatinine after treatment initiation: Serum creatinine levels increase by about 0.1 mg/dL
following dronedarone treatment initiation. The elevation has a rapid onset, reaches a plateau after 7
days and is reversible after discontinuation. If an increase in serum creatinine occurs and plateaus, this
increased value should be used as the patient's new baseline. The change in creatinine levels has been
shown to be the result of an inhibition of creatinine's tubular secretion, with no effect upon the glomerular
filtration rate.
Women of childbearing potential: Premenopausal women who have not undergone a hysterectomy or
oophorectomy must use effective contraception while using dronedarone. Dronedarone caused fetal harm
in animal studies at doses equivalent to recommended human doses. Women of childbearing potential
should be counseled regarding appropriate contraceptive choices taking into consideration their
underlying medical conditions and lifestyle preferences. Pregnancy Category X
Renal function impairment: Patients with renal impairment were included in clinical studies. Because renal
excretion of dronedarone is minimal, no dosing alteration is needed.
Hepatic function impairment: Dronedarone is extensively metabolized by the liver. There is little clinical
experience with moderate hepatic impairment and none with severe impairment. No dosage adjustment is
recommended for moderate hepatic impairment.
Carcinogenesis: In studies in which dronedarone was administered to rats and mice for up to 2 years at
doses of up to 70 mg/kg/day and 300 mg/kg/day, respectively, there was an increased incidence of
histiocytic sarcomas in dronedarone-treated male mice (300 mg/kg/day or 5 times the maximum
recommended human dose based on AUC comparisons), mammary adenocarcinomas in dronedaronetreated
female mice (300 mg/kg/day or 8 times MRHD based on AUC comparisons) and hemangiomas in
dronedarone-treated male rats (70 mg/kg/day or 5 times MRHD based on AUC comparisons).
Fertility impairment:
In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation
caused an increase in irregular estrus cycles and cessation of cycling at doses greater than or equal to 10
mg/kg (equivalent to 0.12 times the MRHD on a mg/m2 basis).
Children: Safety and efficacy in children younger than 18 years of age have not been established.
Elderly: More than 4,500 patients with AF or AFL 65 years of age and older were included in the
dronedarone clinical program (of whom more than 2,000 patients were 75 years of age or older). Efficacy
and safety were similar in elderly and younger patients/
Drug Interactions:
Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6.
Dronedarone's blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and
dronedarone can interact with drugs that are substrates of CYP 3A and CYP 2D6.
Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP
2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport. Pharmacodynamic interactions can be
expected with beta-blockers; calcium antagonists and digoxin.
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In clinical trials, patients treated with dronedarone received concomitant medications including betablockers,
digoxin, calcium antagonists (including those with heart rate-lowering effects), statins, and oral
anticoagulants.
Pharmacodynamic interactions:
Drugs prolonging the QT interval (inducing Torsade de Pointes): Co-administration of drugs prolonging
the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics,
and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointestype
ventricular tachycardia.
Digoxin: Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AVnode\conduction).
In clinical trials, increased levels of digoxin were observed when dronedarone was coadministered
with digoxin. GI disorders were also increased. Because of the pharmacokinetic interaction
and possible pharmacodynamic interaction, reconsider the need for digoxin therapy. If digoxin treatment
is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.
Calcium channel blockers:
Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate
dronedarone's effects on conduction. (primarily diltiazem and verapamil)
Give low doses of calcium channel blockers initially and increase only after ECG verification of good
tolerability.
Beta-blockers:
In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination
with beta-blockers.
Give low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.
Effects of other drugs on dronedarone:
Ketoconazole and other potent CYP 3A inhibitors: Repeated doses of ketoconazole, a strong CYP 3A
inhibitor, resulted in a 17-fold increase in dronedarone exposure and a 9-fold increase in Cmax.
Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as, itraconazole,
voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated.
Grapefruit juice: Grapefruit juice, a moderate inhibitor of CYP 3A, resulted in a 3-fold increase in
dronedarone exposure and a 2.5-fold increase in Cmax. Therefore, patients should avoid grapefruit juice
beverages while taking dronedarone.
Rifampin and other CYP 3A inducers: Rifampin decreased dronedarone exposure by 80%. Avoid rifampin
or other CYP 3A inducers, such as phenobarbital, carbamazepine, phenytoin, and St John's wort with
dronedarone because they decrease its exposure significantly.
Calcium channel blockers: Verapamil and diltiazem are moderate CYP 3A inhibitors and increase
dronedarone exposure by approximately 1.4- to 1.7-fold.
Pantoprazole: Pantoprazole, a drug that increases gastric pH, did not have a significant effect on
dronedarone pharmacokinetics.
Effects of dronedarone on other drugs:
Statins: Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively.
Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label
recommendations for use with CYP 3A and P-gP inhibitors such as dronedarone.
Calcium channel blockers: Dronedarone increases calcium channel blocker (verapamil, diltiazem or
nifedipine) exposure by 1.4- to 1.5-fold.
Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range: Dronedarone can
increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow
therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.
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Beta-blockers and other CYP 2D6 substrates: Dronedarone increased propranolol exposure by
approximately 1.3-fold following single dose administration. Dronedarone increased metoprolol exposure
by 1.6-fold following multiple dose administration. Other CYP 2D6 substrates, including other betablockers,
tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have
increased exposure upon coadministration with dronedarone.
Digoxin and P-glycoprotein substrates: Dronedarone increased digoxin exposure by 2.5-fold by inhibiting
the P-gP transporter. Other P-gP substrates are expected to have increased exposure when
coadministered with dronedarone.
Warfarin and losartan (CYP 2C9 substrates):
In healthy subjects, dronedarone at a dose of 600 mg twice daily increased S-warfarin exposure by 1.2-
fold with no change in R-warfarin and with no clinically significant increase in INR. In clinical trials in
patients with AF/AFL, there was no observed excess risk of bleeding compared with placebo when
dronedarone was coadministered with oral anticoagulants. Monitor INR per the warfarin label.
No interaction was observed between dronedarone and losartan.
Theophylline (CYP 1A2 substrate): Dronedarone does not increase steady state theophylline exposure.
Oral contraceptives: No decreases in ethinyl estradiol and levonorgestrel concentrations were observed
in healthy subjects receiving dronedarone concomitantly with oral contraceptives.
Adverse Reactions:
The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5
placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of
6285 patients were randomized and treated, 3282 patients with MULTAQ 400 mg twice daily, and 2875
with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up
was 30 months.
In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the
dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for
discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the
placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).
The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were
diarrhea, nausea, abdominal pain, vomiting, and asthenia
Adverse Effect
Placebo
(N=2875)
Dronedarone
(N=3282)
Diarrhea 6% 9%
Nausea 3% 5%
Abdominal pain 3% 4%
Vomiting 1% 2%
Dyspepsia 1% 2%
Asthenia 5% 7%
Bradycardia 1% 3%
Rash, dermatitis 3% 5%
Serum creatinine increased >/=10% at 5 days 21% 51%
QTc Bazett prolonged (>450ms males and 19% 28%
>470 ms females)
Photosensitivity and dysgeusia have been reported in less than 1%
In the event of overdosage, monitor the patient's cardiac rhythm and blood pressure. Treatment should be
supportive and based on symptoms.
It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis,
peritoneal dialysis or hemofiltration). There is no specific antidote available.
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Dronedarone was developed to lack any iodine moieties and thus not cause thyroid or pulmonary toxicity.
Interestingly, in vitro, dronedarone caused more damage than amiodarone to alveolar macrophages in
rabbits, and in a rat study, dronedarone was associated with hypothyroid like
effects possibly resulting from selective inhibition of the thyroid receptor alpha1. Because of
the relatively small number of patients evaluated in clinical trials and the lack of headtohead
trials with amiodarone, it is not yet clear whether dronedarone and amiodarone differ in terms of these
adverse effects or the incidence of other troublesome adverse effects associated with amiodarone such
as liver toxicity.
Administration/Dosage/Storage & Cost:
The only recommended dosage of dronedarone is 400 mg twice daily in adults. Dronedarone should be
taken as 1 tablet with the morning meal and 1 tablet with the evening meal.
Treatment with Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine,
disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (eg, ketoconazole) must be
stopped before starting dronedarone.
Cost $259.98/60 x 400 mg tabs drugstore.com
Storage and stability:
Store at 25°C (77°F): excursions permitted to 15° to 30°C (59° to 86°F).
Patient Information:
Dronedarone should be administered with a meal. Warn patients not to take dronedarone with grapefruit
juice.
If a dose is missed, patients should take the next dose at the regularly scheduled time and should not
double the dose.
Advise patients to consult a health care provider if they develop signs or symptoms of worsening heart
failure such as acute weight gain, dependent edema, or increasing shortness of breath.
Advise patients to inform their health care provider of any history of heart failure, rhythm disturbance
other than atrial fibrillation or flutter or predisposing conditions, such as uncorrected hypokalemia.
Dronedarone may interact with some drugs; therefore, advise patients to report to their health care
provider the use of any other prescription, nonprescription medication, or herbal products, particularly St.
John's wort.1
Summary:
The FDA approved the use of dronedarone for the treatment of atrial fibrillation and atrial flutter, but
specified that dronedarone should be limited to patients who (like those enrolled in the ATHENA trial) do
not have significant heart failure. Dronedarone has a pharmacologic mechanism of action that is similar to
that of amiodarone, but dronedarone lacks an iodine moiety, which may result in less thyroid and
pulmonary toxicity. However, it should be
noted that none of the clinical trials with dronedarone have lasted for more than two years
and some of the unusual toxicities seen with amiodarone may not appear until the drug
has been taken for for several years. So, while dronedarone at this point looks reasonably
safe, its true safety profile will not be known until it has been in use for a substantial
period of time. During clinical trials, dronedarone has been demonstrated to decrease AF recurrence by
approximately 25% (probably less than amiodarone but we do not have any head to head data) and to
reduce the incidence of the combined end point of hospitalization for cardiac causes and all-cause
mortality. However, the results of an additional trial suggest that dronedarone should not be used in
patients with severe (class III or IV) heart failure, as these patients demonstrated an increased mortality
risk with dronedarone treatment. Worsening renal function has also been associated with dronedarone,
but the clinical relevance of this is a matter of some debate.
In vitro, dronedarone has been demonstrated to be metabolized (>84%) by the CYP3A4 isoenzymes and
to be a moderate inhibitor of the CYP3A4 and CYP2D6 isoenzymes. In addition, the main active
metabolite of dronedarone (SR 35021) has also been demonstrated to have the potential to inhibit
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CYP2C9, CYP2C19, and CYP1A2. we need more information on the potential for clinically significant
drug-drug interactions
Piccini and colleagues (JACC 2009 54:1089–95) conducted a systematic overview of all randomized,
controlled trials evaluating dronedarone or amiodarone for the prevention of atrial fibrillation (AF) to
determine relative efficacy and safety profiles, as there are limited direct comparison trials. A model
incorporating all trial evidence found amiodarone to be superior to dronedarone (odds ratio [OR]: 0.49) for
the prevention of recurrent AF; however, there was a trend toward higher all-cause mortality (OR: 1.61)
and higher overall adverse events requiring drug discontinuation with amiodarone (OR: 1.81). For every
1,000 patients treated with dronedarone instead of amiodarone, the authors estimate 228 more
recurrences of AF in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring
discontinuation of the drug.
An ongoing randomized trial is comparing dronedarone and amiodarone for the prevention of AF
recurrences, the trial is called DIONYSUS
Paris, France – December 23, 2008 – Sanofi-aventis today reported the results of the DIONYSOS trial,
evaluating the efficacy and safety of dronedarone versus amiodarone for the maintenance of sinus
rhythm in 504 patients with persistent Atrial Fibrillation (AF) for a short treatment duration (mean follow up
of 7 months).
Unsurprisingly, dronedarone showed a decrease of safety events vs. amiodarone but more occurrences
of the composite primary endpoint (AF recurrence or premature drug discontinuation for intolerance or
lack of efficacy). There were 184 patients (73.9%) who reached the primary endpoint in the dronedarone
arm as compared to 141 (55.3%) in the amiodarone arm (p

BENZYL ALCOHOL 5% LOTION – Ulesfia (yoo-LESS-fee-ah) by Sciele Pharma
1S
INDICATIONS: Benzyl alcohol 5% lotion is indicated for the topical treatment of head lice infestation in
patients 6 months of age and older. It does not have ovicidal activity. Benzyl alcohol lotion, like all other
lice therapies, should be used in combination with an overall lice management program that includes
washing in hot water or dry cleaning all recently worn clothing, hats, used bedding, and towels; cleaning
personal care items (eg, combs, brushes, hair clips) with hot water; and using a fine-tooth comb or special
nit comb to remove dead lice and nits from the hair.
The Food and Drug Administration (FDA)-approved indications for the available pediculocides are
summarized in Table 1. Other forms of therapy have included the use of essential oils, fixed oils, siliconebased
fluids, and simple physical removal of the lice and nits.
Table 1. Indications for Products Approved for Treatment of Head Lice
Benzyl Alcohol 5%
(Ulesfia)
Lindane 1% a
Malathion
(Ovide)
Permethrin 1%
(Nix)
Pyrethrins
and
Piperonyl
Butoxide
(Rid, A-200,
Triple X)
Rx or OTC Rx Rx Rx OTC b OTC
Pharmacolo
gy
Asphyxiant
Organochlori
ne
pediculocide
Organophosphat
e pediculocide
Pyrethroid
pediculocide
Pyrethroid
pediculocide
Head lice c X X X X X
Pubic lice c X X
Body lice c
X
Scabies X Xb
a Only for use in patients who cannot tolerate or who have failed other treatments.
b Permethrin 5% cream (Rx) is indicated for scabies.
c Lindane, malathion, permethrin, and pyrethrins and piperonyl butoxide are indicated for the treatment of
lice and their eggs (nits); benzyl alcohol is only active against the lice.
CLINICAL PHARMACOLOGY: Benzyl alcohol inhibits lice from closing their respiratory spiracles, which
allows the vehicle to obstruct the spiracles and causes the lice to asphyxiate. Some investigators believe
that drugs working by this type of mechanism of action are less likely to cause resistance than traditional
pesticides.
PHARMACOKINETICS: In pharmacokinetic studies assessing benzyl alcohol 5% lotion applied for 3
times the normal exposure period, benzyl alcohol was quantified in a single plasma sample in 4 (21%) of
19 subjects. Out of a total of 102 samples analyzed, 3 of the subjects in the 6 months to 3 years of age
group had quantifiable levels at 0.5 hours posttreatment and 1 subject in the 4 to 11 years of age group
had quantifiable levels at 1 hour posttreatment.
COMPARATIVE EFFICACY: Study results were only reported in the package insert and meeting
abstracts. Complete descriptions of methods or results are not available. It is not clear if use of a nit comb
was included in any of the study protocols.
The efficacy of the benzyl alcohol 5% lotion was assessed in 2 multicenter, randomized, double-blind,
vehicle-controlled studies including 628 subjects 6 months of age and older with active head lice
infestation. For the efficacy evaluation, the youngest subject from each household was enrolled in the
treatment cohort and received either benzyl alcohol lotion or vehicle. Other infested household members
were enrolled in a secondary cohort and received the same treatment as the youngest family member.
109

The secondary cohort was not included in the efficacy evaluation, but was evaluated for safety. All
patients received treatment with benzyl alcohol or vehicle 2 times, separated by 1 week.
In the first study, 125 subjects were enrolled in the treatment cohort and randomized to receive benzyl
alcohol lotion (63 subjects) or vehicle (62 subjects). Fourteen days after treatment, 76.2% (48/63) of
subjects in the benzyl alcohol group were free of live lice compared with 4.8% (3/62) in the vehicle group.
The other study also enrolled 125 subjects in the treatment cohort: 64 in the benzyl alcohol group and 61
in the vehicle group. Fourteen days after treatment, 75% (48/64) of subjects in the benzyl alcohol group
were free of live lice, compared with 26.2% (16/61) in the vehicle group.
Two phase 2, observer-blinded, dose-ranging studies also compared the efficacy and safety of benzyl
alcohol lotion with permethrin 1% (RID). These studies enrolled 123 subjects (81 in study 1 and 42 in
study 2) between 2 and 70 years of age who had at least 3 live lice and 10 eggs. Treatment with benzyl
alcohol lotion was administered with a 10-minute application on 2 occasions, 1 week apart. The primary
efficacy end point was the percentage of subjects with treatment success based on the presence of live
lice at the end of the study. At day 1 posttreatment, the benzyl alcohol 5% and 10% lotion and permethrin
treatment groups had an average of 2 live lice compared with a mean of 7.7 live lice in the vehicle group
(P = 0.004). There were more dead lice (P < 0.001), more moribund lice (P = 0.047), and fewer walking
lice (P < 0.001) in the benzyl alcohol and permethrin groups compared with placebo. At day 15, all of the
active treatment groups exhibited more than 70% overall success. In a minimum effective dose study, in
which the hair was fully saturated during treatment, overall treatment success was 90.5% with benzyl
alcohol 5% lotion and 81% with benzyl alcohol 2.5% lotion. (J Am Acad Dermatol.
2006;54(3)(suppl):AB61 and Clin Pharmacol Ther. 2006;79:P9)
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: The contraindications, warnings, and
precautions for the FDA-approved products available for the treatment of head lice are compared in Table
2.
CONTRAINDICATIONS
The prescribing information lists no contraindications to the use of benzyl alcohol lotion in children 6
months of age and older.
WARNINGS AND PRECAUTIONS
Intravenous administration of products containing benzyl alcohol has been associated with neonatal
gasping syndrome. The syndrome consists of severe metabolic acidosis, gasping respirations,
progressive hypotension, seizures, CNS depression, intraventricular hemorrhage, and death in preterm,
low birth weight infants. Neonates may be at risk for gasping syndrome if treated with benzyl alcohol
lotion. Although expected systemic exposure of benzyl alcohol from proper use of the lotion is expected to
be substantially lower than that reported in association with gasping syndrome, the minimum amount of
benzyl alcohol at which toxicity may occur is not known.
Eye irritation may occur if eye exposure occurs. Patients should be advised to avoid exposure to the
eyes. If the lotion comes into contact with the eyes, flush immediately with water.
Contact dermatitis may occur with benzyl alcohol lotion.
The safety in children younger than 6 months of age has not been established. Use is not recommended
in patients younger than 6 months of age because of the potential for increased systemic absorption
caused by a high ratio of skin surface area to body mass and the potential for an immature skin barrier.
Benzyl alcohol lotion is in Pregnancy Category B. There are no studies in pregnant women. Animal
reproductive studies did not reveal teratogenicity. Benzyl alcohol lotion should be used during pregnancy
only if clearly needed.
It is not known whether benzyl alcohol is excreted in human milk. Caution is advised if benzyl alcohol
lotion is used in a breast-feeding woman.
110

Table 2. Contraindications, Warnings, and Precautions of Various Pediculocides
Benzyl
Alcohol 5%
Lindane
1% Malathion
Permethrin
1%
Pyrethrins and
Piperonyl
Butoxide
Contraindications
Hypersensitivity X X X X
Infants/Neonates
X
Premature infants
Seizure disorders
Atopic dermatitis or
psoriasis
X
X
X
Black Box Warnings
Second-line use only
Neurologic toxicity
Proper use/avoid
retreatment
X
X
X
Warnings and Precautions
Eye irritation X X X
Contact dermatitis
X
Skin irritation X X X
Asthma X X
Neonatal gasping
syndrome
X
Neurotoxicity/Deaths
Concomitant use of oilbased
products
X
X
Flammable
X
Special Populations
Children 6 mo and older Caution 6 y and
older
2 mo and
older
NP a
Pregnancy Category B C B B NP
Breast-feeding mothers Caution Not
recommended
Caution
Not
recommended
NP
a NP = not provided
ADVERSE REACTIONS: The most common adverse reactions (occurring in more than 1% of patients
and more frequently with benzyl alcohol lotion than placebo) have included ocular irritation, applicationsite
irritation, and application-site anesthesia and hypoesthesia. Other reactions occurring more
frequently in benzyl alcohol lotion–treated patients than vehicle recipients, among a subset of patients
without these symptoms prior to treatment, included pruritus, erythema, pyoderma, and ocular irritation.
The incidence of these reactions is summarized in Table 3. Other less frequently occurring reactions
included application-site dryness, application-site excoriation, paresthesia, application-site dermatitis,
111

excoriation, thermal burn, dandruff, rash, and skin exfoliation.
Table 3. Common Adverse Reactions Observed With Benzyl Alcohol Lotion
for the Treatment of Pediculosis Capitis
Benzyl Alcohol Lotion
Vehicle
Pruritus 14/116 (12%) 3/67 (4%)
Erythema 32/309 (10%) 19/217 (9%)
Pyoderma 22/308 (7%) 10/230 (4%)
Ocular irritation 26/428 (6%) 3/313 (1%)
Application-site irritation 11/478 (2%) 2/336 (1%)
Application-site anesthesia
and hypoesthesia
10/478 (2%) 0/336 (0%)
Pain 5/478 (1%) 1/336 (0%)
DRUG INTERACTIONS: Drug interaction studies have not been conducted with benzyl alcohol lotion.
RECOMMENDED MONITORING: Patients should be monitored for treatment response. The hair should
be examined for live lice periodically after a course of treatment.
DOSING: Benzyl alcohol lotion should be applied to dry hair. Enough lotion should be used to completely
saturate the scalp and hair. Table 4 provides an estimated amount of lotion to be used per treatment. The
lotion should be left in the hair for 10 minutes and then rinsed off with water. Avoid contact with eyes and
if the lotion does come in contact with the eyes, the eyes should be immediately flushed with water.
Treatment should be repeated in 7 days.
Table 4. Recommended Quantity of Benzyl Alcohol Lotion to Be Prescribed Based on Hair Length
Hair Length
Amount of Lotion per Treatment
Short 0 to 2 in 4 to 6 oz (½ to ¾ bottle)
2 to 4 in 6 to 8 oz (¾ to 1 bottle)
Medium 4 to 8 in 8 to 12 oz (1 to 1½ bottle)
8 to 16 in 12 to 24 oz (1½ to 3 bottles)
Long 16 to 22 in 24 to 32 oz (3 to 4 bottles)
Over 22 in
32 to 48 oz (4 to 6 bottles)
PRODUCT AVAILABILITY/COST and STORAGE: Benzyl alcohol 5% lotion received FDA approval April
9, 2009. It is a white topical lotion containing benzyl alcohol 5%, water, mineral oil, sorbitan monooleate,
polysorbate 80, carbomer 934P, and trolamine. It is supplied in 8-ounce polypropylene bottles.
The cost per 8 ounce bottle is $30.51 AWP
Benzyl alcohol lotion should be stored at controlled room temperature (20° to 25°C; 68° to 77°F) with
excursions permitted between 15° and 30°C (59° and 86°F). The bottles should be protected from
freezing.
CONCLUSION: Benzyl alcohol lotion offers an alternative to traditional pediculocides, with a unique
mechanism of action less prone to resistance. Use with a nit comb should be recommended, as with all
112

pediculocides, to improve outcomes. A flea comb is also effective. Although benzyl alcohol kills lice, it is
not ovicidal and does not get rid of the lice eggs, which necessitates a second treatment 1 week after the
first treatment. Any of these regimens should be used with an overall lice management program including
washing in hot water or dry cleaning of all recently worn clothing, hats, bedding and towels. Personal care
items such as combs, brushes, and hair clips should also be washed in hot water. Both lice and eggs are
killed by exposure for 5 minutes to temperatures greater than 53.5 degrees C (128.3 degrees F). Head
lice survive less than 1-2 days if they fall off a person and cannot feed; nits cannot hatch and usually die
within a week if they are not kept at the same temperature as that found close to the human scalp.
Spending much time and money on housecleaning activities is not necessary to avoid reinfestation by lice
or nits that may have fallen off the head or crawled onto furniture or clothing.
N Engl J Med 2010;362:896-905 Oral Ivermectin versus Malathion Lotion for Difficult-to-Treat Head
Lice a multicenter, cluster-randomized, double-blind, double-dummy, controlled trial comparing oral
ivermectin (at a dose of 400 µg per kilogram of body weight) with 0.5% malathion lotion, each given on
days 1 and 8, for patients with live lice not eradicated by topical insecticide used 2 to 6 weeks before
enrollment. Patients were at least 2 years of age and weighed at least 15 kg; all were treated at the study
sites. The primary end point was the absence of head lice on day 15.
Results: A total of 812 patients from 376 households were randomly assigned to receive either
ivermectin or malathion. In the intention-to-treat population, 95.2% of patients receiving ivermectin were
lice-free on day 15, as compared with 85.0% of those receiving malathion (absolute difference, 10.2
percentage points; 95% confidence interval [CI], 4.6 to 15.7; P

GUANFACINE EXTENDED-RELEASE Tabs - INTUNIV by Shire
INDICATION: INTUNIV is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
The efficacy of INTUNIV was studied for the treatment of ADHD in two controlled clinical trials (8 and 9
weeks in duration) in children and adolescents ages 6 to 17 who met DSM-IV criteria for ADHD. The
effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not been systematically evaluated
in controlled trials.
PHARMACOLOGY: Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a
central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.
Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity
for this receptor subtype than for the alpha2B or alpha2C subtypes.
Guanfacine is a known antihypertensive agent (Tenex). By stimulating alpha2A-adrenergic receptors,
guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood
vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.
It has been suggested by Easton et al. that guanfacine acts on the prefrontal cortex (probably postsynaptically
at alpha- 2 receptors) to increase cognitive and associated functions, known to be
dysfunctional in ADHD sufferers, and also helps in the regulation of locomotor activity via inhibitory
control of subcortical brain regions, particularly the caudate putamen and nucleus
accumbens (Psychopharmacol 2006, 189:369-385). Thus guanfacine appeared to have the ability to 'turn
down' striatal activity, possibly of benefit in the treatment of motoric hyperactivity.
Levy suggests that “the data suggest a possible hierarchy of specificity in the current medications used in
the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal
attentional and working memory deficits. Stimulants may have broader effects on both vigilance and
motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety,
social affect, and sedation via noradrenergic transmission.”(Behavioral and Brain Functions 2008 Feb
28;4:12).
PHARMACOKINETICS: Absorption and Distribution Guanfacine is readily absorbed and approximately
70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV
the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.
Immediate-release guanfacine and INTUNIV have different pharmacokinetic characteristics; dose
substitution on a milligram for milligram basis will result in differences in exposure.
A comparison across studies suggests that the Cmax is 60% lower and AUC0-∞ 43% lower, respectively,
for INTUNIV compared to immediate-release guanfacine. Therefore, the relative bioavailability of
INTUNIV to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults
following the administration of INTUNIV 1 mg once daily and immediate-release guanfacine 1mg once
daily are summarized in Table 4.
Table 4: Pharmacokinetic Parameters in Adults
Parameter
INTUNIV 1 mg once
daily (n=52)
Immediate-release
guanfacine 1 mg once daily
(n=12)
Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6
AUC0-∞ (ng.h/mL) 32 ± 9 56 ± 15
tmax (h) 6.0 (4.0 – 8.0) 3.0 (1.5-4.0)
t½ (h) 18 ± 4 16 ± 3
Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and
adults. After oral administration of multiple doses of INTUNIV 4 mg, the Cmax was 10 ng/mL compared to
7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and
114

adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body
weight of children compared to adolescents and adults.
The pharmacokinetics were affected by intake of food when a single dose of INTUNIV 4 mg was
administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%)
compared to dosing in a fasted state.
Dose Proportionality Following administration of INTUNIV in single doses of 1 mg, 2 mg, 3 mg, and 4 mg
to adults, Cmax and AUC0-∞ of guanfacine were proportional to dose.
Metabolism and Elimination In vitro studies with human liver microsomes and recombinant CYP’s
demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic
microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and
exposure is affected by CYP3A4/5 inducers/inhibitors.
Renal and Hepatic Impairment The impact of renal impairment on PK of guanfacine in children was not
assessed.
CLINICAL DATA: The efficacy of INTUNIV in the treatment of ADHD was established in 2 placebocontrolled
trials in children and adolescents ages 6-17. Study 1 evaluated 2 mg, 3 mg and 4 mg of
INTUNIV dosed once daily in an 8-week, double-blind, placebo-controlled, parallel-group, fixed dose
design (n=345). Study 2 evaluated 1 mg, 2 mg, 3 mg and 4 mg of INTUNIV dosed once daily in a 9-week,
double-blind, placebo-controlled, parallel-group, fixed-dose design (n=324). In Studies 1 and 2, patients
were randomized to a fixed dose of INTUNIV. Doses were titrated in increments of up to 1 mg/week. The
lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs). Patients
who weighed less than 25 kg (55 lbs) were not included in either study.
Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered
and scored ADHD Rating Scale-IV (ADHD-RS), which includes both hyperactive/impulsive and inattentive
subscales. In both studies, the primary outcome was the change from baseline to endpoint in mean
ADHD-RS scores.
The mean reductions in ADHD-RS scores at endpoint were statistically significantly greater for INTUNIV
compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically
significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies,
as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2.
Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted
(mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant
improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12
mg/kg/day were shown to provide additional benefit.
Controlled, long-term efficacy studies (>9 weeks) have not been conducted.
Subgroup analyses were performed to identify any differences in response based on gender or age (6-12
vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis
of gender. Analyses by age subgroup revealed a statistically significant treatment effect only in the 6-12
age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into
these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the
adolescent subgroup. In these studies, patients were randomized to a fixed dose of INTUNIV rather than
optimized by body weight. Therefore, it is likely that some adolescent patients were randomized to a dose
that resulted in relatively low plasma guanfacine concentrations compared to the younger sub-group.
Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which
systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body
weight and plasma guanfacine concentrations.
115

A long-term, open-label extension was conducted to study the safety profile and effectiveness of GXR for
up to 2 years. At the completion of the 8-week fixed-dose escalation study, participating subjects were
eligible to enter this open-label extension designed to assess the long-term safety and effectiveness of
GXR. Subjects included 240 children 6–17 years of age with a diagnosis of ADHD who participated in the
preceding randomized trial. GXR was initiated at 2 mg/day and titrated as needed in 1-mg increments to a
maximum of 4 mg/day to achieve optimal clinical response. Mean duration of exposure to GXR prior to
tapering was 8.8±8.1 months; 32 subjects were exposed for a full 24 months. The most common adverse
events were somnolence (30.4%), headache (26.3%), fatigue (14.2%), and sedation (13.3%).
Somnolence, sedation, and fatigue were usually transient. Cardiovascular-related adverse events were
uncommon, although small reductions in mean blood pressure and pulse rate were evident at monthly
visits. Changes from baseline to endpoint in systolic blood pressure, diastolic blood pressure, and pulse
rate were –0.8 mmHg, –0.4 mmHg, and –1.9 beats per minute (bpm), respectively ADHD Rating Scale,
Version IV, total and subscale scores improved significantly from baseline to endpoint for all dose groups
(P

with TS+ADHD, aged 8 to 16 years. The initial dose was 0.5 mg/day and it could be increased every 3-4
days as clinically indicated and tolerated. Seven of the 10 children were maintained on 1.5 mg/day in 2 or
3 divided doses.The duration of follow-up was 4 to 20 weeks, and the majority of subjects were treated
with 1.5 mg/day. Ratings of tic severity and ADHD symptoms were obtained using the Yale Global Tic
Severity Scale (YGTSS), the Tic Symptom Self Report (TSSR), and the Conners Parent Rating Scale. In
addition, blind Continuous Performance Tests (CPTs) were performed at baseline and at two follow-up
intervals in eight subjects. Results: Guanfacine was associated with significant decreases in both
commission errors (p < .02) and omission errors (p < .01) on the CPT. In addition, guanfacine caused a
significant decrease in severity of motor (p < .02) and phonic (p < .02) tics as measured by the TSSR and
the YGTSS, respectively. The most common side effects were transient sedation and headaches.
Conclusion: Guanfacine may provide a safe alternative therapy for children with ADHD in the presence of
tics. (J. Am. Acad. Child Adolesc. Psychiatry, 1995, 34, 9:1140-1146).
CONTRAINDICATIONS: History of hypersensitivity to INTUNIV, its inactive ingredients, or other products
containing guanfacine (e.g. TENEX).
WARNINGS AND PRECAUTIONS:
• Hypotension, bradycardia, and syncope: Use INTUNIV with caution in patients at risk for
hypotension, bradycardia, heart block, or syncope (e.g., those taking antihypertensives). Measure heart
rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on
therapy. Advise patients to avoid becoming dehydrated or overheated..
• Sedation and somnolence: Occur commonly with INTUNIV. Consider the potential for additive
sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or
driving until they know how they respond to INTUNIV.
• Other guanfacine-containing products: Do not use INTUNIV concomitantly with other products
containing guanfacine (e.g., Tenex)
• Pregnancy Category B
• The safety and efficacy of INTUNIV in pediatric patients less than 6 years of age have not been
established. For children and adolescents 6 years and older, efficacy beyond 9 weeks and safety beyond
2 years of treatment have not been established
ADVERSE EFFECTS:
Table 1: Percentage of Patients Experiencing Common (≥ 2%) Adverse
Reactions in Short-Term Studies 1 and 2
Adverse Reaction Term Placebo (N=149) All Doses of
INTUNIV (N=513)
Somnolencea 12% 38%
Headache 19% 24%
Fatigue 3% 14%
Abdominal pain (upper) 7% 10%
Nausea 2% 6%
Lethargy 3% 6%
Dizziness 4% 6%
Irritability 4% 6%
Hypotension/Decreased blood 4% 6%
pressure
Decreased appetite 3% 5%
Dry mouth 1% 4%
Constipation 1% 3%
Table 3: Percentage of Patients Experiencing Common (≥ 5%) Adverse
Reactions during Long-Term (Up to 10 months), Flexible-dose, Open-
Label Follow-up from Studies 1 and 2
Adverse Reaction Term All Doses of INTUNIV (N=446)
Somnolencea 45%
Headache 26%
117

Fatigue 15%
Abdominal pain (upper) 11%
Hypotension / Decreased Blood
10%
Pressure
Vomiting 9%
Dizziness 7%
Nausea 7%
Weight increased 7%
Irritability 6%
Adverse Reactions Leading to Discontinuation - Eighteen percent (18%) of patients receiving INTUNIV
discontinued from long-term studies due to adverse events. The most frequent adverse reactions leading
to discontinuation (≥ 2%) were somnolence (3%), syncopal events (2%), increased weight (2%),
depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation in the long-term
studies (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure,
sedation, headache, and lethargy.
Serious Adverse Reactions – In long-term open label studies, serious adverse reactions occurring in
more than one patient were syncope (2%) and convulsion (0.4%).
Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV demonstrated similar
growth compared to normative data. Patients taking INTUNIV had a mean increase in weight of 1 kg (2
lbs) compared to those receiving placebo over a comparative treatment period. Patients receiving
INTUNIV for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8
cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the
long-term studies compared to when they began receiving INTUNIV.
DRUG INTERACTIONS: Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5
inducers/inhibitors.
CYP3A4/5 Inhibitors: Use caution when INTUNIV is administered to patients taking ketoconazole and
other strong CYP3A4/5 inhibitors, since elevation of plasma guanfacine concentration increases the risk
of adverse events such as hypotension, bradycardia, and sedation. There was a substantial increase in
the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine
exposure increased 3-fold (AUC).
CYP3A4 Inducers: When patients are taking INTUNIV concomitantly with a CYP3A4 inducer, an increase
in the dose of INTUNIV within the recommended dose range may be considered. There was a significant
decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4
inducer. The exposure to guanfacine decreased by 70% (AUC).
Valproic Acid: Co-administration of guanfacine and valproic acid can result in increased concentrations of
valproic acid. The mechanism of this interaction is unknown, although both guanfacine (via a Phase I
metabolite, 3-hydroxy guanfacine) and valproic acid are metabolized by glucuronidation, possibly
resulting in competitive inhibition. When INTUNIV is coadministered with valproic acid, monitor patients
for potential additive CNS effects, and consider monitoring serum valproic acid concentrations.
Adjustments in the dose of valproic acid may be indicated when co-administered with INTUNIV.
Antihypertensive Drugs: Use caution when INTUNIV is administered concomitantly with antihypertensive
drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope)
CNS Depressant Drugs: Caution should be exercised when INTUNIV is administered concomitantly with
CNS depressant drugs (e.g. alcohol, sedative/hypnotics, benzodiazepines, barbiturates, and
antipsychotics) due to the potential for additive pharmacodynamic effects (e.g., sedation, somnolence).
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HOW SUPPLIED/COST/STORAGE AND HANDLING:
INTUNIV is
1 mg 2 mg 3 mg 4 mg
supplied in 1 mg,
2 mg, 3 mg, and
4 mg strength
extended-release
tablets in 100
count bottles.
Color White/off-white White/off-white Green Green
Shape Round Caplet Round Caplet
Debossment 503 / 1mg 503 / 2mg 503 / 3mg 503 / 4mg
(top/bottom)
NDC number 54092-513-02 54092-515-02 54092-517-02 54092-519-02
Cost: $145.98/30 tablets
Generic guanfacine tablets (Not the extended release) 1 mg $20.98/30 tabs, 2 mg $25.98/30
DOSAGE: INTUNIV is an extended-release tablet and should be dosed once daily. Tablets should not be
crushed, chewed or broken before swallowing because this will increase the rate of guanfacine release.
Do not administer with high fat meals, due to increased exposure.
Do not substitute for immediate-release guanfacine tablets on a mg-mg basis, because of differing
pharmacokinetic profiles. INTUNIV has a delayed Tmax, reduced Cmax and lower bioavailability
compared to those of the same dose of immediate-release guanfacine.
Dose Selection: If switching from immediate-release guanfacine, discontinue that treatment, and titrate
with INTUNIV according to the following recommended schedule.Begin at a dose of 1 mg/day, and adjust
in increments of no more than 1 mg/week. Maintain the dose within the range of 1-4 mg once daily,
depending on clinical response and tolerability. In clinical trials, patients were randomized to doses of 1
mg, 2 mg, 3 mg or 4 mg and received INTUNIV once daily in the morning. Clinically relevant
improvements were observed beginning at doses in the range 0.05 to 0.08 mg/kg once daily. Efficacy
increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once
daily may provide additional benefit. Doses above 4 mg/day have not been studied.
In clinical trials, there were dose-related and exposure-related risks for several clinically significant
adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to
dosing INTUNIV on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of
treatment.
Maintenance Treatment: The effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not
been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient.
Discontinuation: In a pharmacodynamic study in healthy young adult volunteers receiving INTUNIV (4 mg
once daily) or placebo, the effects of abrupt discontinuation were compared to tapering. There were
greater mean increases in systolic and diastolic blood pressure and heart rate after abrupt discontinuation
of INTUNIV, but these changes generally reflected a return to original baseline and were not meaningfully
different for the two discontinuation strategies. However, infrequent, transient elevations in blood pressure
above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of
guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more
than 1 mg every 3 to 7 days.
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Missed Doses: When reinitiating patients to the previous maintenance dose after two or more missed
consecutive doses, physicians should consider titration based on patient tolerability.
SUMMARY: The Practice Parameter for the Assessment and Treatment of Children and Adolescents
With Attention-Deficit/Hyperactivity Disorder (Journal of the American Academy of Child & Adolescent
Psychiatry 2007; 46: 894-921)
Selection of Agent:
“The clinician and family face the choice of which agent to use for the initial treatment of the patient with
ADHD. The American Academy of Pediatrics (2001), an international consensus statement (Kutcher et
al., 2004), and the Texas Children's Medication Project (Pliszka et al., 2006a) have recommended
stimulants as the first line of treatment for ADHD, particularly when no comorbidity is present. Direct
comparisons of the efficacy of atomoxetine with that of MPH (Michelson, 2004) and amphetamine (Wigal
et al., 2004) have shown a greater treatment effect of the stimulants, and in a meta-analysis of
atomoxetine and stimulant studies, the effect size for atomoxetine was 0.62 compared with 0.91 and 0.95
for immediate-release and long-acting stimulants, respectively (Faraone et al., 2003). However,
atomoxetine may be considered as the first medication for ADHD in individuals with an active substance
abuse problem, comorbid anxiety, or tics. Atomoxetine is preferred if the patient experiences severe side
effects to stimulants such as mood lability or tics (Biederman et al., 2004). When dosed twice daily,
effects on late evening behavior may be seen.”
“It is the sole choice of the family and the clinician as to which agent should be used for the patient's
treatment, and each patient's treatment must be individualized. Nothing in these guidelines should be
construed by third-party payers as justification for requiring a patient to be a treatment failure (or
experience side effects) to one agent before allowing the trial of another.”
This document also states “ [alpha]-Agonists (clonidine and guanfacine) have been widely prescribed for
patients with ADHD, for the disorder itself, for comorbid aggression, or to combat side effects of tics or
insomnia. Extensive controlled trials of these agents are lacking. Connor et al. (1999) performed a metaanalysis
of 11 studies of clonidine in the treatment of ADHD. The studies were highly variable in both
method and outcome, and open-label studies showed a larger effect than controlled studies.
Nevertheless, the review suggested a small to moderate effect size for clonidine in the treatment of
ADHD. One small double-blind trial showed the superiority of guanfacine over placebo in the treatment of
children with ADHD and comorbid tics (Scahill et al., 2001). A gradual titration is required and clinical
consensus suggests the [alpha]-agonists are more successful in treating hyperactive/impulsive symptoms
than inattention symptoms, although this remains to be proven by clinical trials. In recent years clinical
consensus has led to the use of clonidine as adjunctive therapy to treat tics or stimulant-induced insomnia
rather than as a primary treatment for ADHD. If the [alpha]-agonist is deemed ineffective after an
adequate trial, the medication should be tapered gradually over 1 to 2 weeks to avoid a sudden increase
in blood pressure.”
Based upon non-comparative trials improvements in ADHD scores appear to be comparable to
atomoxetine at lower doses and similar to stimulants at higher doses but we need head to head
comparisons. There is also very limited data with use of combination therapy with guanfacine ER and
psychostimulants which suggest a reduction in some the adverse effects. The place in therapy for this
new agent is still to be determined.
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Pitavastatin - Livalo by Kowa and Lilly (FDA approved 8-3-2009 but still not marketed)
INDICATIONS: Pitavastatin is indicated for patients with primary hyperlipidemia and mixed dyslipidemia
as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B (apo B), triglycerides (TG), and to increase high-density lipoprotein
cholesterol (HDL-C). Pitavastatin has not been studied in Fredrickson type I, III, or V dyslipidemia. The
effect of pitavastatin on cardiovascular morbidity and mortality has not been determined.
CLINICAL PHARMACOLOGY: Pitavastatin is a synthetic competitive lipophilic 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. In addition to effects on lipid parameters,
preliminary studies suggest pitavastatin may reduce bone resorption (Intern Med. 2007;46(24):1967-
1973).
PHARMACOKINETICS: Following oral administration, pitavastatin peak concentration (C max ) is reached
in about 1 hour. Oral bioavailability is 51%. Administration with a high-fat meal reduced the C max by 43%
but did not affect overall exposure. The pitavastatin elimination half-life is 10 to 12 hours. Pitavastatin is
marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major metabolite in human
plasma is the lactone which is formed via an ester-type pitavastatin glucuronide conjugate by uridine 5'-
diphosphate (UDP) glucuronosyltransferase (UGT1A3 and UGT2B7). Lactonization is the major metabolic
pathway. Approximately 15% of the dose is excreted in the urine and 79% in the feces. In patients with
moderate renal impairment (glomerular filtration rate 30 to 60 mL/min per 1.73 m 2 ) and end-stage renal
disease (ESRD) receiving hemodialysis, pitavastatin area under the curve (AUC) is 79% and 86% higher
than those of healthy volunteers, respectively, and the C max is 60% and 40% higher, respectively.
Pitavastatin pharmacokinetics have not been assessed in patients with mild renal impairment or severe
renal impairment not receiving hemodialysis. In patients with mild to moderate hepatic impairment (Child-
Pugh A and B), plasma concentrations of pitavastatin are increased.
Dose-Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from
Baseline at Week 12)
Treatment N# LDL-C Apo-B TC TG HDL-C
Placebo 53 -3 -2 -2 1 0
LIVALO 1mg 52 -32 -25 -23 -15 8
LIVALO 2mg 49 -36 -30 -26 -19 7
LIVALO 4mg 51 -43 -35 -31 -18 5
Pitavastatin vs Atorvastatin: Mean Change From Baseline to Week 12
in Patients With Type 2 Diabetes
Treatment LDL-C Apo B TC TG HDL-C
Pitavastatin 4 mg (n = 274) −41% −32% −28% −20% 7%
Atorvastatin 20 mg (n = 136) −43% −34% −32% −27% 8%
Pitavastatin vs Simvastatin: Mean Change From Baseline to Week 12
Treatment LDL-C Apo B TC TG HDL-C
Pitavastatin 2 mg (n = 307) −39% −30% −28% −16% 6%
Pitavastatin 4 mg (n = 319) −44% −35% −32% −17% 6%
Simvastatin 20 mg (n = 107) −35% −27% −25% −16% 6%
Simvastatin 40 mg (n = 110) −43% −34% −31% −16% 7%
ADVERSE REACTIONS: Pitavastatin was well tolerated in clinical trials, with an incidence of adverse
events similar to the comparator statins and placebo. The most frequent adverse effects, occurring in at
least 2% of patients receiving one of the available doses, were myalgia (1.9%, 2.8% and 3.1% on 1, 2
and 4 mg doses at 12 weeks) , back pain, diarrhea, constipation, and pain in extremity. Hypersensitivity
121

eactions, including rash, pruritus, and urticaria, have been reported with the use of pitavastatin. In
controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of
pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse
reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg)
and myalgia (0.5% on 4 mg).
DRUG INTERACTIONS: Several agents (cyclosporine, rifampicin, rifamycin, clarithromycin, and
indinavir) have the potential to interact with the organic anion transporting polypeptide 1B1–mediated
uptake of pitavastatin. Cyclosporine significantly increased pitavastatin exposure, and coadministration is
contraindicated. With concomitant cyclosporine, pitavastatin C max was increased 6.6-fold and the AUC
was increased 4.6-fold. Concurrent erythromycin increases pitavastatin exposure. Pitavastatin C max was
increased 3.6-fold and the AUC was increased 2.8-fold. With concurrent erythromycin, the pitavastatin
dosage should be limited to 1 mg once daily. Concurrent rifampin increases pitavastatin exposure.
Pitavastatin C max was increased 2-fold and the AUC was increased 29%. With concurrent rifampin, the
pitavastatin dosage should be limited to 2 mg once daily. Use with fibrates or niacin may increase the risk
of adverse skeletal muscle effects.
DOSING: Pitavastatin is administered orally once daily, with or without food, at any time of day. The
dosage range is 1 to 4 mg once daily. The recommended starting dose for patients with primary
hyperlipidemia and mixed dyslipidemia is 2 mg. The maximum dosage is 4 mg per day. Doses greater
than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical
studies. Do not exceed 4 mg once daily dosing of LIVALO.
In patients with moderate renal impairment (glomerular filtration rate, 30 to 60 mL/min/1.73 m 2 ) or ESRD
on hemodialysis, the recommended starting dosage is 1 mg once daily and the maximum dosage is 2 mg
once daily.
PRODUCT AVAILABILITY and STORAGE: Pitavastatin received Food and Drug Administration
approval on August 3, 2009. It is available as 1, 2, and 4 mg tablets supplied in bottles of 90 tablets.
Pitavastatin has been available in Japan since 2003 and in Korea since 2005.
CONCLUSION: Pitavastatin appears to improve lipid parameters to an extent similar to atorvastatin and
simvastatin; however, clinical outcome studies have not yet been reported.
122

Sipuleucel – T - Provenge by Dendreon Corp (FDA qpproved 4-29-2010)
INDICATION: An autologous cellular immunotherapy indicated for the treatment of minimally symptomatic
or asymptomatic metastatic castrate resistant (hormone refractory) prostate cancer.
CLINICAL PHARMACOLOGY: PROVENGE (sipuleucel-T) is an autologous cellular immunotherapy
designed to stimulate a patient’s own immune system against cancer, it has been called the first
personalized treatment for cancer. PROVENGE is manufactured in several steps. First the patient’s
blood is run through a machine in a process known as leukapheresis. During the process, some of the
patient’s immune cells are collected. These immune cells are then exposed to a protein intended to
stimulate and direct them against prostate cancer. Following this exposure, the activated immune cells
are then returned to the patient to treat the prostate cancer. The active components of PROVENGE are
autologous antigen presenting cells (APCs) and the protein called PAP-GM-CSF. APCs are activated
during a defined culture period with a recombinant human protein, PAP-GM-CSF, consisting of prostatic
acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocytemacrophage
colony-stimulating factor (GM-CSF), an immune cell activator. It is designed to induce an
immune response targeted against PAP, an antigen expressed in most prostate cancers. The cellular
composition of PROVENGE will vary, depending on the cells obtained from the individual patient during
leukapheresis. In addition to the APCs, the product also contains T cells, B cells, natural killer (NK) cells,
and other cells.
CLINICAL DATA: The effectiveness of PROVENGE was studied in 512 patients with metastatic castrate
resistant (hormone refractory) prostate cancer in a randomized, double-blind, placebo-controlled,
multicenter trial. The study showed an increase in overall survival of approximately 4 months for patients
receiving PROVENGE treatments as compared to the control group (IE 25 months on average vs. 21
momnths in the placebo group).
ADVERSE EFFECTS: Common adverse reactions reported during a safety evaluation of 601 patients
who received PROVENGE were chills (53%), fatigue (41%), fever (31%), back pain (30%), nausea (22%),
joint ache (20%) and headache (18%). The majority of adverse reactions were mild or moderate in
severity. Serious adverse reactions that were reported in patients receiving PROVENGE included some
acute infusion reactions and stroke (3.5% vs. 2.6%). Only 1.5% of patients stopped the drug because of
adverse effects. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an
acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of
patients reporting acute infusion reactions, the events were mild or moderate. Fevers and chills generally
resolved within 2 days (71.9% and 89.0%, respectively).
DOSAGE/ADMINISTRATION: Each dose of PROVENGE contains a minimum of 50 million autologous
CD54 + cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer’s Injection, USP in a
sealed, patient-specific infusion bag. Remove the PROVENGE infusion bag from the insulated shipping
container and inspect the bag for signs of leakage. Contents of the bag will be slightly cloudy, with a
cream-to-pink color. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots.
Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag
leaks or if clumps remain in the bag. Infusion must begin prior to the expiration date and time indicated on
the Cell Product Disposition Form and Product Label. Do not initiate infusion of expired PROVENGE.
Once the PROVENGE infusion bag is removed from the insulated container, it should remain at room
temperature for no more than 3 hours.
PROVENGE is administered intravenously in a three-dose schedule at approximately two week intervals.
Each dose is preceded by the leukapheresis procedure approximately three days prior to the scheduled
treatment, and is administered only to the patient from whom the cells were obtained. Administer
PROVENGE via intravenous infusion over a period of approximately 60 minutes. Do not use a cell filter.
PROVENGE is supplied in a sealed, patient-specific infusion bag; the entire volume of the bag should be
infused. Observe the patient for at least 30 minutes following each infusion
Dendreon toll-free number: 1-877-336-3736
Within the first year of FDA approval, Dendreon anticipates being able to manufacture PROVENGE
to support the treatment of about 2,000 patients. At launch, treatment will be available through
approximately 50 centers across the country previously approved as clinical trial sites. Cost is
expected to be between $50,000 and $90,000 per patient.
123

Summary of
the Pearl
Indexes and
the Cumulative
Contraceptive
Failure Rates
Study
Estradiol valerate and estradiol valerate/dienogest) tablets - Natazia by Bayer
(FDA approved 5-6-2010)
INDICATION: Nataziz is the first four-phasic oral contraceptive marketed in the United States. Fourphasic
refers to the doses of progestin and estrogen varying at four times throughout each 28-day
treatment cycle.
CLINICAL PHARMACOLOGY:
Natazia consists of 28 film-coated, unscored tablets in the following order:
2 dark yellow tablets each containing 3 mg estradiol valerate
5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
2 dark red tablets each containing 1 mg estradiol valerate
2 white tablets (inert)
The contraceptive effect of C OCs is based on the interaction of various factors, the most important of
which are the inhibition of ovulation and the changes in the cervical secretion. The estrogen in Natazia is
estradiol valerate, a synthetic prodrug of 17ß-estradiol.
The progestin in Natazia is dienogest (DNG). DNG displays properties of 19-nortestosterone derivatives
as well as properties associated with progesterone derivatives.
CLINICAL DATA:
Age
Group
Relative Treatment
Exposu re Cycles1
Number of
Pregnancies within
13 Cycles and 7
Days after Last
Treatment
Pearl Index
Upper Limit
of 95% CI
Contraceptive
Failure Rate at
the end of the
First Year
North America 18–35 3,969 5 1.64 3.82 0.016
Europe 18–35 11,275 9 1.04 1.97 0.010
Based on the results of two clinical studies, 1 to 2 women out of 100 women, may get pregnant during the
first year they use Natazia.
DRUG INTERACTIONS: Dienogest is a substrate of cytochrome P450 (CYP) 3A4. Women who take
medications that are strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and
St. John’s wort) should not choose Natazia as their oral contraceptive while using these inducers and for
at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive
efficacy.
WARNINGS:
Box Warning to Women who Smoke: Do not use Natazia if you smoke cigarettes and are over 35 years
old. Smoking increases your risk of serious cardiovascular side effects (heart a nd blood vessel problems)
from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with
age and the number of cigarettes you smoke.
ADVERSE EFFECTS:
Adverse Reactions Leading to Study Discontinuation: 11.5% of the women discontinued from the
clinical trials due to an adverse reaction; the most frequent a dverse reactions leading to discontinuation
were metrorrhagia and irregular menstruation (1.9%), acne (1.2%), headache and migraine (1.0%), and
weight increase (0.7 %).
Common Treatment-Emergent Adverse Reactions (≥ 2%): headache (including migraines) (13.2%),
metrorrhagia and irregular menstruation (8.0%), breast pain, discomfort or tenderness (6.6% ), nausea or
vomiting (6.5%), acne (3.9%) and increased weight (2.8%).
Serious Adverse Reactions: deep vein thrombosis, myocardial infarction, focal nodular hyperplasia of
the liver, uterine leiomyoma, and ruptured ovarian cyst.
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Women who are not pregnant and use Natazia, may experience amenorrhea. Based on patient diaries,
amenorrhea occurs in approximately 16% of cycles in women using Natazia. Pregnancy should be ruled
out in the event of amenorrhea occurring in two or more consecutive cycles. Based on patient diaries
from three clinical trials eva luating the safety and efficacy of Natazia, 10-23% of women experienced
intracyclic bleeding per cycle. A total of 38 subjects out of 2,266 (1.7%) discontinued due to metrorr hagia
or irregular menstruation.
DOSAGE/ADMINISTRATION:
When to Start Natazia If you start taking Natazia and you did not use a hormonal birth control
method before:
• Take the first dark yellow pill on the first day (Day 1) of your natural me nstrual cycle. The first day
of your menstrual cycle is the first day you start spotting or bleeding.
• Use non-hormonal back-up contraception such as a condom or spermicide for the first 9 days that
you take Natazia.
If you start taking Natazia and you are switching from a combination hormonal method such as:
• another pill
• vaginal ring
• patch
• Take the first dark yellow pill on the first day of your period. Do not continue taking the pills from
your previous birth control pack. If you do not have a period, contact your healthcare provider before you
start Natazia.
• If you previously used a vaginal rin g or transdermal patch, you should start using Natazia on the
day the ring or patch is removed.
• Use a non-hormonal back-up method such as a condom or spermicide for the first 9 days you
take Natazia.
If you start taking Natazi a and you are switching from a progestin-only method such as a:
• progestin-only pill
• implant
• intrauterine system
• injection
• Take the first dark yellow pill on the day you would have taken your next progestin-only pill or on
the day of removal of your implant or intrauterine system or on the day when you would have had your
next injection.
• Use a non-hormonal back-up method such as a condom or spermicide for the first 9 days you
take Natazia.
What Should I Do if I Miss any Pills
If you forgot to start a new blister pack, you may already be pregnant. Use back-up contraception (such
as condoms and spermicides) anytime you have sex. Call your healthcare provider if you are unsure
whether you are pregnant.
• Do not take more than 2 pills in one day. On the days y ou take 2 pills to make up for missed pills,
you may feel a little sick to your stomach (nauseous).
• If you start vomiting or have diarrhea with in 4 hours of taking your pill, take another pill of the
same color from your extra blister pack.
If you are less than 12 hours late taking your pill
• Take your pill as soon as you remember
• Take the next pill at the usual time
• You do not need to use back-up contraception
If you miss ONE PILL for more than 12 hours Days 1–17
• Take your missed pill immediately
• Take your next pill at the usual time (you may have to take two pills that day)
• Use back-up contraception for the next 9 days
• Continue taking one pill each day at the same time for the rest of your cycle
125

Days 18–24
• Do not take any pills from your current blister pack and throw the pack away
• Take Day 1 pill from a new blister pack
• Use back-up contraception for the next 9 days
• Continue taking one pill from the new blister pack at the same time each day
Days 25–28
• Take your missed pill immediately
• Take your next pill at the usual time (you may have to take two pills that day)
• No back-up contraception is needed
• Continue taking one pill each day at the same time for the rest of your cycle
If you miss TWO PILLS in a row
Days 1–17 (if you miss the pills for Days 17 and 18, follow the instructions for Days 17–25 instead)
• Do not take the missed pills. Instead, take the pill for the day on which you fir st noticed you had
missed pills.
• Use back-up contraception for the next 9 days
• Continue taking one pill each day at the same time for the rest of your cycle
Days 17–25 (if you miss the pills for Days 25 and 26, follow the instructions for Days 25–28
instead)
• Do not take any pills from your current blister pack and throw the pack away
• Take Day 3 pill from a new blister pack
• Use back-up contraception for the next 9 days
• Continue taking one pill from the new blister pack at the same time each day
Days 25–28
• Do not take any pills from your current blister pack and throw the pack away
• Start a new pack on the same day or start a new pack on the day you usually start a new pack
• No back-up contraception is needed
• Continue taking one pill from the new pack at the same time each da y, for the rest of your cycle
126

Ketorolac tromethamine Nasal Spray- Sprix by Roxro Pharma
(FDA Approved 5-14-2010)
INDICATION: SPRIX is indicated in adult patients for the short term (up to 5 days) management of
moderate to moderately severe pain that requires analgesia at the opioid level. Do not use SPRIX
concomitantly with other formulations of ketorolac or other NSAIDs The3 drug has not been shown to be
safe and effective in pediatric patients 17 years of age and younger.
PHARMACOKINETICS: The intranasal dosage of 31.5 mg produces a C-Max that is between the C-max
produced by the IM administration of the drug at doses of 15 to 30 mg with a similar t-max of about 0.75
hr, the elimination half life is also similar at 5-6 hours.
CLINICAL DATA:
The effect of SPRIX on acute pain was evaluated in two multi-center, randomized, double-blind,
placebocontrolled studies. In a study of adults who had undergone elective abdominal or orthopedic
surgery, 300 patients were randomized and treated with SPRIX or placebo administered every 8 hours
and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was
demonstrated as a statistically significant greater reduction in the summed pain intensity difference over
48 hours in patients who received SPRIX as compared to those receiving placebo. The clinical relevance
of this is reflected in the finding that patients treated with SPRIX required 36% less morphine over 48
hours than patients treated with placebo.
In a study of adults who had undergone elective abdominal surgery, 321 patients were randomized and
treated with SPRIX or placebo administered every 6 hours and morphine administered via patient
controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant
greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX
as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that
patients treated with SPRIX required 26% less morphine over 48 hours than patients treated with
placebo.
BOX WARNING: Limitations of Use-GASTROINTESTINAL, BLEEDING,
CARDIOVASCULAR, and RENAL RISK the same as with all NSAIDs
Adverse Effects: Based upon data in 455 patients with up to 5 days of therapy:
Nasal discomfort 15%; rhinalgia 13%; lacrimation increased 5%; throat irritation 3%; oliguria 3% and rash
3%.In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal
hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of
bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%)
treated with placebo (hematoma).
Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30
weeks gestation. SPRIX can cause fetal harm when administered to a pregnant woman. Human data
demonstrate that use of NSAIDs at or after 30 weeks gestation increases the risk of premature closure of
the ductus arteriosus.
CONTRAINDICATIONS:
• Known hypersensitivity to ketorolac, aspirin, other NSAIDs, or
• Use in patients with active peptic ulcer disease, recent GI bleeding or perforation, or a history of peptic
ulcers or GI bleeding
• Use in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or
other NSAIDs
• Use as a prophylactic analgesic before any major surgery
• Use during the perioperative period in the setting of coronary artery bypass graft (CABG) surgery
DOSAGE/ADMINISTRATION: Adult Patients < 65 Years of Age Dosage:
The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The
maximum daily dose is 126 mg (four doses).
Reduced Doses for Special Populations:
127

For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the
recommended dose is 15.75 mg SPRIX (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The
maximum daily dose is 63 mg (four doses)
HOW SUPPLIED:Preservative-free SPRIX Nasal Spray is supplied in boxes containing 1 single-day nasal
spray bottle or 5 single-day nasal spray bottles.. Each single day nasal spray bottle contains a sufficient
quantity of solution to deliver 8 sprays for a total of 126 mg of
ketorolac tromethamine. Each spray delivers 15.75 mg of ketorolac tromethamine. The delivery system is
designed to administer precisely metered doses of 100 µL per spray. Store unopened SPRIX between
36°F and 46°F (2°C and 8°C). During use, keep containers of SPRIX Nasal Spray at controlled room
temperature, between 59°F and 86°F
(15°C and 30°C) out of direct sunlight. Bottles of SPRIX should be discarded within 24 hours of priming.
Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24
hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if
the bottle still contains some liquid.
128

DENOSUMAB – Prolia by Amgen
INDICATIONS: Denosumab is indicated for the treatment of postmenopausal women with osteoporosis at
high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or
patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal
women with osteoporosis, Denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures
Denosumab is undergoing evaluation for use in the treatment of several conditions associated with bone
loss, including rheumatoid arthritis, and cancer treatment–induced bone loss in breast cancer and
prostate cancer patients, as well as to delay bone metastases and inhibit and treat bone destruction
associated with cancer.
CLINICAL PHARMACOLOGY: Denosumab is a fully human monoclonal antibody to the receptor
activator of nuclear factor-kappa B ligand (RANKL). RANKL is a mediator of osteoclast formation,
function, and survival. RANKL binds to its receptor (RANK) on the surface of precursor and mature
osteoclasts, and stimulates these cells to mature and resorb bone. Denosumab binds with high specificity
and affinity to RANKL, inhibiting osteoclast-mediated bone resorption and osteoclast maturation and
survival. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival,
thereby decreasing bone resorption and increasing bone mass and strength in both cortical and
trabecular bone.
In clinical studies, treatment with 60 mg of denosumab resulted in reduction in the bone resorption marker
serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by
1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39-68% of subjects 1-3
months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially
attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab
levels diminished, reflecting the reversibility of the effects of denosumab on bone remodeling. These
effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by
denosumab was similar to that observed in patients initiating denosumab treatment.
PHARMACOKINETICS: Denosumab has exhibited nonlinear, dose-dependent pharmacokinetics.
Following subcutaneous administration, denosumab serum levels are detectable as early as 1 hour after
administration and reach maximum serum concentrations between 3 and 29 days. Serum levels 70% to
80% of maximum occur within 72 hours after administration.
The mean half-life is 25 to 46 days. No accumulation or change in denosumab pharmacokinetics with
time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.
The pharmacokinetics of denosumab was not affected by age across all populations studied whose ages
ranged from 28-87 years. The pharmacokinetics of denosumab was not affected by gender or race.
In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree
of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal
impairment is not necessary.
COMPARATIVE EFFICACY:
Postmenopausal osteoporosis FDA Approved
Denosumab was evaluated in a randomized, double-blind, placebo-controlled study enrolling 332
postmenopausal women with lumbar spine bone mineral density (BMD) T-scores between −1 and −2.5
(mean, −1.61) and no history of fracture after the age of 25 years. Mean patient age was 59.4 years,
mean time since onset of menopause was 10 years, and most patients were white (83%). Patients
received subcutaneous placebo (166 patients) or denosumab 60 mg (166 patients) every 6 months for 2
years, with randomization stratified by time since onset of menopause (5 years or less, 162 patients;
more than 5 years, 170 patients). All women also received calcium 1,000 mg/day and vitamin D
supplementation 400 or 800 units/day based on baseline serum 25-hydroxyvitamin D levels. The
numbers of patients who completed the trial were 144 in the placebo group and 142 in the denosumab
group. The primary end point, the percent change in lumbar spine BMD by dual energy x-ray
absorptiometry at 24 months, was a 6.5% increase in the denosumab group compared with a 0.6%
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decline in the placebo group (P < 0.0001). Results were similar in both strata. BMD was also increased at
the total hip (3.4% vs −1.1%), one-third radius (1.4% vs −2.1%), and total body (2.4% vs −1.4%) with
denosumab compared with placebo (P < 0.0001). Lumbar spine BMD was increased in 96% of patients in
the denosumab group compared with 39% in the placebo group (P < 0.0001). Markers of bone turnover
were decreased with denosumab compared with placebo. Levels of C-telopeptide type 1 (CTX-1) were
reduced 89% from baseline in the denosumab group at 1 month, compared with a 3% reduction in the
placebo group (P < 0.0001). Continued CTX-1 suppression was maintained with reductions from baseline of
63% to 88%. Clinical fractures occurred in 4% of patients in the placebo group and 1% in the denosumab
group. (J Clin Endocrinol Metab. 2008;93(6):2149-2157).
The primary efficacy trial that lead to FDA approval was completed in 7868 women between the ages of
60 and 90 years who had a bone mineral density T score of less than −2.5 but not less than −4.0 at the
lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab
or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral
fracture. Secondary end points included nonvertebral and hip fractures.
Results: As compared with placebo, denosumab reduced the risk of new radiographic vertebral
fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group
(risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P

71% for the pooled denosumab groups and 79% for the bisphosphonate group. Overall, 74% (157/211) of
denosumab-treated patients achieved a reduction of 65% or more compared with 63% (27/43) of
bisphosphonate-treated patients. Skeletal-related events (fracture, surgery or radiation to bone, or spinal
cord compression) occurred in 9% (20/211) of denosumab-treated patients compared with 16% (7/43) of
bisphosphonate-treated patients; the most common event was fracture (Ann Rheum Dis. 2007;66(suppl
2):abstract 428).
The effects of denosumab were also assessed in a randomized study enrolling 111 patients with bone
metastases from prostate (50 patients), breast (46 patients), or other cancers or myeloma (15 patients)
and elevated urinary NTX during IV bisphosphonate treatment. The median time of prior bisphosphonate
therapy was 5.3 months. Patients received continued bisphosphonate IV every 4 weeks (37 patients) or
subcutaneous denosumab 180 mg every 12 weeks (36 patients) or every 4 weeks (38 patients). The
primary study end point, the proportion of patients with urinary NTX less than 50 nM BCE/mM creatinine
at week 13, was achieved in 71% of denosumab-treated patients compared with 29% of patients treated
with continued bisphosphonates (P < 0.001). Similar results were observed at week 25 (64% with
denosumab vs 37% with bisphosphonate) (J Clin Oncol. 2008;26(suppl):abstract 3596).
Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone
loss and an increased risk of fracture. Amgen investigated the effects of denosumab, a fully human
monoclonal antibody against receptor activator of nuclear factor-κB ligand, on bone mineral density and
fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.
Methods
In this double-blind, multicenter study, they randomly assigned patients to receive denosumab at a dose
of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point
was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points
included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at
all three sites at 36 months, as well as incidence of new vertebral fractures.
Results
At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group
as compared with a loss of 1.0% in the placebo group (P

no effect on joint space narrowing or measures of rheumatoid arthritis disease activity (Arthritis Rheum.
2008;58(5):1299-1309).
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS: REMS/Medication Guide
Hypocalcemia may be exacerbated by the use of denosumab.. Pre-existing hypocalcemia must be
corrected prior to initiating therapy with denosumab. In patients predisposed to hypocalcemia and
disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid
surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [creatinine
clearance < 30 mL/min] or receiving dialysis), clinical monitoring of calcium and mineral levels
(phosphorus and magnesium) is highly recommended
Hypocalcemia following denosumab administration is a significant risk in patients with severe renal
impairment [creatinine clearance < 30 mL/min], or receiving dialysis. Instruct all patients with severe renal
impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance
of maintaining calcium levels with adequate calcium and vitamin D supplementation
Denosumab should be considered contraindicated in patients with a known history of hypersensitivity
reaction to denosumab.
Serious Infections In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious
infections leading to hospitalization were reported more frequently in the denosumab group than in the
placebo group Serious skin infections, as well as infections of the abdomen, urinary tract, and ear,
were more frequent in patients treated with denosumab. Endocarditis was also reported more frequently
in denosumab treated subjects. The incidence of opportunistic infections was balanced between placebo
and densoumab groups, and the overall incidence of infections was similar between the treatment
groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe
infection, including cellulitis.
Patients on concomitant immunosuppressant agents or with impaired immune systems may be at
increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with
denosumab. In patients who develop serious infections while on denosumab,
Dermatologic Adverse Reactions In a large clinical trial of over 7800 women with postmenopausal
osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at
a significantly higher rate in the denosumab group compared to the placebo group. Most of these events
were not specific to the injection site. Consider discontinuing Prolia if severe symptoms develop
Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally
associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in
patients receiving denosumab.. A routine oral exam should be performed by the prescriber prior to
initiation of denosumab treatment. A dental examination with appropriate preventive dentistry should be
considered prior to treatment with denosumab in patients with risk factors for ONJ such as invasive dental
procedures (e.g., tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant
therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g.,
periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures).
Good oral hygiene practices should be maintained during treatment with denosumab.
Suppression of Bone Turnover In clinical trials in women with postmenopausal osteoporosis, treatment
with denosumab resulted in significant suppression of bone remodeling as evidenced by markers of bone
turnover and bone histomorphometry The significance of these findings and the effect of long-term
treatment with denosumab are unknown. The long-term consequences of the degree of suppression of
bone remodeling observed with denosumab may contribute to adverse outcomes such as osteonecrosis
of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.
ADVERSE REACTIONS: In the large pivotal trial in 7800 plus women, the incidence of all-cause
mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the denosumab group. The
incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the
denosumab group. The percentage of patients who withdrew from the study due to adverse events was
2.1% and 2.4% for the placebo and denosumab groups, respectively
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The most frequently observed adverse reactions in denosumab studies have included upper respiratory
tract infection, arthralgia, back pain, nasopharyngitis, extremity pain, hypertension, influenza-like illness,
urinary tract infection (4.9% vs 4.3%), gastroesophageal reflux disease (2.1% vs 1.7%), upper abdominal
pain (3.3% vs 2.9%), peripheral edema (4.9% vs 4.0%), hypercholesterolemia (7.2% vs 6.1%), bone pain
(3.7% vs 3.0%), myalgia (2.9% vs 2.4%), sciatica (4.6% vs 3.8%) and rash (2.5% vs 2.0%).
Adverse reactions did not differ in frequency between denosumab- and placebo-treatment groups
DRUG INTERACTIONS: Drug interactions have not been described or evaluated to date
RECOMMENDED MONITORING: BMD should be monitored periodically to assess response to therapy.
DOSING:. The recommended dose of denosumab is 60 mg administered as a single subcutaneous
injection once every 6 months. Administer denosumab via subcutaneous injection in the upper arm, the
upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU
vitamin D daily
PRODUCT AVAILABILITY/ COST and STORAGE: Denosumab – Prolia is available in two formulations
- 1 mL of a 60 mg/mL solution in a single-use prefilled syringe and as 1 mL of a 60 mg/mL solution in a
single-use vial Prior to administration, Prolia may be removed from the refrigerator and brought to room
temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30
minutes. Do not warm Prolia in any other way Do Not shake or freeze this medication. Cost: $825.00 per
60 mg dose WAC or about $1,650 per patient per year plus the cost of administration.
CONCLUSION: Denosumab offers a unique mechanism of action in increasing BMD and reducing bone
turnover, suggesting a variety of potential uses, including osteoporosis treatment and prevention. It
effectively increases BMD in postmenopausal women, as well as in patients with cancer and rheumatoid
arthritis; data also demonstrates that denosumab reduces fractures in patients with osteoporosis.
Additional data are necessary to determine the nature and frequency of adverse reactions and drug
interactions, as well as any potential for long-term toxicity. A REMS/Medication Guide is mandated by the
FDA along with a 10 yer psot marketing surveillance program
The recent editorial from the NEJM where the fracture data was published probably best sums up the
place in therapy at this time. Given the similar efficacy data with bisphosphenates PO and injectable, the
lack of long term data in a community setting and the potential major concern about long-term use of
denosumab relates to its possible effects on the immune system, since RANKL is expressed not just on
bone cells but also on immune cells. Until we get more data it is probably not a first line agent and we still
need better agents that promote bone growth which are still in the pipeline.
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