New Drug Update 2010-2011 Faculty Disclaimer - CME Conferences
New Drug Update 2010-2011 Faculty Disclaimer - CME Conferences
New Drug Update 2010-2011 Faculty Disclaimer - CME Conferences
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2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> <strong>2010</strong>-<strong>2011</strong><br />
C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS<br />
Professor of Clinical Pharmacy and Outcome Sciences<br />
South Carolina College of Pharmacy<br />
Professor of Family Medicine<br />
Medical University of South Carolina<br />
Charleston, South Carolina<br />
weartcw@musc.edu<br />
<strong>Faculty</strong> <strong>Disclaimer</strong><br />
• I am on the speaker’s bureau for Pfizer in<br />
the areas of cardiovascular disease and<br />
pain.<br />
• I am a consultant for Merck in the area of<br />
outcomes research<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Colchicine<br />
• September 30, <strong>2010</strong> FDA notified companies to stop<br />
manufacturing single-ingredient oral colchicine within 45 days<br />
and must stop shipping this unapproved product in interstate<br />
commerce within 90 days.<br />
• Colcrys is the only FDA-approved single-ingredient oral<br />
colchicine product available on the U.S. market. Approved by<br />
the FDA in 2009, Colcrys’ prescribing information contains<br />
important safety data and recommendations on drug<br />
interactions and dosing not available with unapproved<br />
products<br />
– Max dose 3 x 0.6 mg tabs per acute attack (NOT 4.8 mg total dose)<br />
– Colchicine is a substrate for CYP 3A4 and efflux pumps (P-glycoprotein)<br />
Immunization <strong>Update</strong><br />
October 28, <strong>2010</strong> ACIP Recommends Tdap for patients 65 y/o<br />
and older<br />
• Tdap can replace Td in adults aged 65 years and older in those<br />
who have not previously received Tdap. In addition, adults<br />
aged 65 years or older who anticipate contact with children<br />
aged 12 months or younger should also be vaccinated to<br />
protect both themselves and the infant.<br />
• Tdap vaccine was not licensed for use in adults aged 65 years<br />
or older until 7/8/<strong>2011</strong>; however, data from the Vaccine<br />
Adverse Event Reporting System suggest that the "safety<br />
profile of Tdap vaccine in these adults is as safe as the Td<br />
vaccine."<br />
• "Tdap can be administered regardless of interval since the last<br />
tetanus or diphtheria containing vaccines."<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Immunization <strong>Update</strong><br />
• December 22, <strong>2010</strong> HPV Vaccine – Gardasil UPDATE The FDA<br />
approved vaccination in people ages 9 through 26 years for<br />
the prevention of anal cancer and associated precancerous<br />
lesions due to human papillomavirus (HPV) types 6, 11, 16,<br />
and 18. Gardasil was studied in a randomized, controlled trial<br />
of men who self-identified as having sex with men (MSM).<br />
This population was studied because it has the highest<br />
incidence of anal cancer. At the end of the study period,<br />
Gardasil was shown to be 78 percent effective in the<br />
prevention of HPV 16- and 18-related AIN. Because anal<br />
cancer is the same disease in both males and females, the<br />
effectiveness data was used to support the indication in<br />
females as well. (N Engl J Med <strong>2011</strong>; 364:401-411)<br />
PPI’s and Fracture Risk<br />
• May 25, <strong>2010</strong> FDA Safety Alert PPI’s and Fracture Risk FDA is<br />
revising the prescription and over-the-counter (OTC) labels for<br />
a class of drugs called proton pump inhibitors to include new<br />
safety information about a possible increased risk of fractures<br />
of the hip, wrist, and spine with the use of these medications.<br />
– Six epidemiological studies that reported an increased risk of fractures<br />
of the hip, wrist, and spine with proton pump inhibitor use. Some<br />
studies found that those at greatest risk for these fractures received<br />
high doses of proton pump inhibitors or used them for one year or<br />
more. The majority of the studies evaluated individuals 50 years of age<br />
or older and the increased risk of fracture primarily was observed in<br />
this age group.<br />
– Individuals at risk for osteoporosis should have their bone status<br />
managed according to current clinical practice, and should take<br />
adequate vitamin D and appropriate calcium supplementation. (IE a<br />
soluble calcium salt like calcium citrate)<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Bisphosphonates and Atypical Fractures<br />
Oct 13, <strong>2010</strong> FDA MedWatch Bisphosphonates (Osteoporosis<br />
<strong>Drug</strong>s): Label Change - Atypical Fractures Atypical<br />
subtrochanteric femur fractures are fractures in the bone just<br />
below the hip joint.<br />
These fractures are very uncommon and appear to account for<br />
less than 1% of all hip and femur fractures overall. The median<br />
BP treatment duration in patients with atypical subtrochanteric<br />
and femoral shaft fractures is 7 years.<br />
The FDA recommends:<br />
• Evaluate any patient who presents with new thigh or groin<br />
pain to rule out a femoral fracture. More than half of patients<br />
reported with atypical femoral fractures have had a prodrome of<br />
thigh or groin pain before suffering an overt break.<br />
Bisphosphonates and Atypical Fractures<br />
Educate physicians and patients about this symptom and for<br />
physicians to ask patients on BPs and other potent antiresorptive<br />
agents about thigh or groin pain. Complaints of thigh or groin<br />
pain in a patient on BPs require urgent radiographic evaluation<br />
of both femurs (even if pain is unilateral).<br />
• Discontinue potent antiresorptive medications (including<br />
bisphosphonates) in patients who have evidence of a femoral<br />
shaft fracture. anecdotal findings suggest that teriparatide<br />
therapy can improve or hasten healing of these fractures<br />
• Consider periodic reevaluation of the need for continued<br />
bisphosphonate therapy, particularly in patients who have been<br />
treated for over 5 years. Patients without a recent fracture and<br />
with femoral neck T scores > -2.5 after the initial therapeutic<br />
course, consideration may be given to a “drug holiday”<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Pioglitazone and Bladder Cancer?<br />
• September 17, <strong>2010</strong> FDA Ongoing Safety Review of Actos<br />
(pioglitazone) and Potential Increased Risk of Bladder Cancer<br />
– After Two Years Exposure In preclinical carcinogenicity studies of<br />
pioglitazone, bladder tumors were observed in male rats receiving<br />
doses of pioglitazone that produced blood drug levels equivalent to<br />
those resulting from a clinical dose.<br />
– Additionally, results from two, three-year controlled clinical studies of<br />
Actos (the PROactive study and a liver safety study) demonstrated a<br />
higher percentage of bladder cancer cases in patients receiving Actos<br />
versus comparators<br />
– A ten-year, observational cohort study as well as a nested case-control<br />
study in patients with diabetes who are members of Kaiser<br />
Permanente Northern California (KPNC) health plan.<br />
• A planned five-year interim analysis was performed with data collected from<br />
January 1, 1997 through April 30, 2008, the risk of bladder cancer increased with<br />
increasing dose and duration of Actos use, reaching statistical significance after 24<br />
months of exposure<br />
Pioglitazone and Bladder Cancer?<br />
• <strong>Update</strong> 6-16-<strong>2011</strong> The FDA warned that the diabetes drug<br />
Actos, known generically as pioglitazone, increases the risk of<br />
bladder cancer by at least 40% when used for more than a<br />
year or in higher cumulative doses. The agency said it will<br />
require changes in the label of the drug to reflect the new<br />
findings.<br />
• The FDA is not taking any further action against Actos until it<br />
receives further results from an ongoing study of the drug,<br />
but France has already suspended sales and Germany has<br />
warned physicians not to prescribe the drug to new patients.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Acetaminophen <strong>Update</strong><br />
January 13, <strong>2011</strong> FDA <strong>Drug</strong> Safety Communication: Prescription<br />
Acetaminophen Products to be Limited to 325 mg Per Dosage<br />
Unit - The FDA is asking drug manufacturers to limit the strength<br />
of acetaminophen in prescription drug products, which are<br />
predominantly combinations of acetaminophen and opioids. This<br />
action will limit the amount of acetaminophen in these products<br />
to 325 mg per tablet, capsule, or other dosage unit, making<br />
these products safer for patients.<br />
• In addition, a Boxed Warning highlighting the potential for<br />
severe liver injury and a Warning highlighting the potential for<br />
allergic reactions (e.g., swelling of the face, mouth, and<br />
throat, difficulty breathing, itching, or rash) are being added<br />
to the label of all prescription drug products that contain<br />
acetaminophen.<br />
PPI’s and Low Serum Magnesium<br />
March 2, <strong>2011</strong> FDA Safety Communication: Proton Pump Inhibitor<br />
drugs (PPIs) - Low Magnesium Levels Can Be Associated With<br />
Long-Term Use<br />
• Prescription proton pump inhibitor (PPI) drugs may cause low<br />
serum magnesium levels (hypomagnesemia) if taken for<br />
prolonged periods of time (in most cases, longer than one<br />
year). Low serum magnesium levels can result in serious<br />
adverse events including muscle spasm (tetany), irregular<br />
heartbeat (arrhythmias), and convulsions (seizures); however,<br />
patients do not always have these symptoms. Treatment of<br />
hypomagnesemia generally requires magnesium supplements.<br />
In approximately one-quarter of the cases reviewed,<br />
magnesium supplementation alone did not improve low serum<br />
magnesium levels and the PPI had to be discontinued<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Immunization <strong>Update</strong><br />
March 24, <strong>2011</strong> Approval Letter – Zostavax for patients<br />
age 50-59 years<br />
• Compared with placebo, ZOSTAVAX significantly<br />
reduced the risk of developing zoster by 69.8% (95%<br />
CI [54.1 - 80.6%]) in 22,439 subjects 50 to 59 years of<br />
age. Data from the Shingles Prevention Study<br />
demonstrated 64% (95% CI 56-71%) efficacy in<br />
patients age 60-69 years and 41% (95% CI 28 -52%)<br />
efficacy for patients age 70-79 years and. only 18%<br />
(95% CI -29 – 48%) efficacy in patients age 80 and<br />
above.<br />
<strong>New</strong> Influenza Vaccine<br />
• MAY 10, <strong>2011</strong> The FDA has approved the first Fluzone<br />
Intradermal vaccine for adults 18 through 64 years old. It will<br />
be available for the <strong>2011</strong>-12 influenza season.<br />
– Sanofi Pasteur's new product has a needle less than a<br />
tenth of an inch long, attached to a pre-filled syringe that<br />
holds a smaller amount of influenza vaccine than the<br />
company' standard flu shots.<br />
– patients have said they prefer the shorter, slimmer needles<br />
of the Fluzone Intradermal vaccine, but there's no data yet<br />
on whether they are less painful<br />
– Reactions around the injection site, including redness,<br />
swelling and itching, were more common with the new<br />
vaccine than with an intramuscular vaccine, company<br />
research found.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
NIH Stops AIM-HIGH Trial<br />
• May 26, <strong>2011</strong> The AIM-HIGH trial, which stands for<br />
Atherothrombosis Intervention in Metabolic Syndrome with<br />
Low HDL/High Triglycerides: Impact on Global Health, enrolled<br />
3,414 participants with a history of cardiovascular disease<br />
who were taking a statin drug to keep their LDL cholesterol<br />
low. Study participants also had low HDL cholesterol and high<br />
triglycerides. Patients were randomly assigned to either high<br />
dose, extended-release niacin (Niaspan) in gradually<br />
increasing doses up to 2,000 mg per day (1,718 people) or a<br />
placebo treatment (1,696 people). All participants were<br />
prescribed simvastatin (Zocor), and 515 participants were<br />
given a second LDL cholesterol-lowering drug, ezetimibe<br />
(Zetia), in order to maintain LDL cholesterol levels at the<br />
target range between 40-80 mg/dL.<br />
NIH Stops AIM-HIGH Trial<br />
• The study’s DSMB concluded that high dose, extended-release<br />
niacin offered no benefits beyond statin therapy alone in<br />
reducing cardiovascular-related complications in this trial.<br />
The rate of clinical events was the same in both treatment<br />
groups, and there was no evidence that this would change by<br />
continuing the trial andthe DSMB recommended that the<br />
NHLBI end the study.<br />
• There was also a small and unexplained increase in ischemic<br />
stroke rates in the high dose, extended-release niacin group.<br />
– The Coronary <strong>Drug</strong> Project Trial with IR niacin found an increase in A<br />
Fib which might explain the stroke risk?<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Recent FDA Approval<br />
• May 27, <strong>2011</strong> The FDA approved Dificid (fidaxomicin) tablets<br />
by Optimer Pharmaceuticals for the treatment of Clostridium<br />
difficile-associated diarrhea (CDAD).<br />
– The safety and efficacy of Dificid were demonstrated in two trials that<br />
included 564 patients with CDAD that compared Dificid with<br />
vancomycin, a common antibiotic used to treat CDAD. The clinical<br />
response was similar in the Dificid group compared with the<br />
vancomycin group in both studies. In some patients with CDAD,<br />
symptoms can return. In the Dificid trials, a greater number of patients<br />
treated with Dificid had a sustained cure three weeks after treatment<br />
ended versus those patients treated with vancomycin.<br />
– Dificid, a macrolide antibacterial, should be taken 200 mg two times a<br />
day for 10 days with or without food. Cost ~ $2,800.00<br />
– The most common side effects reported with Dificid included nausea,<br />
vomiting, headache, abdominal pain, and diarrhea.<br />
FDA Safety <strong>Update</strong> Simvastatin<br />
• SEARCH was a seven-year, randomized, double-blind clinical<br />
trial comparing the efficacy and safety of simvastatin 80 mg to<br />
simvastatin 20 mg, with or without vitamin B12 and folate, in<br />
survivors of myocardial infarction.<br />
• At the end of the trial, the incidence of major vascular events<br />
was 25.7% in the 20-mg group versus 24.5% in the 80-mg<br />
group [RR=0.094, 95% CI (0.88, 1.01); p=0.10]. Due in part to<br />
greater use of off-study LDL-C lowering medication in the<br />
simvastatin 20 mg group versus the 80-mg group, the<br />
difference in mean levels of LDL-C between the two treatment<br />
groups was 13 mg/dL instead of the expected difference of 20<br />
mg/dL.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
FDA Safety <strong>Update</strong> Simvastatin<br />
• Fifty-two patients (0.9%) in the 80-mg group versus one<br />
patient (0.02%) in the 20-mg group developed myopathy<br />
(defined as unexplained muscle weakness or pain with a<br />
serum CK >10 times the upper limit of normal [ULN]). This was<br />
higher than the labeled risk (based on clinical trial data) of<br />
0.53%.<br />
• Twenty-two patients (0.4%) in the 80-mg group versus no<br />
patient in the 20-mg group developed rhabdomyolysis<br />
(defined as unexplained muscle weakness or pain with serum<br />
CK >40 times ULN).<br />
• The risks for myopathy and rhabdomyolysis with simvastatin<br />
80 mg were highest in the first 12 months of treatment, 5 per<br />
1000 person-years and 2 per 1000 person-years, respectively,<br />
and decreased to 1 per 1000 person-years and 0.4 per 1000<br />
person-years after that.<br />
FDA Safety <strong>Update</strong> Simvastatin<br />
6-8-<strong>2011</strong> FDA Safety <strong>Update</strong><br />
• Based upon data from the SEARCH Trial the FDA is<br />
recommending limiting the use of the highest<br />
approved dose of the cholesterol-lowering<br />
medication, simvastatin (80 mg) because of<br />
increased risk of muscle damage.<br />
• Simvastatin 80 mg should be used only in patients<br />
who have been taking this dose for 12 months or<br />
more without evidence of muscle injury (myopathy).<br />
• Simvastatin 80 mg should not be started in new<br />
patients, including patients already taking lower<br />
doses of the drug.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
FDA Safety <strong>Update</strong> Simvastatin<br />
FDA is requiring changes to the simvastatin label to add new<br />
contraindications (should not be used with certain medications)<br />
and dose limitations for using simvastatin with certain<br />
medicines.<br />
• Contraindicated with : Itraconazole, Ketoconazole,<br />
Posaconazole (<strong>New</strong>), Erythromycin, Clarithromycin,<br />
Telithromycin, HIV/HCV protease inhibitors, Nefazodone,<br />
Gemfibrozil (old 10mg), Cyclosporine (old 10 mg), and Danazol<br />
(old 10mg).<br />
• Maximum 10 mg simvastatin dose with: Amiodarone (old<br />
20mg), Verapamil (old 20mg) and Diltiazem (old 40 mg).<br />
• Maximum 20 mg simvastatin dose with: Amlodipine (<strong>New</strong>)<br />
and Ranolazine (<strong>New</strong>)<br />
Varenicline Safety <strong>Update</strong><br />
6-16-<strong>2011</strong> FDA safety update Chantix (varenicline) may increase<br />
the risk of certain cardiovascular adverse events in patients with<br />
cardiovascular disease<br />
FDA reviewed a randomized, double-blind, placebo-controlled<br />
clinical trial designed to assess the efficacy and safety of Chantix<br />
for smoking cessation in 700 patients aged 35 to 75 years with<br />
stable, documented cardiovascular disease (other than, or in<br />
addition to, hypertension) that had been diagnosed at least two<br />
months prior to the screening visit. Patients were randomized to<br />
treatment with Chantix 1 mg twice daily (n=350) or placebo<br />
(n=350). The study consisted of a 12-week treatment period that<br />
was followed by a 40-week non-treatment period.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Varenicline Safety <strong>Update</strong><br />
Adjudicated Cardiovascular Events During the 52-Week<br />
Study Period (1% in any group) Rigotti et al Circulation<br />
<strong>2011</strong>;121:221-229<br />
Varenicline N=353* n (%) Placebo N=350 n (%)<br />
Nonfatal myocardial infarction 7 (2.0) 3 (0.9)<br />
Need for coronary<br />
revascularizaon†<br />
8 (2.3) 3 (0.9)<br />
Hospitalization for angina pectoris 8 (2.3) 8 (2.3)<br />
<strong>New</strong> diagnosis of peripheral<br />
vascular disease (PVD) or<br />
admission for a procedure for the<br />
treatment of PVD<br />
5 (1.4) 3 (0.9)<br />
The FDA recommends providers weigh the known benefits of Chantix against its<br />
potential risks when deciding to use the drug in smokers with cardiovascular disease.<br />
They also are working with the manufacturer to gain further data and plan on further updates.<br />
Varenicline Safety <strong>Update</strong><br />
• A recent meta-analysis (early release CMAJ 7-4-<strong>2011</strong>)<br />
of 14 double blind randomized controlled trials<br />
involving 8216 participants. The trials ranged in<br />
duration from 7 to 52 weeks. Varenicline was<br />
associated with a significantly increased risk of<br />
serious adverse cardiovascular events compared with<br />
placebo (1.06% [52/4908] in varenicline group v.<br />
0.82% [27/3308] in placebo group; Peto odds ratio<br />
[OR] 1.72, 95% confidence interval [CI] 1.09–2.71.<br />
RRI 72%; ARI 0.24%; NNH ~400<br />
– 57.3% of the weight of this meta-analysis comes from the<br />
recent Circulation data by Rigotti<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Citalopram hydrobromide (Celexa)<br />
Safety Alert<br />
August 24, <strong>2011</strong> FDA <strong>Drug</strong> Safety<br />
Communication: Abnormal heart rhythms<br />
associated with high doses of citalopram.<br />
• Previously doses up to 60 mg per day were<br />
FDA approved but based upon new data and<br />
case reports of dose related QT interval<br />
prolongation, leading to an abnormal heart<br />
rhythm (including Torsade de Pointes),<br />
citalopram should no longer be used at doses<br />
greater than 40 mg per day.<br />
Citalopram hydrobromide (Celexa)<br />
Safety Alert<br />
• Patients at particular risk for developing prolongation<br />
of the QT interval include those with underlying<br />
heart conditions and those who are predisposed to<br />
low levels of potassium and magnesium in the blood.<br />
• Studies have not shown a benefit in the treatment of<br />
depression at doses higher than 40 mg per day.<br />
• Citalopram and sertraline are the recommended<br />
agents of choice for patients with depression and<br />
CVD according to the AHA/APA<br />
– Circulation 2008;118:1768-75<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
American Diabetes Association<br />
ADA/EASD Guidelines 2008 <strong>Update</strong> (Diabetes Care 2009; 32:193–203)<br />
Avoid Use of Glyburide?<br />
In-hospital mortality in patients on sulfonylureas before admission (n = 459) according to the type of sulfonylureas and stratified by<br />
specific subgroups (J Clin Endocrinol Metab, November <strong>2010</strong>, 95(11):4993–5002)<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Proposed Recommendations for Use of<br />
Metformin Based on e-GFR<br />
Diabetes Care <strong>2011</strong>;34:1435<br />
eGFR (ml/min per 1.73m2)<br />
Action<br />
>60 No renal contraindication to metformin<br />
>45 Continue use<br />
Increase monitoring of renal function (every 3–6<br />
months)<br />
30 Prescribe metformin with caution<br />
Use lower dose (e.g., 50%, or half-maximal dose)<br />
Closely monitor renal function (every 3-6 months) Do<br />
not start new patients on metformin<br />
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Liraglutide – Victoza<br />
Liraglutide – Victoza<br />
LEAD 6 Trial (Lancet 2009; 374:39-47)<br />
• Inadequately controlled type 2 diabetes patients on<br />
maximally tolerated doses of metformin, sulfonylurea, or<br />
both, were stratified by previous oral antidiabetic therapy<br />
and randomly assigned to receive additional liraglutide 1·8<br />
mg once a day (n=233) or exenatide 10 g twice a day<br />
(n=231) in a 26-week open-label study.<br />
• Liraglutide reduced mean HbA1c significantly more than did<br />
exenade (1·12% vs 0·79%; esmated treatment<br />
dierence 0·33; 95% CI 0·47 to 0·18; p
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Liraglutide – Victoza<br />
Risk of Thyroid C-cell Tumors BLACK BOX WARNING<br />
• Liraglutide causes dose-dependent and treatmentduration-dependent<br />
thyroid C-cell tumors<br />
(adenomas and/or carcinomas) at clinically relevant<br />
exposures in both genders of rats and mice.<br />
• In the clinical trials, there have been 4 reported cases<br />
of thyroid C-cell hyperplasia among Victoza-treated<br />
patients and 1 case in a comparator-treated patient<br />
(1.3 vs. 0.6 cases per 1000 patient-years).<br />
– a 5 year epidemiological study using a large healthcare<br />
claims database to compare the development of thyroid<br />
cancer among patients with T2DM who use Victoza to<br />
those who are not using this medicine.<br />
– develop a medullary thyroid cancer registry to monitor<br />
how many cases of medullary thyroid cancer occur each<br />
year for at least 15 years<br />
Liraglutide – Victoza<br />
• It is unknown whether Victoza will cause<br />
thyroid C-cell tumors, including medullary<br />
thyroid carcinoma (MTC), in humans<br />
• Counsel patients regarding the risk for MTC<br />
and the symptoms of thyroid tumors (e.g. a<br />
mass in the neck, dysphagia, dyspnea or<br />
persistent hoarseness).<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Liraglutide – Victoza<br />
Pancreatitis: Warnings and Precautions<br />
• In five clinical trials including more than 3,900<br />
people, there were seven cases of pancreatitis in<br />
patients using liraglutide and one case in a patient<br />
using another diabetes medicine. This constituted a<br />
4:1 imbalance of pancreatitis cases, when<br />
considering the number of patient exposures (2.2 vs.<br />
0.6 cases per 1000 patient-years).<br />
• Patients taking liraglutide should be aware of the<br />
symptoms of pancreatitis, such as severe abdominal<br />
pain that may also radiate into the back, possibly<br />
with nausea, and vomiting.<br />
Liraglutide – Victoza<br />
Adverse Effects in Clinical Trials %__<br />
• Nausea 28.4<br />
• Diarrhea 17.1<br />
• Vomiting 10.9<br />
• Constipation 9.9<br />
• Upper Respiratory Tract Infection 9.5<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Liraglutide – Victoza<br />
Linagliptin – Tradjenta<br />
by Boehringer Ingelheim and Lilly<br />
• A dipeptidyl peptidase-4<br />
(DPP-4) inhibitor indicated<br />
as an adjunct to diet and<br />
exercise to improve<br />
glycemic control in adults<br />
with type 2 diabetes<br />
mellitus<br />
• The recommended dose of<br />
linagliptin is 5 mg once daily<br />
with or without food.<br />
• Cost $243.60/30<br />
tablets AWP<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Linagliptin – Tradjenta<br />
• Linagliptin is an inhibitor of DPP-4, an enzyme that<br />
degrades the incretin hormones glucagon-like<br />
peptide-1 (GLP-1) and glucose-dependent<br />
insulinotropic polypeptide (GIP). Thus, linagliptin<br />
increases the concentrations of active incretin<br />
hormones, GLP-1 and GIP which both increase<br />
glucose stimulated insulin biosynthesis and secretion<br />
from pancreatic beta cells. Furthermore, GLP-1 also<br />
reduces glucagon secretion from pancreatic alpha<br />
cells, resulting in a reduction in hepatic glucose<br />
output.<br />
Linagliptin – Tradjenta<br />
• The effective half-life for accumulation of linagliptin,<br />
as determined from oral administration of multiple<br />
doses of linagliptin 5 mg, is approximately 12 hours.<br />
• Following administration of an oral [14C]-linagliptin<br />
dose to healthy subjects, approximately 85% of the<br />
administered radioactivity was eliminated via the<br />
enterohepatic system (80%) or urine (5%) within 4<br />
days of dosing.<br />
• No dose adjustment is recommended in patients<br />
with renal impairment.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
<strong>Drug</strong> Interactions<br />
Linagliptin – Tradjenta<br />
• Linagliptin is a weak to moderate inhibitor of CYP isozyme<br />
CYP3A4, but does not inhibit other CYP isozymes and is not an<br />
inducer of CYP isozymes.<br />
• Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-<br />
gp mediated transport of digoxin at high concentrations.<br />
Based on the results of limited drug interaction studies,<br />
linagliptin is considered unlikely to cause interactions with<br />
P-gp substrates at therapeutic concentrations.<br />
• Inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure<br />
to linagliptin to subtherapeutic and likely ineffective<br />
concentrations. For patients requiring use of such drugs, an<br />
alternative to linagliptin is strongly recommended.<br />
Linagliptin – Tradjenta<br />
Clinical Trials Monotherapy:<br />
• 496 patients mean A1c 8.0 treated with<br />
linagliptin 5 mg QD vs. placebo for 24 weeks<br />
– A1c -0.4% linagliptin (L) vs. +0.3% placebo (P)<br />
(difference from placebo -0.7%)<br />
– Patients achieving A1c
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Linagliptin – Tradjenta<br />
Add on to Metformin:<br />
• 701 patients on at least 1500 mg/d metformin and<br />
not at goal A1c (mean baseline 8.1 and 8.0%) had<br />
either linagliptin 5 mg or placebo added for 24 weeks<br />
– A1c -0.5% L vs. +0.15% P (difference from placebo -0.6%)<br />
– Patients achieving A1c
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Linagliptin – Tradjenta<br />
Add on to pioglitazone (30mg) for 24 weeks<br />
• 389 patients (baseline A1c 8.6%) linagliptin 5 mg plus<br />
pioglitazone 30mg (LP) vs. piogltazone plus placebo (PP)<br />
(patients who did not get to goal could have rescue therapy<br />
with metformin added)<br />
– A1c -1.1% LP vs. -0.6% PP<br />
– FPG -32.6 mg/dl LP vs. -18.4 mg/dl PP<br />
– Metformin rescue was added on 7.9% with LP vs. 14.1% PP<br />
– Weight changes +2.3 Kg LP and +1.2 Kg PP<br />
• Diabetes Obes Metab. <strong>2011</strong>;13(7):653-661. 10.111/j.1463-<br />
1326.<strong>2011</strong>.01391.x.<br />
Linagliptin – Tradjenta<br />
Contraindication:<br />
• Linagliptin is contraindicated in patients with a history of hypersensitivity<br />
reactions (eg, urticaria, angioedema, bronchial hyperreactivity).<br />
Adverse Effects:<br />
• In the clinical trial program, pancreatitis was reported in 8 of 4687<br />
patients (4311 patient years of exposure) while being treated with<br />
linagliptin compared with 0 of 1183 patients (433 patient years of<br />
exposure) treated with placebo. Three additional cases of pancreatitis<br />
were reported following the last administered dose of linagliptin<br />
• When linagliptin was administered in combination with metformin and a<br />
sulfonylurea, 181 of 791 (22.9%) of patients reported hypoglycemia<br />
compared with 39 of 263 (14.8%) of patients administered placebo in<br />
combination with metformin and a sulfonylurea<br />
– When used in combination with an insulin secretagogue (e.g., sulfonylurea), a lower<br />
dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Linagliptin – Tradjenta<br />
• There have been no clinical studies<br />
establishing conclusive evidence of<br />
macrovascular or microvascular risk reduction<br />
with linagliptin<br />
• Linagliptin has not been studied in<br />
combination with insulin<br />
• Linagliptin is an alternative to sitagliptin and<br />
saxagliptin for the treatment of patients with<br />
type 2 diabetes and it does not need a dosage<br />
reduction in patients with renal dysfunction.<br />
Pancreatitis, Pancreatic, and Thyroid<br />
Cancer With Glucagon-Like<br />
Peptide-1–Based Therapies<br />
GASTROENTEROLOGY <strong>2011</strong>;141:150–156<br />
• US Food and <strong>Drug</strong> Administration’s database of reported<br />
adverse events for those associated with the dipeptidyl<br />
peptidase4 inhibitor sitagliptin and the glucagon-like peptide-<br />
1 mimetic exenatide, from 2004-2009; data on adverse events<br />
associated with 4 other medications were compared as<br />
controls.(rosiglitazone, nateglinide, repaglinide and glipizide)<br />
• The primary outcomes measures were rates of reported<br />
pancreatitis, pancreatic and thyroid cancer, and all cancers<br />
associated with sitagliptin or exenatide, compared with other<br />
therapies.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-<br />
Like Peptide-1–Based Therapies<br />
GASTROENTEROLOGY <strong>2011</strong>;141:150–156<br />
Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-<br />
Like Peptide-1–Based Therapies<br />
GASTROENTEROLOGY <strong>2011</strong>;141:150–156<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Pancreatitis, Pancreatic, and Thyroid Cancer With<br />
Glucagon-Like Peptide-1–Based Therapies<br />
GASTROENTEROLOGY <strong>2011</strong>;141:150–156<br />
• “In conclusion, analysis of the FDA adverse event reporting<br />
database suggests that the GLP-1 class of drugs being widely<br />
promoted for treatment of type 2 diabetes could have serious<br />
unintended and unpredicted side effects.”<br />
• “Pancreatitis is 6-fold more likely to be reported in association<br />
with sitagliptin or exenatide than other therapy”<br />
• “We have a concern that there is a significantly increased<br />
association of thyroid cancer and pancreatic cancer with these<br />
therapies.”<br />
• “The most obvious conclusion from these studies is that careful<br />
long-term monitoring of patients treated with GLP-1 mimetics<br />
or DPP-4 inhibitors is required.”<br />
Pancreatitis, Pancreatic, and Thyroid Cancer With<br />
Glucagon-Like Peptide-1–Based Therapies<br />
GASTROENTEROLOGY <strong>2011</strong>;141:150–156<br />
• “For now this analysis of the FDA data base<br />
does not establish that pancreatitis,<br />
pancreatic and thyroid cancer are caused<br />
by GLP-1based therapy. It simply raises the<br />
level of concern that they may be and that<br />
the appropriate prospective studies are<br />
required to rule them out.”<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
GLP-1–Based Therapies: The Dilemma of<br />
Uncertainty<br />
Gastroenterology <strong>2011</strong>; 141:20-23<br />
• The accompanying editorial states “…more reliable studies<br />
must be performed. Until then, the questions about the<br />
potential link between GLP-1–based therapies and<br />
pancreatitis and tumorigenesis remain open. The fact that<br />
GLP-1–based therapies have no record of lowering clinical<br />
endpoints (ie, mortality, stroke, myocardial infarction)<br />
does not inspire confidence and more informative<br />
prospective randomized trials with such patient-relevant<br />
clinical endpoints are urgently required.”<br />
• “For the sake of patients, history will hopefully not repeat<br />
itself in the case of GLP-1–based drugs. Two thoughts<br />
remain: primum non nocere and “vigilance equals<br />
avoidance.”<br />
Dabigatran- Pradaxa<br />
by Boehringer Ingelheim<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dabigatran - Pradaxa<br />
• A direct thrombin<br />
inhibitor indicated to<br />
reduce the risk of stroke<br />
and systemic embolism<br />
in patients with nonvalvular<br />
atrial fibrillation<br />
• 75 mg and 150 mg<br />
capsules BID $253.00/60<br />
• No need to monitor INR<br />
• Not reversible with<br />
vitamin K or FFP<br />
(consider factor<br />
concentrates or dialysis)<br />
Dabigatran- Pradaxa<br />
RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy),<br />
a randomized trial comparing two blinded doses of dabigatran (110<br />
mg twice daily and 150 mg twice daily) with open-label warfarin<br />
(dosed to target INR of 2 to 3) in 18,113 patients with non-valvular,<br />
persistent, paroxysmal, or permanent atrial fibrillation and one or<br />
more of the following additional risk factors:<br />
• Previous stroke, transient ischemic attack (TIA), or systemic<br />
embolism<br />
• Left ventricular ejection fraction
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dabigatran- Pradaxa<br />
Table 1: Event rates by INR time in range vs dabigatran 110 BID and 150 mg BID<br />
Event %/yr<br />
Stroke* +<br />
SEE<br />
Warf<br />
n=6022<br />
Warf Q 4<br />
TTR < 53%<br />
Warf Q 1-2<br />
TTR > 67%<br />
Dabig 110<br />
n=6015<br />
Dabig 150<br />
n=6076<br />
1.69 2.2 1.3 1.53 1.11**<br />
NNT 173<br />
Maj Bld 3.36 4.6 2.7 2.71** 3.11<br />
MI 0.53 Na Na 0.72 0.74**<br />
NNH 476<br />
Comp. 7.64 11.9 5.3 7.09 6.91<br />
*"Stroke" includes hemorrhagic stroke, **stat. sig. vs warfarin in original report.<br />
Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. Warf 4th quartile = ITTR < 53.4%,<br />
1st & 2nd quartile = ITTR > 67.1%.<br />
N Engl J Med 2009; 361:1139-1151<br />
Dabigatran- Pradaxa<br />
Risk of extracranial and intracranial bleeding (% per year) by age<br />
End point<br />
Warfarin<br />
(%)<br />
Dabigatran 110<br />
mg (%)<br />
Dabigatran 150<br />
mg (%)<br />
P<br />
Extracranial bleeding<br />
Age 75 3.44 4.10 4.68 0.001<br />
Intracranial bleeding<br />
Age 75 1.00 0.37 0.41 0.28<br />
Circulation <strong>2011</strong>;123:2363-2372<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dabigatran- Pradaxa<br />
• Compared to warfarin, both doses of dabigatran<br />
were associated with a significantly lower rate of<br />
haemorrhagic stroke, life-threatening bleeds, and<br />
intracranial haemorrhage (ICH) with and without<br />
haemorrhagic stroke; dabigatran 110 mg also<br />
showed a significant reduction in major bleeding<br />
compared to warfarin<br />
• Warfarin has statistically significantly fewer GI bleeds<br />
compared to both doses of dabigatran, and<br />
significantly fewer major GI bleeds and lifethreatening<br />
GI bleeds than dabigatran 150 mg<br />
Dabigatran- Pradaxa<br />
• The rates of adverse reactions leading to treatment<br />
discontinuation in RE-LY were 21% for dabigatran 150 mg and<br />
16% for warfarin. The most frequent adverse reactions<br />
leading to discontinuation of dabigatran were bleeding and<br />
gastrointestinal events (i.e., dyspepsia, nausea, upper<br />
abdominal pain, gastrointestinal hemorrhage, and diarrhea).<br />
– NNH 20 patients<br />
• <strong>Drug</strong> Interactions<br />
– The concomitant use of dabigatran with P-gp inducers<br />
(e.g., rifampin) reduces exposure to dabigatran and should<br />
generally be avoided<br />
– P-gp inhibitors ketoconazole, verapamil, amiodarone,<br />
quinidine, and clarithromycin do not require dose<br />
adjustments<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dabigatran- Pradaxa<br />
ACCF/AHA/HRS <strong>2011</strong> Focused <strong>Update</strong><br />
Recommendation Class I<br />
“Dabigatran is useful as an alternative to warfarin for<br />
the prevention of stroke and systemic<br />
thromboembolism in patients with paroxysmal to<br />
permanent AF and risk factors for stroke or systemic<br />
embolization who do not have a prosthetic heart valve<br />
or hemodynamically significant valve disease, severe<br />
renal failure (creatinine clearance 50 mL/min, start warfarin 3 days before<br />
discontinuing dabigatran.<br />
– For CrCl 31-50 mL/min, start warfarin 2 days before<br />
discontinuing dabigatran.<br />
– For CrCl 15-30 mL/min, start warfarin 1 day before<br />
discontinuing dabigatran.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dabigatran- Pradaxa<br />
• DOSING: Recommended Dose for patients with creatinine<br />
clearance (CrCl) >30 mL/min, the recommended dose of<br />
dabigatran is 150 mg taken orally, twice daily, with or without<br />
food. For patients with CrCl 15-30 mL/min, or patients 75 years<br />
of age or older the recommended dose is 75 mg twice daily<br />
•<br />
– Instruct patients to swallow the capsules whole. Breaking,<br />
chewing, or emptying the contents of the capsule can result<br />
in increased exposure.<br />
– Pradaxa capsules will hydrolyze over time when exposed to<br />
humidity, causing a breakdown of active ingredient, and<br />
rendering the medication less effective. Pradaxa is<br />
packaged in a 30-day supply bottle with a desiccant cap or<br />
in unit-of-use blister packaging to minimize product<br />
breakdown from moisture.<br />
Rivaroxaban – Xarelto<br />
by Bayer HealthCare AG and Janssen Pharmaceuticals<br />
Rivaroxaban exhibits a linear pharmacokinetic<br />
relationship with a rapid onset of action, resulting<br />
in maximal factor Xa inhibition in approximately 3<br />
hours. Maintenance of the anti–factor Xa effect<br />
lasted 8 to 12 hours, depending on the dose of<br />
rivaroxaban.<br />
Terminal half-life of rivaroxaban is approximately 9<br />
hours in adults and 12 hours in elderly patients<br />
(older than 65 years of age). Elimination of<br />
rivaroxaban occurs by multiple routes: renal (onethird<br />
is excreted unchanged), biliary/fecal, and<br />
hepatic (through CYP-450 3A4). Renal function<br />
impairment may influence elevated plasma<br />
concentrations and increased anti-Xa activity;<br />
therefore, dose adjustments may be required<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
• July 5, <strong>2011</strong> The FDA approved rivaroxaban a factor Xa<br />
inhibitor indicated for the prophylaxis of deep vein<br />
thrombosis (DVT) which may lead to pulmonary embolism<br />
(PE) in patients undergoing knee or hip replacement.<br />
• The recommended dose of is 10 mg taken orally once daily<br />
with or without food. The initial dose should be taken at least<br />
6 to 10 hours after surgery once hemostasis has been<br />
established.<br />
– For patients undergoing hip replacement surgery,<br />
treatment duration of 35 days is recommended.<br />
– For patients undergoing knee replacement surgery,<br />
treatment duration of 12 days is recommended.<br />
Rivaroxaban - Xarelto<br />
RECORD is a global program involving more than 12,500 patients,<br />
comparing rivaroxaban 10 mg QD with SC enoxaparin in patients<br />
following either total hip or knee replacement surgery.<br />
• RECORD comprised four pivotal Phase III clinical<br />
– RECORD 1 and 2: total hip replacement surgery<br />
• RECORD 1: Both treatments continued for 35+/-4 days (N Engl J Med. 2008;358:2765-<br />
2775)<br />
• RECORD 2: Rivaroxaban continued for 35+/-4 days; enoxaparin 10-14 days (Lancet.<br />
2008;372:31-39)<br />
– RECORD 3 and 4: total knee replacement surgery<br />
• RECORD 3: Both treatments continued for 10-14 days (N Engl J Med. 2008;358:2776-<br />
2786)<br />
• RECORD 4: Both treatments continued for 10–14 days (Lancet 2009;373:1673-80)<br />
– Results of a pre-specified pooled analysis of RECORD1, 2 and 3 showed<br />
that rivaroxaban significantly reduced the composite of symptomatic VTE<br />
and all-cause mortality during the 2-week active controlled period by 56%<br />
compared with enoxaparin (0.4% versus 0.8%, respectively; odds ratio:<br />
0.44; p=0.005) while maintaining a similar safety profile.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
• RECORD 1 (Hip) R=1.1% vs. E=3.9%, RRR 71%,<br />
ARR 2.8%, NNT=36<br />
• RECORD 2 (Hip) R=2.0% vs. E=8.4%, RRR 76%,<br />
ARR 6.4%, NNT=16<br />
• RECORD 3 (Knee) R=9.7% vs. E=18.8%,<br />
RRR 48%, ARR 9.1%, NNT=11<br />
• RECORD 4 (Knee) R=6.9% vs. E=10.1%,<br />
RRR 31%, ARR 3.19%, NNT=32<br />
Rivaroxaban - Xarelto<br />
• Additional Clinical Trials completed or under<br />
way include: (NOT FDA Approved!)<br />
– EINSTEIN: VTE treatment (Phase III) (N Engl J Med<br />
<strong>2010</strong>; 363:2499-2510)<br />
– ROCKET AF: Stroke prevention in patients with<br />
atrial fibrillation (Phase III) (N Engl J Med<br />
<strong>2011</strong>;365:883-91)<br />
– MAGELLAN: VTE prevention in hospitalized,<br />
medically ill patients (Phase III)<br />
– ATLAS ACS TIMI 46: Secondary prevention of acute<br />
coronary syndrome (Phase II) (Lancet 2009; 374: 29 –<br />
38)<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
• BOX WARNING: SURGICAL SETTINGS--SPINAL/EPIDURAL<br />
HEMATOMA: Epidural or spinal hematomas may occur in<br />
patients who are anticoagulated and are receiving neuraxial<br />
anesthesia or undergoing spinal puncture. These hematomas<br />
may result in long-term or permanent paralysis. Consider<br />
these risks when scheduling patients for spinal procedures.<br />
Factors that can increase the risk of developing epidural or<br />
spinal hematomas in these patients include:<br />
– use of indwelling epidural catheters<br />
– concomitant use of other drugs that affect hemostasis, such as<br />
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,<br />
other anticoagulants<br />
– a history of traumatic or repeated epidural or spinal punctures<br />
– a history of spinal deformity or spinal surgery.<br />
Rivaroxaban - Xarelto<br />
• Avoid concomitant administration of rivaroxaban<br />
with combined P-gp and strong CYP3A4 inhibitors<br />
(e.g., ketoconazole, itraconazole, lopinavir/ritonavir,<br />
ritonavir, indinavir/ritonavir, and conivaptan) which<br />
cause significant increases in rivaroxaban exposure<br />
that may increase bleeding risk.<br />
• When clinical data suggest a change in exposure is<br />
unlikely to affect bleeding risk (e.g., clarithromycin,<br />
erythromycin), no precautions are necessary during<br />
coadministration with drugs that are combined P-gp<br />
and CYP3A4 inhibitors.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
• Patients with any degree of renal impairment with<br />
concurrent use of P-gp and weak to moderate<br />
CYP3A4 inhibitors may have significant increases in<br />
exposure which may increase bleeding risk<br />
• Avoid concomitant use of rivaroxaban with drugs<br />
that are combined P-gp and strong CYP3A4 inducers<br />
(e.g., carbamazepine, phenytoin, rifampin, St. John’s<br />
wort). Consider increasing the rivaroxaban dose if<br />
these drugs must be co-administered<br />
Rivaroxaban - Xarelto<br />
• Avoid the use of rivaroxaban in patients with severe<br />
renal impairment (CrCl
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
Rivaroxaban - Xarelto<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
ROCKET-AF Trial<br />
• The ROCKET AF study was a multicenter, doubleblind,<br />
randomized trial of once-daily oral rivaroxaban<br />
20 mg or 15 mg daily in patients with a creatinine<br />
clearance of 30 to 49 ml per minute) compared with<br />
dose-adjusted warfarin (INR 2-3) in moderate-tohigh-risk<br />
patients with nonvalvular AF. The authors<br />
hypothesized that rivaroxaban is noninferior to<br />
warfarin at preventing the composite of stroke<br />
(ischemic and hemorrhagic) and systemic embolism.<br />
The 14,264 enrolled patients (median age, 73; 40%<br />
women) had a mean CHADS2 score of 3.5; about half<br />
had a CHADS2 score of 4.<br />
– N Engl J Med <strong>2011</strong>;365:883-91.<br />
ROCKET-AF Trial<br />
• Median follow-up was 707 days.<br />
• In the warfarin group, the overall mean proportion of<br />
time in therapeutic international normalized ratio<br />
range was 55%.<br />
– N Engl J Med <strong>2011</strong>;365:883-91.<br />
• On Sept 9, <strong>2011</strong> the FDA Cardiovascular and Renal<br />
<strong>Drug</strong>s Advisory Committee recommended approval<br />
of rivaroxaban for the prevention of stroke and<br />
systemic embolism in patients with non-valvular<br />
atrial fibrillation (AF) by a 9-2 vote.<br />
– The FDA had expressed concern over the low rate of<br />
desired INR’s)<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Outcome<br />
ROCKET-AF Trial<br />
Rivaroxaban<br />
(n=7081)<br />
Warfarin<br />
(n=7090)<br />
N Egl J Med <strong>2011</strong>;365:883-91.<br />
Hazard ratio<br />
(95% CI) p<br />
Primary end point,<br />
noninferiority<br />
Primary end point, on<br />
treatment superiority<br />
Primary end point,<br />
intention-to-treat<br />
superiority<br />
Vascular death,<br />
stroke,<br />
embolism<br />
1.71 2.16 0.79 (0.66-0.96)<br />
NNT 222<br />
2 g/dL hemoglobin<br />
drop<br />
2.77 2.26 1.22 (1.03-1.44)<br />
NNH 197<br />
Transfusion 1.65 1.32 1.25 (1.01-1.55)<br />
NNH 304<br />
Critical organ<br />
bleeding<br />
Bleeding causing<br />
death<br />
Intracranial<br />
hemorrhage<br />
0.82 1.18 0.69 (0.53-0.91)<br />
NNT 278<br />
0.24 0.48 0.50 (0.31-0.79)<br />
NNT 455<br />
0.49 0.74 0.67 (0.47-0.94)<br />
NNT 400<br />
0.019<br />
0.044<br />
0.007<br />
0.003<br />
0.019<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Rivaroxaban - Xarelto<br />
• 9/22/<strong>2011</strong> Advisors for the European Medicines<br />
Agency (EMA) have paved the way for two new<br />
indications for rivaroxaban in Europe. The EMA's<br />
Committee for Medicinal Products for Human<br />
Use (CHMP) issued two "positive opinions" for<br />
the oral factor Xa inhibitor: one in the setting of<br />
the prevention of stroke and systemic embolism<br />
in nonvalvular atrial fibrillation (AF) and one for<br />
the treatment of venous thromboembolism<br />
(VTE), deep vein thrombosis (DVT), and<br />
pulmonary embolism (PE)<br />
Ticagrelor – Brilinta<br />
by Astra Zeneca<br />
90 mg tablets Loading dose 180 mg then 90 mg BID<br />
$217.20 per month WAC<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor - Brilinta<br />
• Ticagrelor and its major metabolite reversibly<br />
interact with the platelet P2Y12 ADP-receptor to<br />
prevent signal transduction and platelet<br />
activation. Ticagrelor and its active metabolite<br />
are approximately equipotent.<br />
• Transitioning from clopidogrel to ticagrelor<br />
resulted in an absolute inhibition of platelet<br />
inhibition (IPA) increase of 26.4% and from<br />
ticagrelor to clopidogrel resulted in an absolute<br />
IPA decrease of 24.5%. Patients can be<br />
transitioned from clopidogrel to ticagrelor<br />
without interruption of antiplatelet effect<br />
Mean inhibition of platelet aggregation (±SE) following<br />
single oral doses of placebo, 180 mg ticagrelor, or 600<br />
mg clopidogrel<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor - Brilinta<br />
• Metabolism: CYP3A4 is the major enzyme responsible<br />
for ticagrelor metabolism and the formation of its<br />
major active metabolite. Ticagrelor and its major active<br />
metabolite are weak P-glycoprotein substrates and<br />
inhibitors.<br />
• The mean t1/2 is approximately 7 hours for ticagrelor<br />
and 9 hours for the active metabolite.<br />
• The mean absolute bioavailability of ticagrelor is about<br />
36%, (range 30%-42%) and it can be taken without<br />
regard to meals.<br />
• The effects of age, gender, ethnicity, renal impairment<br />
and mild hepatic impairment on the pharmacokinetics<br />
of ticagrelor are modest and do not require dose<br />
adjustment.<br />
Ticagrelor - Brilinta<br />
Effects of Other <strong>Drug</strong>s on Ticagrelor<br />
• CYP3A4 is the major enzyme responsible for ticagrelor<br />
metabolism and the formation of its major active<br />
metabolite.<br />
– Strong CYP3A inhibitors (e.g., atazanavir, clarithromycin,<br />
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,<br />
ritonavir, saquinavir, telithromycin and voriconazole)<br />
substantially increase ticagrelor exposure and are not<br />
recommended<br />
– Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem<br />
and verapamil) and do not require a dosage adjustment<br />
– CYP3A inducers (e.g., rifampin, dexamethasone, phenytoin,<br />
carbamazepine, and phenobarbital) substantially reduce<br />
ticagrelor blood levels and are not recommended<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor - Brilinta<br />
Effects of Ticagrelor on Other Medications:<br />
• Patients receiving more than 40 mg per day of<br />
simvastatin or lovastatin may be at increased risk of<br />
statin-related adverse effects.<br />
• Monitor digoxin levels with initiation of or any change<br />
in ticagrelor because of P-glycoprotein transporter<br />
inhibition<br />
Concomitant Aspirin Maintenance Dose: In PLATO, use of<br />
ticagrelor with maintenance doses of aspirin above 100<br />
mg decreased the effectiveness of ticagrelor. Therefore,<br />
after the initial loading dose of aspirin (usually 325 mg),<br />
use ticagrelor with a maintenance dose of aspirin of 75-<br />
100 mg<br />
Ticagrelor – Brilinta<br />
N Engl J Med 2009;361:1045-57<br />
• PLATO Trial, a randomized double-blind study comparing<br />
ticagrelor (180 mg LD then 90 mg BID)(N=9333) to<br />
clopidogrel (300mg LD then 75 mg QD) (N=9291), both<br />
given in combination with aspirin (75-100 mg QD but<br />
higher doses were allowed per investigator) and other<br />
standard therapy, in patients with acute coronary<br />
syndromes (ACS). Patients were treated for at least 6<br />
months and for up to 12 months.<br />
– Patients were predominantly male (72%) and Caucasian (92%).<br />
About 43% of patients were >65 years and 15% were >75 years.<br />
– Primary endpoint was the composite of first occurrence of<br />
cardiovascular death, non-fatal MI (excluding silent MI), or nonfatal<br />
stroke. The components were assessed as secondary<br />
endpoints<br />
– Median exposure to study drug was 277 days<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor – Brilinta<br />
N Engl J Med 2009;361:1045-57<br />
Endpoint<br />
Primary Composite<br />
(CV death, MI, CVA)<br />
Secondary Endpoints<br />
Ticagrelor<br />
N=9333<br />
Clopidogrel<br />
N=9291<br />
Hazard Ratio<br />
(95% CI)<br />
9.8% 11.7% 0.84<br />
(0.77-0.92)<br />
CV death 4.0% 5.1% 0.79<br />
(0.69-0.91)<br />
MI 5.8% 6.9% 0.84<br />
(0.75-0.95)<br />
Stroke 1.5% 1.3% 1.17<br />
(0.91-1.52)<br />
All cause mortality 4.5% 5.9% 0.78<br />
(0.69-0.89)<br />
In-stent thrombosis<br />
(11,289 pts with<br />
PCI/stenting)<br />
1.3% 1.9% 0.67<br />
(0.50-0.91)<br />
P-value ARR/NNT<br />
0.0003 1.9%/53<br />
0.0013 1.1%/91<br />
0.0045 1.1%/91<br />
0.22<br />
0.0003 1.4%/72<br />
0.0091 0.6%/167<br />
Ticagrelor – Brilinta<br />
N Engl J Med 2009;361:1045-57.<br />
• No significant difference in the rates of major bleeding<br />
was found between the ticagrelor and clopidogrel<br />
groups (11.6% and 11.2%, respectively; P = 0.43)<br />
• Ticagrelor was associated with a higher rate of major<br />
bleeding not related to coronary-artery bypass grafting<br />
(4.5% vs. 3.8%, P = 0.03, ARI = 0.7%, NNH = 143)<br />
including more instances of fatal intracranial bleeding<br />
and fewer of fatal bleeding of other types.<br />
• In a genetic substudy of PLATO (n=10,285), the effects<br />
of ticagrelor compared to clopidogrel on thrombotic<br />
events and bleeding were not significantly affected by<br />
CYP2C19 genotype.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
PLATO: CV Death, MI, Stroke by<br />
maintenance aspirin dose in the US and<br />
outside the US<br />
Ticagrelor – Brilinta<br />
N Engl J Med 2009;361:1045-57<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor – Brilinta<br />
• Dyspnea was usually mild to moderate in intensity and often<br />
resolved during continued treatment. If a patient develops new,<br />
prolonged, or worsened dyspnea during treatment with ticagrelor,<br />
exclude underlying diseases that may require treatment. If dyspnea<br />
is determined to be related to ticagrelor, no specific treatment is<br />
required; continue ticagrelor without interruption<br />
• Serum Uric Acid: Serum uric acid levels increased approximately 0.6<br />
mg/dL from baseline on ticagrelor and approximately 0.2 mg/dL on<br />
clopidogrel in PLATO. The difference disappeared within 30 days of<br />
discontinuing treatment. Reports of gout did not differ between<br />
treatment groups in PLATO (0.6% in each group).<br />
• Serum Creatinine: In PLATO, a >50% increase in serum creatinine<br />
levels was observed in 7.4% of patients receiving ticagrelor<br />
compared to 5.9% of patients receiving clopidogrel. The increases<br />
typically did not progress with ongoing treatment and often<br />
decreased with continued therapy.<br />
Ticagrelor – Brilinta<br />
BOX WARNING: BLEEDING RISK<br />
• BRILINTA, like other antiplatelet agents, can cause significant, sometimes<br />
fatal, bleeding .<br />
• Do not use BRILINTA in patients with active pathological bleeding or a<br />
history of intracranial hemorrhage.<br />
• Do not start BRILINTA in patients planned to undergo urgent coronary<br />
artery bypass graft surgery (CABG). When possible, discontinue BRILINTA<br />
at least 5 days prior to any surgery.<br />
• Suspect bleeding in any patient who is hypotensive and has recently<br />
undergone coronary angiography, percutaneous coronary intervention<br />
(PCI), CABG, or other surgical procedures in the setting of BRILINTA.<br />
• If possible, manage bleeding without discontinuing BRILINTA. Stopping<br />
BRILINTA increases the risk of subsequent cardiovascular events.<br />
• WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS<br />
• Maintenance doses of aspirin above 100 mg reduce the effectiveness of<br />
BRILINTA and should be avoided. After any initial dose, use with aspirin<br />
75-100 mg per day<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Ticagrelor – Brilinta<br />
DOSAGE AND ADMINISTRATION:<br />
• Initiate ticagrelor treatment with a 180 mg (two<br />
90 mg tablets) loading dose and continue<br />
treatment with 90 mg twice daily with or without<br />
food<br />
• After the initial loading dose of aspirin (usually<br />
325 mg), use ticagrelor with a daily maintenance<br />
dose of aspirin of 75-100 mg (typically 81mg)<br />
COST: $7.24 per day or $217.20 per month WAC<br />
Dronedarone – Multaq<br />
by Sanofi Aventis<br />
• Indicated to reduce the<br />
risk of cardiovascular<br />
hospitalization in patients<br />
with paroxysmal or<br />
persistent atrial fibrillation<br />
(AF) or atrial flutter (AFL),<br />
with a recent episode of<br />
AF/AFL and associated<br />
cardiovascular risk factors<br />
• Dose 400 mg tablets BID<br />
with food $297.00/60<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
• ATHENA was a double blind, and randomized placebocontrolled<br />
study of dronedarone in 4628 patients with a<br />
recent history of AF/AFL who were in sinus rhythm or who<br />
were to be converted to sinus rhythm.<br />
– The objective of the study was to determine whether dronedarone<br />
could delay death from any cause or hospitalization for cardiovascular<br />
reasons.<br />
– Subjects were randomized and treated for up to 30 months (median<br />
follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301<br />
patients) or placebo (2327 patients), in addition to conventional<br />
therapy for cardiovascular diseases that included beta-blockers (71%),<br />
ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin<br />
(14%), calcium antagonists (14%), statins (39%), oral anticoagulants<br />
(60%), aspirin (44%), other chronic antiplatelet therapy (6%) and<br />
diuretics (54%).<br />
ATHENA Results:<br />
Dronedarone - Multaq<br />
• Primary endpoint (median follow up 22 months)<br />
– Cardiovascular hospitalization or death from any cause 913<br />
(39.2%) placebo vs 727 (31.6%) dronedarone HR 0.76 or<br />
24% RRR, 7.6% ARR, NNT=14, p
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
ANDROMEDA Study (Increased Mortality in Patients with Severe<br />
Heart Failure)<br />
• Patients recently hospitalized with symptomatic heart failure<br />
and severe left ventricular systolic dysfunction were<br />
randomized to either MULTAQ 400 mg twice daily or matching<br />
placebo, with a primary composite end point of all-cause<br />
mortality or hospitalization for heart failure.<br />
• After enrollment of 627 of 1000 planned patients (310 and<br />
317 in the dronedarone and placebo groups, respectively),<br />
and a median follow-up of 63 days, the trial was terminated<br />
because of excess mortality in the dronedarone group.<br />
Twenty-five (25) patients in the dronedarone group (8.1%)<br />
versus 12 patients in the placebo group (3.8%) had died,<br />
hazard ratio 2.13; 95% CI: 1.07 to 4.25; p=0.027. ARI 4.3%,<br />
NNH = 26.<br />
Dronedarone - Multaq<br />
BOX WARNING: HEART FAILURE<br />
• MULTAQ is contraindicated in patients with NYHA Class IV<br />
heart failure, or NYHA Class II - III heart failure with a recent<br />
decompensation requiring hospitalization or referral to a<br />
specialized heart failure clinic<br />
• Contraindications:<br />
– Second- or third-degree atrioventricular (AV) block or sick sinus<br />
syndrome (except when used in conjunction with a functioning<br />
pacemaker)<br />
– Bradycardia less than 50 bpm<br />
– Concomitant use of strong CYP 3A inhibitors, such as ketoconazole,<br />
itraconazole, voriconazole, cyclosporine, telithromycin,<br />
clarithromycin, nefazodone, and ritonavir<br />
– Concomitant use of drugs or herbal products that prolong the QT<br />
interval and might increase the risk of Torsade de Pointes, such as<br />
phenothiazine anti-psychotics, tricyclic antidepressants, certain oral<br />
macrolide antibiotics, and Class I and III antiarrhythmics<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
• DIONYSOS Trial evaluating the efficacy and safety of<br />
dronedarone versus amiodarone for the<br />
maintenance of sinus rhythm in 504 patients with<br />
persistent Atrial Fibrillation (AF) for a short<br />
treatment duration (mean follow up of 7 months).<br />
– AF recurrence or premature drug discontinuation for<br />
intolerance or lack of efficacy). There were 184 patients<br />
(73.9%) who reached the primary endpoint in the<br />
dronedarone arm as compared to 141 (55.3%) in the<br />
amiodarone arm (p
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
Recommendation for Rate Control During Atrial Fibrillation<br />
• <strong>2011</strong> Focused <strong>Update</strong> Recommendation Comments Class III–No Benefit<br />
• Treatment to achieve strict rate control of heart rate (
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
<strong>New</strong> Safety Concern July 7, <strong>2011</strong> Paris, France<br />
Sanofi, maker of dronedarone (Multaq), has<br />
suspended its phase 3b trial of its<br />
antiarrhythmic drug due to a significant increase<br />
in cardiovascular events seen in patients<br />
randomized to dronedarone. The PALLAS trial<br />
(begun 7-<strong>2010</strong>) was testing the drug in ~10,000<br />
patients with permanent atrial fibrillation and at<br />
least one other cardiovascular disease risk<br />
factor; at present, dronedarone is approved in<br />
patients with nonpermanent AF.<br />
Events during the PALLAS study as of<br />
June 30, <strong>2011</strong>.(FDA MedWatch 7-21-<strong>2011</strong>)<br />
CV Death, Myocardial<br />
Infarction, Stroke, Systemic<br />
Embolism*<br />
Death, Unplanned CV<br />
Hospitalization*<br />
Multaq<br />
N=1572<br />
n (%)<br />
Placebo<br />
N=1577<br />
n (%)<br />
Hazard<br />
Ratio/NNH<br />
32 (2) 14 (0.9) 2.3/91 0.009<br />
118 (7.5) 81 (5.1) 1.5/42 0.006<br />
Death 16 (1) 7 (0.4) 2.3 0.065<br />
Myocardial Infarction 3 (0.2) 3 (0.2) 1.0 1<br />
Stroke 17 (1.1) 7 (0.4) 2.4/143 0.047<br />
Heart Failure Hospitalization 34 (2.2) 15 (1) 2.3/84 0.008<br />
*coprimary endpoints<br />
p-value<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Dronedarone - Multaq<br />
Sept 22, <strong>2011</strong> The European Medicines Agency<br />
(EMA) recommends restricting the use of the<br />
antiarrhythmic medication dronedarone. The<br />
committee states that because of the increased<br />
risk of liver, lung, and cardiovascular adverse<br />
events, dronedarone "should only be prescribed<br />
after alternative treatment options have been<br />
considered." Patients currently taking<br />
dronedarone should have their treatment<br />
reassessed by their physician at their next<br />
scheduled visit<br />
Pitavastatin - Livalo<br />
by Kowa and Lilly<br />
• A synthetic competitive<br />
lipophilic 3-hydroxy-3-<br />
methylglutaryl-coenzyme A<br />
(HMG-CoA) reductase<br />
inhibitor.<br />
• Pitavastatin elimination<br />
half-life is 10 to 12 hours<br />
• The effect of pitavastatin<br />
on cardiovascular morbidity<br />
and mortality has not been<br />
determined.<br />
• Pitavastatin is<br />
administered orally once<br />
daily, with or without<br />
food, at any time of day.<br />
The dosage range is 1 to<br />
4 mg once daily. The<br />
maximum dosage is 4 mg<br />
per day.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Pitavastatin - Livalo<br />
• Mean Change from Baseline to Week 12<br />
Treatment LDL-C Apo B TC TG HDL-C<br />
Pitavastatin 2 mg (n= 307) -39% -30% -28% -16% 6%<br />
Pitavastatin 4 mg (n= 319) -44% -35% -32% -17% 6%<br />
Simvastatin 20 mg (n= 107) -35% -27% -25% -16% 6%<br />
Simvastatin 40 mg (n= 110) -43% -34% -31% -16% 7%<br />
The most frequent adverse effects, occurring in at least 2% of patients<br />
receiving one of the available doses, were myalgia, back pain, diarrhea,<br />
constipation, and pain in extremity.<br />
Pitavastatin - Livalo<br />
• DRUG INTERACTIONS: Several agents<br />
(cyclosporine-avoid, rifampin-max 2mg,<br />
eryrthromycin-max 1 mg, gemfibrozil and<br />
lopinovir/retonavir-caution) have the<br />
potential to interact with the organic anion<br />
transporting polypeptide–mediated uptake of<br />
pitavastatin.<br />
• 1, 2, and 4 mg tablets supplied in bottles of<br />
90 tablets. The cost for all three doses is<br />
$119.00/30 AWP.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Denosumab – Prolia<br />
by Amgen<br />
Dosage 60 mg Sub Q every 6 months $990.00/dose AWP<br />
Denosumab - Prolia<br />
• A fully human<br />
monoclonal antibody to<br />
the receptor activator of<br />
nuclear factor-kappa B<br />
ligand (RANKL)<br />
.<br />
• Prevention of the<br />
RANKL/RANK<br />
interaction inhibits<br />
osteoclast formation,<br />
function, and survival,<br />
thereby decreasing<br />
bone resorption and<br />
increasing bone mass<br />
and strength in both<br />
cortical and trabecular<br />
bone.<br />
FDA approved for the treatment of<br />
postmenopausal women with<br />
osteoporosis at high risk for fracture,<br />
defined as a history of osteoporotic<br />
fracture, or multiple risk factors for<br />
fracture; or patients who have failed or<br />
are intolerant to other available<br />
osteoporosis therapy<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Denosumab - Prolia<br />
• FREEDOM Trial<br />
– 7868 women between the ages of 60 and<br />
90 years who had a bone mineral density T<br />
score of less than 2.5 but not less than<br />
4.0 at the lumbar spine or total hip.<br />
– Subjects were randomly assigned to<br />
receive either 60 mg of denosumab or<br />
placebo subcutaneously every 6 months<br />
for 36 months<br />
– The primary end point was new vertebral<br />
fracture. Secondary end points included<br />
nonvertebral and hip fractures<br />
Denosumab - Prolia<br />
• FREEDOM Trial results at 3 years<br />
Fracture Type Placebo Denosumab RRR ARR NNT<br />
Vertebral 7.2% 2.3% 68% 4.9% 21<br />
Non-vertebral 8.0% 6.5% 20% 1.5% 67<br />
Hip 1.2% 0.7% 40% 0.5% 200<br />
Eczema and increased rates of hospitalization for cellulitis were the<br />
only two statistically significant adverse effects reported in this trial<br />
along with an increase in flatulence.<br />
N Engl J Med 2009;361:756-65<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
FREEDOM Trial 5 Year Data<br />
• May 2, <strong>2011</strong> (San Diego, California) — Results from the first 2 years of the<br />
international multicenter (FREEDOM) trial 10 year extension, in 4550<br />
postmenopausal women with osteoporosis, showed that the drug<br />
maintains its efficacy in improving bone mineral density (BMD) and<br />
reducing the incidence of fractures over 5 years without any increase in<br />
adverse events, according to researchers here at the American Association<br />
of Clinical Endocrinologists 20th Annual Meeting and Clinical Congress.<br />
– In the fourth and fifth year of denosumab treatment, those in the original intervention<br />
group (2342 women) experienced further benefits in BMD of the lumbar spine and hip.<br />
In the fourth year, BMD of the lumbar spine increased by 1.9% in the long-term<br />
treatment group and BMD of the hip increased by 0.7%. In the fifth year of treatment,<br />
BMD of the lumbar spine increased by 1.7% in the long-term treatment group and BMD<br />
of the total hip increased by 0.6%.<br />
– The de novo group (2207 women) in the extension trial experienced improvements in<br />
BMD similar to those seen in the intervention group in the first 2 years of the original<br />
FREEDOM trial. In the first 2 years of their treatment, the crossover group experienced a<br />
7.9% increase in lumbar spine BMD and a 4.1% increase in total hip BMD (P < .0001,<br />
compared with baseline).<br />
FREEDOM Trial 5 Year Data<br />
• The yearly incidence of new vertebral fractures was 1.4% in<br />
the long-term denosumab group and 0.9% in the crossover<br />
group. Rates of new nonvertebral fractures were also low,<br />
with a yearly incidence of 1.4% in the fourth year and 1.1% in<br />
the fifth year for the long-term treatment group. In contrast,<br />
the yearly incidence rate of new nonvertebral fractures in the<br />
crossover group was 2.4% in the first year of treatment and<br />
1.7% in the second year of treatment<br />
• The incidence of serious adverse events were low, with just 2<br />
cases of osteonecrosis of the jaw and 1 case of cellulitis in the<br />
crossover group of the extension trial. Three subjects in the<br />
long-term treatment group experienced cellulitis.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Denosumab - Prolia<br />
Risedronate – Atelvia<br />
by Warner Chilcott<br />
• Like other oral agents in this<br />
class the oral bioavailabilty is<br />
very poor ~0.063%<br />
• Dosage of delayed-release<br />
risedronate is 35 mg once<br />
weekly, taken in the morning<br />
immediately following<br />
breakfast with at least 4<br />
ounces of plain water.<br />
– The tablets should be<br />
swallowed whole while the<br />
patient is in an upright<br />
position. Patients should<br />
be instructed not to lie<br />
down for 30 minutes.<br />
Cost: Dosepak of 4 tablets of 35mg<br />
for $121.78 AWP.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Risedronate - Atelvia<br />
• The efficacy of Atelvia 35 mg once-a-week in the<br />
treatment of postmenopausal osteoporosis was<br />
demonstrated in a randomized, double-blind, activecontrol<br />
trial of approximately 900 subjects.<br />
• All patients in this study received supplemental<br />
calcium (1000 mg/day) and vitamin D (800 – 1000<br />
IU/day).<br />
• The primary efficacy endpoint was percent change in<br />
lumbar spine bone mineral density at 1 year.<br />
• Atelvia 35 mg once-a -week administered after<br />
breakfast was shown to be non-inferior to<br />
risedronate sodium immediate-release 5 mg daily<br />
(3.3% vs. 3.1% increase in lumbar spine BMD)<br />
Risedronate - Atelvia<br />
HIP Trial (NEJM 2001;344:333-340)<br />
• 5445 women 70 to 79 years old who had osteoporosis<br />
(indicated by a T score for BMD at the femoral neck that was<br />
more than 4 SD below the mean peak value in young adults<br />
or lower than -3 plus a nonskeletal risk factor for hip<br />
fracture, such as poor gait or a propensity to fall) and 3886<br />
women at least 80 years old who had at least one<br />
nonskeletal risk factor for hip fracture or low bone mineral<br />
density at the femoral neck (T score, lower than -4<br />
• Patients were randomly assigned to receive treatment with<br />
oral risedronate (2.5 or 5.0 mg daily) or placebo for three<br />
years.<br />
• The primary end point was the occurrence of hip fracture.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Risedronate - Atelvia<br />
HIP Trial results: (NEJM 2001;344:333-340)<br />
• Hip fractures<br />
Group Placebo n % Fx <strong>Drug</strong> n % Fx RRR P Value ARR NNT<br />
Overall 3134 3.9% 6197 2.8% 30% 0.02 1.1% 91<br />
Age 70-79 1821 3.2% 3624 1.9% 40% 0.009 1.3% 77<br />
+Hx Vert Fx 575 5.7% 1128 2.3% 60% 0.003 3.4% 30<br />
-Hx Vert Fx 875 1.6% 1773 1.0% 40% 0.14 ns<br />
Age 80+* 1313 5.1% 2573 4.2% 20% 0.35 ns<br />
*Women 80 and older did not have to have documented osteoporosis on the<br />
basis of low T-scores only one or more clinical risk factors, BMD is a better<br />
predictor of fracture risk than clinical risk factors in the absence of a history of fracture.<br />
Non-vertebral fractures (overall)<br />
11.2% placebo vs. 9.4% risedronate RRR 20% (P=0.03);<br />
ARR 2.8%; NNT 33<br />
Risedronate - Atelvia<br />
Table 4. Adverse Reactions Occurring in 3% of Patients With Delayed-Release<br />
vs Immediate-Release Risedronate<br />
Delayed-Release 35 mg Weekly<br />
After Breakfast (n = 307)<br />
Immediate-Release 5 mg Daily<br />
Before Breakfast (n = 307)<br />
Diarrhea 8.8% 4.9%<br />
Influenza 7.2% 6.2%<br />
Arthralgia 6.8% 7.8%<br />
Back pain 6.8% 5.9%<br />
Abdominal pain 5.2% 2.9%<br />
Constipation 4.9% 2.9%<br />
Vomiting 4.9% 1.6%<br />
Bronchitis 3.9% 4.2%<br />
Dyspepsia 3.9% 3.9%<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Vilazodone HCl - Viibryd<br />
by Trovis/Forest<br />
• Approved for the treatment of<br />
adults with major depressive<br />
disorder (MDD).<br />
• An SSRI and partial serotonin<br />
5-HT1A receptor agonist.<br />
• It is not clear what role the<br />
partial agonist activity<br />
contributes to the clinical<br />
activity of vilazodone.(like<br />
adding buspirone to an SSRI?)<br />
• Metabolized by CYP 3A4 and<br />
has a T1/2 of about 25 hours<br />
• 10, 20 and 40<br />
mg tablets<br />
Vilazodone HCl - Viibryd<br />
• A randomized, double-blind, placebo-controlled trial with<br />
an 8-week treatment duration enrolled 410 adults 18 to<br />
65 years of age diagnosed with a single or recurrent<br />
episode of MDD lasting for periods between 4 weeks<br />
and 2 years with a score of at least 22 on the 17-item<br />
Hamilton Rating Scale for Depression (HAM-D-17) and a<br />
score of at least 2 on the HAM-D-17 item 1 (depressed<br />
mood). (J Clin Psychiatry. 2009;70(3):326-333)<br />
– Patients were randomized (1:1) to receive placebo or vilazodone<br />
10 mg/day in week 1. The dosage was increased to 20 mg/day in<br />
week 2, and then to 40 mg/day for the remainder of the 8-week<br />
study.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Vilazodone HCl - Viibryd<br />
• The primary outcome of the study was mean change<br />
from baseline to week 8 (end of treatment) on the<br />
Montgomery-Asberg Depression Rating Scale (MADRS)<br />
total score.<br />
– Mean change from baseline to week 8 in MADRS total score<br />
was 12.9 with vilazodone compared with 9.6 with placebo (P =<br />
0.001).<br />
– Vilazodone also resulted in significant reductions in the HAM-D-<br />
17 (10.4 vs 8.6, P = 0.022),<br />
– Response, defined as a 50% or greater reduction in total score<br />
from baseline to week 8 on the MADRS or HAM-D-17 total<br />
scores, or a score of 1 or 2 on the CGI-I, was achieved in 40% to<br />
48% of vilazodone-treated patients compared with 28% to 32%<br />
of placebo recipients.<br />
– The discontinuation rate in the vilazodone arm was 9.3%<br />
compared with 4.9% in the placebo group (primarily diarrhea)<br />
Vilazodone HCl - Viibryd<br />
WARNINGS AND PRECAUTIONS<br />
• Vilazodone labeling includes class cautions regarding<br />
clinical worsening and suicide risk (Box Warning),<br />
serotonin syndrome, neuroleptic malignant–like<br />
syndrome, seizures, abnormal bleeding, activation of<br />
mania/hypomania, and hyponatremia<br />
• A gradual dosage reduction is recommended to minimize<br />
discontinuation symptoms<br />
• The vilazodone dose should be reduced to 20 mg when<br />
coadministered with strong CYP3A4 inhibitors.<br />
• Coadministration of vilazodone with CYP3A4 inducers<br />
can result in reduced vilazodone concentrations, and<br />
may reduce its effectiveness.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Vilazodone HCl - Viibryd<br />
Table 3. Most Common Adverse Events With Vilazodone Reported<br />
in Placebo-Controlled Depression Studies in Patients With MDD<br />
Vilazodone 40 mg/day (n = 436) Placebo (n = 433)<br />
Diarrhea 28% 9%<br />
Nausea 23% 5%<br />
Dizziness 9% 5%<br />
Dry mouth 8% 5%<br />
Insomnia 6% 2%<br />
Vomiting 5% 1%<br />
Fatigue 4% 3%<br />
Abnormal dreams 4% 1%<br />
Libido decreased 4% < 1%<br />
Somnolence 3% 2%<br />
Orgasm abnormal 3% 0%<br />
Vilazodone HCl - Viibryd<br />
Dosing:<br />
• The recommended dosage of vilazodone is 40 mg once<br />
daily. Therapy should be initiated with a dosage of 10 mg<br />
once daily for 7 days, then 20 mg once daily for an<br />
additional 7 days, and then increased to 40 mg once<br />
daily. When discontinuing therapy, the dosage should be<br />
reduced gradually.<br />
• Vilazodone should be taken with food. Administration<br />
without food may result in inadequate absorption and<br />
reduced effectiveness.<br />
• Cost $144.00/30 x 40 mg tabs WAC<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Roflumilast - Daliresp<br />
by Forest Labs • Dose 500 mcg QD with<br />
or without food<br />
• Indicated as a treatment to<br />
reduce the risk of COPD<br />
exacerbations in patients with<br />
severe COPD associated with<br />
chronic bronchitis and a<br />
history of exacerbations<br />
• Neutrophils, eosinophils, and<br />
monocytes contain PDE4.<br />
Roflumilast is believed to<br />
exert an anti-inflammatory<br />
effect through inhibition of<br />
PDE4 in these cell types<br />
• Cost $211.50/30 tabs<br />
WAC<br />
Roflumilast - Daliresp<br />
• The pharmacologically active N-oxide metabolite is<br />
estimated to account for about 90% of roflumilast’s<br />
overall pharmacologic effects. The elimination halflife<br />
of the N-oxide metabolite is approximately 21 to<br />
27 hours. Roflumilast N-oxide is predominantly<br />
metabolized via CYP3A4<br />
• <strong>Drug</strong> Interactions: Use with strong cytochrome P450<br />
enzyme inducers (e.g. rifampicin, phenobarbital,<br />
carbamazepine, phenytoin) is not recommended.<br />
• CYP3A4 inhibitors or dual inhibitors that inhibit both<br />
CYP3A4 and CYP1A2 simultaneously (e.g.,<br />
erythromycin, ketoconazole, fluvoxamine, enoxacin,<br />
cimetidine) may increase roflumilast systemic<br />
exposure and may result in increased adverse<br />
reactions. The risk of such concurrent use should be<br />
weighed carefully against benefit.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Roflumilast - Daliresp<br />
• 3 placebo controlled trials in patients with COPD and<br />
at least 1 exacerbation requiring steroids in the last<br />
year randomized to either roflumilast 500 mcg or<br />
placebo QD for 52 weeks.<br />
– Change in postbrochodilator FEV ranged from<br />
39-61 ml increase with roflumilast vs. placebo<br />
– Minimal reduction in moderate to severe<br />
exacerbations in 2 of the 3 trials- RR 0.85 and 0.82<br />
(RRR 15 and 18%) (0.19 and 0.28 exacerbations<br />
per year)<br />
Roflumilast - Daliresp<br />
• Roflumilast 500 mcg plus salmeterol in patients with<br />
moderate to severe COPD vs. placebo plus<br />
salmeterol for 24 weeks.<br />
– Change in postbrochodilator FEV 1 60 ml increase<br />
with roflumilast vs. placebo<br />
– Non-significant reduction in mild, moderate or<br />
severe exacerbations with roflumilast vs. placebo<br />
RR 0.79 (P=0.1408) 2.4 VS. 1.9 exacerbations per<br />
year<br />
– Proportion of patients with a moderate or severe<br />
exacerbation RR 0.6 (P=0.0015) 18% vs. 11%<br />
– ARR 7%, NNT ~15<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Roflumilast - Daliresp<br />
• Roflumilast 500 mcg plus tiotropium in patients with<br />
moderate to severe COPD vs. placebo plus<br />
tiotropium for 24 weeks.<br />
– Change in postbronchodilator FEV 1<br />
81 ml<br />
increase with roflumilast vs. placebo<br />
– Non-significant reduction in number of mild,<br />
moderate or severe exacerbations with roflumilast<br />
vs. placebo RR 0.84 (P=0.357) 2.2 vs. 1.8<br />
exacerbations per year<br />
– Proportion of patients with a moderate or severe<br />
exacerbation RR 0.73 NS (P=0.0867)<br />
Roflumilast - Daliresp<br />
Warnings and Precautions;<br />
• Acute bronchospasm: Do not use for the relief of acute<br />
bronchospasm.<br />
• Psychiatric Events including Suicidality: Advise patients ,their<br />
caregivers, and families to be alert for the emergence or worsening of<br />
insomnia, anxiety, depression, suicidal thoughts or other mood<br />
changes, and if such changes occur to contact their healthcare<br />
provider. Carefully weigh the risks and benefits of treatment with<br />
roflumilast in patients with a history of depression and/or suicidal<br />
thoughts or behavior. In 8 controlled clinical trials 5.9% (263) of<br />
patients treated with roflumilast 500 mcg daily reported psychiatric<br />
adverse reactions compared to 3.3% (137) treated with placebo<br />
• Weight Decrease: Monitor weight regularly. If unexplained or clinically<br />
significant weight loss occurs, evaluate weight loss and consider<br />
discontinuation of roflumilast. In the clinical trials weight loss was<br />
reported in 7.5% (331) of patients treated with roflumilast 500 mcg<br />
once daily compared to 2.1% (89) treated with placebo and in the trials<br />
that lasted 1 year 20% of patients receiving roflumilast experienced<br />
moderate weight loss (defined as between 5-10% of body weight)<br />
compared to 7% of patients who received placebo.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Roflumilast - Daliresp<br />
Indacaterol – Arcapta Neohaler<br />
by Novartis<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Indacaterol – Arcapta Neohaler<br />
• A long acting beta 2 agonist that increases cyclic AMP levels<br />
which causes relaxation of bronchial smooth muscle. FDA<br />
approved for the long term, once-daily maintenance<br />
bronchodilator treatment of airflow obstruction in patients<br />
with chronic obstructive pulmonary disease (COPD), including<br />
chronic bronchitis and/or emphysema<br />
• Not indicated to treat acute deteriorations of chronic<br />
obstructive pulmonary disease<br />
– In vitro studies have shown that indacaterol has more than 24-fold<br />
greater agonist activity at beta 2-receptors compared to beta 1-<br />
receptors and 20-fold greater agonist activity compared to beta 3-<br />
receptors. This selectivity profile is similar to formoterol.<br />
– The effective half-life, calculated from the accumulation of indacaterol<br />
after repeated dosing with once daily doses between 75 mcg and 600<br />
mcg ranged from 40 to 56 hours which is consistent with the observed<br />
time-to-steady state of approximately 12-15 days.<br />
Indacaterol – Arcapta Neohaler<br />
BOX WARNING: ASTHMA-RELATED DEATH<br />
• Long-acting beta2-adrenergic agonists (LABA) increase the risk<br />
of asthma-related death. Data from a large placebo-controlled<br />
US study that compared the safety of another long-acting<br />
beta2-adrenergic agonist (salmeterol) or placebo added to<br />
usual asthma therapy showed an increase in asthma-related<br />
deaths in patients receiving salmeterol. This finding with<br />
salmeterol is considered a class effect of LABA, including<br />
indacaterol, the active ingredient in ARCAPTA NEOHALER. The<br />
safety and efficacy of ARCAPTA NEOHALER in patients with<br />
asthma have not been established. ARCAPTA NEOHALER is not<br />
indicated for the treatment of asthma.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Indacaterol – Arcapta Neohaler<br />
Table 2. Pharmacokinetic Parameters for Inhaled Long-Acting<br />
Beta-2 Agonists Administered Using a Portable Inhaler<br />
Pharmacokinetic<br />
Parameter<br />
Formoterol Indacaterol Salmeterol<br />
C max 5 min 15 min 20 min<br />
Half-life 7 to 10 h 30 h 5.5 h<br />
Exchanged in the<br />
urine<br />
2% to 18% < 1% NS<br />
The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the<br />
contents of one 75 mcg capsule using the NEOHALER inhaler. The dose should be<br />
administered once daily every day at the same time of the day by the orally inhaled route<br />
only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do<br />
not use ARCAPTA NEOHALER more than one time every 24 hours.<br />
ARCAPTA capsules must always be stored in the blister, and only removed<br />
IMMEDIATELY BEFORE USE<br />
Indacaterol – Arcapta Neohaler<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Indacaterol – Arcapta Neohaler<br />
Dose-ranging in COPD<br />
• A 2-week, randomized, double-blinded, placebo-controlled<br />
design that enrolled 552 patients with a clinical diagnosis of<br />
COPD, who were 40 years or older, had a smoking history of at<br />
least 10 pack years, had a post-bronchodilator FEV1 less than<br />
80% and at least 30% of the predicated normal value and a<br />
post-bronchodilator ratio of FEV1 over forced vital capacity<br />
(FEV1/FVC) of less than 70%. The trial compared doses of<br />
18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active<br />
control group, and placebo. The trial showed that the effect<br />
on FEV1 in patients treated with 18.75 mcg dose was lower<br />
compared to patients treated with other indacaterol doses.<br />
– Although a dose-response relationship was observed at Day 1, the<br />
effect did not clearly differ among the 37.5, 75 and 150 mcg doses by<br />
Day 15<br />
Indacaterol – Arcapta Neohaler<br />
Like other beta2-agonists, indacaterol can produce a clinically significant cardiovascular<br />
effect in some patients as measured by increases in pulse rate, systolic or diastolic blood<br />
pressure, or symptoms. In addition, beta-agonists have been reported to produce ECG<br />
changes, such as flattening of the T wave, prolongation of the QTc interval, and ST<br />
segment depression, although the clinical significance of these findings is unknown<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Buprenorphine Transdermal System - Butrans<br />
by Purdue Pharma<br />
• Indicated for the management<br />
of moderate to severe chronic<br />
pain in patients requiring a<br />
continuous, around-the-clock<br />
opioid analgesic for an<br />
extended period of time.<br />
• A morphine alkaloid. It is a<br />
partial agonist at mu-opioid<br />
receptors, which mediate<br />
analgesia, and an antagonist at<br />
kappa-opioid receptors which<br />
may reduce abstinenceinduced<br />
dysphoria?<br />
Buprenorphine Transdermal System - Butrans<br />
• The transdermal system is designed to deliver<br />
buprenorphine continuously for 7 days.<br />
– It is designed with 5 layers: a beige-colored web backing layer,<br />
an adhesive rim without buprenorphine, a separating layer over<br />
the buprenorphine-containing adhesive matrix, a buprenorphinecontaining<br />
adhesive matrix, and a peel-off release liner. The skin<br />
is the limiting barrier to diffusion into the systemic circulation.<br />
– Steady state is achieved by day 3 during the first application.<br />
The 5, 10, and 20 mcg/h patches provide dose-proportional total<br />
buprenorphine exposure (area under the curve) following 7-day<br />
application.<br />
– Following removal of transdermal buprenorphine, the mean<br />
buprenorphine concentration decreases approximately 50% in<br />
12 hours (range, 10 to 24 hours), with an apparent terminal halflife<br />
of approximately 26 hours.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Buprenorphine Transdermal System - Butrans<br />
• Transdermal buprenorphine was assessed in a study enrolling 1,160<br />
patients with chronic low back pain currently receiving long-term<br />
opioid therapy (morphine 30 to 80 mg equivalent per day). Patients<br />
entered an open-label, dose-titration period with transdermal<br />
buprenorphine for up to 3 weeks following tapering of prior opioids.<br />
Buprenorphine therapy was initiated with the 10 mcg/h dosage for 3<br />
days and then increased to 20 mcg/h for up to 18 days. Patients with<br />
adequate analgesia and tolerable adverse effects at the 20 mcg/h<br />
dosage were randomized to remain on buprenorphine 20 mcg/h or<br />
were switched to low-dosage control (buprenorphine 5 mcg/h) or an<br />
active control (not specified).<br />
– At least a 30% reduction in pain score from screening to end point was achieved<br />
in 49% of patients treated with the 20 mcg/h dosage compared with 33% of<br />
patients treated with the 5 mcg/h dosage<br />
Buprenorphine Transdermal System - Butrans<br />
• 588 patients with persistent non–cancer-related pain<br />
previously treated with oral opioid combination agents<br />
received transdermal buprenorphine during a 7- to 21-<br />
day open-label titration phase; those achieving stable<br />
pain control (267 patients) were randomized to receive<br />
up to 14 days of buprenorphine at the titrated dose or<br />
placebo.<br />
– Treatment was judged ineffective (requiring more than<br />
acetaminophen 1 g as escape medication on any day of the<br />
double-blind phase, requiring a change in study drug or dose,<br />
having difficulty keeping the patch affixed, or discontinuing<br />
treatment because of a lack of efficacy) in 51.2% of<br />
buprenorphine-treated patients compared with 65% of patients<br />
treated with placebo. The odds of ineffective treatment were 1.79<br />
times greater with placebo than with buprenorphine (P = 0.022).<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Buprenorphine Transdermal System - Butrans<br />
CONTRAINDICATIONS:<br />
• Transdermal buprenorphine is contraindicated in patients<br />
who have significant respiratory depression, patients<br />
with severe bronchial asthma, patients who have or are<br />
suspected of having paralytic ileus, and patients with<br />
known hypersensitivity to any of the product’s<br />
ingredients<br />
• Transdermal buprenorphine is also contraindicated in the<br />
management of acute pain, postoperative pain, mild<br />
pain, and intermittent pain, and in patients who require<br />
short-term opioid analgesic therapy<br />
Buprenorphine Transdermal System - Butrans<br />
WARNINGS AND PRECAUTIONS:<br />
• Box warning regarding proper patient selection, potential for abuse,<br />
and dose limitations. Transdermal buprenorphine should only be<br />
used in the management of moderate to severe pain in patients<br />
requiring a continuous, around-the-clock opioid analgesic for an<br />
extended period of time.<br />
• Transdermal buprenorphine should be used with extreme caution in<br />
patients at risk of respiratory depression, particularly patients with<br />
significant chronic obstructive pulmonary disease or cor pulmonale;<br />
patients at risk of substantially decreased respiratory reserve (eg,<br />
asthma, severe obesity, sleep apnea, myxedema, clinically<br />
significant kyphoscoliosis, CNS depression); and patients with<br />
hypoxia, hypercapnia, or preexisting respiratory depression.<br />
• Buprenorphine is a schedule III controlled substance. Clinical risks<br />
for abuse or addiction should be assessed prior to prescribing the<br />
agent.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Buprenorphine Transdermal System - Butrans<br />
Table 2. Adverse Events of Buprenorphine vs Placebo in Patients Being Treated for Chronic Pain<br />
With a Dose That Was Titrated to Effect<br />
Adverse Events<br />
Buprenorphine<br />
(n = 392)<br />
Placebo<br />
(n = 261)<br />
Nausea 23% 8%<br />
Dizziness 16% 8%<br />
Headache 16% 11%<br />
Application-site pruritus 15% 12%<br />
Constipation 14% 5%<br />
Somnolence 14% 5%<br />
Vomiting 11% 2%<br />
Peripheral edema 7% 3%<br />
Application-site erythema 7% 2%<br />
Dry mouth 7% 2%<br />
Application-site rash 6% 6%<br />
Fatigue 5% 1%<br />
Fall 4% 2%<br />
Hyperhidrosis 4% 1%<br />
Pruritus 4% 1%<br />
Buprenorphine Transdermal System - Butrans<br />
DOSING:<br />
• The transdermal system (patch) is applied every 7 days to the upper<br />
outer arm, upper chest, upper back, or side of the chest on either<br />
side of the body.<br />
– Application should be rotated among these 8 sites and a<br />
minimum of 3 weeks should elapse before applying a patch to<br />
the same site.<br />
– The patch should be applied to a hairless or nearly hairless skin<br />
site. The hair at the site should be clipped, not shaven.<br />
– If there are adhesion problems with the patch, the edges may be<br />
taped down with first aid tape or covered with see-through<br />
adhesive dressing (eg, Bioclusive, Tegaderm).<br />
– If the patch falls off during the 7-day dosing interval, a new patch<br />
should be applied at a different skin site.<br />
– The buprenorphine transdermal system should not be cut.<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Buprenorphine Transdermal System - Butrans<br />
DOSING:<br />
• In opioid-naive patients, the initial dosage should always<br />
be 5 mcg/h. The dosage should not be increased until the<br />
patient has been continuously exposed to the previous<br />
dosage for 72 hours.<br />
• Buprenorphine may precipitate withdrawal in patients<br />
who are already on opioids.<br />
– Prior to converting from another opioid to buprenorphine, the<br />
patient’s current around-the-clock opioid should be tapered to no<br />
more than morphine 30 mg or equivalent per day before beginning<br />
buprenorphine.<br />
– Following initiation of buprenorphine therapy, the dose may be<br />
titrated upward after at least 72 hours at the current dose. Individual<br />
dosage titration should be based on the patient’s requirement for<br />
supplemental short-acting analgesics.<br />
– The maximum transdermal buprenorphine dosage is one 20 mcg/h<br />
system because of potential dose-related QTc prolongation.<br />
Buprenorphine Transdermal System - Butrans<br />
Risk Evaluation and<br />
Mitigations Strategy<br />
(REMS) assessment plan<br />
stated in the FDA’s<br />
approval<br />
Including a surveillance<br />
and monitoring system to<br />
detect abuse, misuse,<br />
overdose, and addiction<br />
and any modifications in<br />
provider education and<br />
drug distribution if these<br />
problems exist<br />
The cost for 4 patches<br />
AWP is;<br />
5 mcg -$151.20<br />
10 mcg - $226.80<br />
20 mcg - $401.52<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Azilsartan medoxomil - Edarbi<br />
by Takeda<br />
• Approved for the treatment of<br />
hypertension, alone or in<br />
combination with other<br />
antihypertensive agents.<br />
• No outcome data<br />
• A prodrug that is structurally<br />
related to candesartan.<br />
Azilsartan medoxomil is rapidly<br />
hydrolyzed to azilsartan in the<br />
GI tract.<br />
• T ½ ~ 11 hours<br />
• Cost $86.00 per 30 tablets<br />
drugstore.com<br />
• Usual dose 80 mg<br />
QD with or<br />
without food<br />
Azilsartan medoxomil - Edarbi<br />
Wayne Weart<br />
<strong>New</strong> <strong>Drug</strong> <strong>Update</strong> Part I
2 nd Annual Essentials in Primary Care<br />
Fall Conference<br />
Friday, November 11, <strong>2011</strong><br />
Azilsartan medoxomil - Edarbi<br />
First ARB in combination with chlorthalidone pending<br />
FDA approval<br />
Change in systolic blood pressure:<br />
End point<br />
Clinic SBP<br />
(change from baseline, mm<br />
Hg)<br />
Change in 24-h mean SBP<br />
(change from baseline, mm<br />
Hg)<br />
Azilsartan<br />
Chlorthalidon<br />
e<br />
40/25 (n=355)<br />
Azilsartan<br />
Chlorthalidone<br />
80/25 (n=352)<br />
Olmesartan<br />
HCTZ<br />
40/25 (n=364)<br />
- 42.5 - 44.0 - 37.1