New Drug Update 2010-2011 Faculty Disclaimer - CME Conferences

2 nd Annual Essentials in Primary Care 

Fall Conference 

Friday, November 11, 2011 

New Drug Update 2010-2011 

C. Wayne Weart, Pharm D, FASHP, FAPhA, BCPS 

Professor of Clinical Pharmacy and Outcome Sciences 

South Carolina College of Pharmacy 

Professor of Family Medicine 

Medical University of South Carolina 

Charleston, South Carolina 

weartcw@musc.edu 

Faculty Disclaimer 

• I am on the speaker’s bureau for Pfizer in 

the areas of cardiovascular disease and 

pain. 

• I am a consultant for Merck in the area of 

outcomes research 

Wayne Weart 

New Drug Update Part I




Colchicine 

• September 30, 2010 FDA notified companies to stop 

manufacturing single-ingredient oral colchicine within 45 days 

and must stop shipping this unapproved product in interstate 

commerce within 90 days. 

• Colcrys is the only FDA-approved single-ingredient oral 

colchicine product available on the U.S. market. Approved by 

the FDA in 2009, Colcrys’ prescribing information contains 

important safety data and recommendations on drug 

interactions and dosing not available with unapproved 

products 

– Max dose 3 x 0.6 mg tabs per acute attack (NOT 4.8 mg total dose) 

– Colchicine is a substrate for CYP 3A4 and efflux pumps (P-glycoprotein) 

Immunization Update 

October 28, 2010 ACIP Recommends Tdap for patients 65 y/o 

and older 

• Tdap can replace Td in adults aged 65 years and older in those 

who have not previously received Tdap. In addition, adults 

aged 65 years or older who anticipate contact with children 

aged 12 months or younger should also be vaccinated to 

protect both themselves and the infant. 

• Tdap vaccine was not licensed for use in adults aged 65 years 

or older until 7/8/2011; however, data from the Vaccine 

Adverse Event Reporting System suggest that the "safety 

profile of Tdap vaccine in these adults is as safe as the Td 

vaccine." 

• "Tdap can be administered regardless of interval since the last 

tetanus or diphtheria containing vaccines." 

Wayne Weart 






• December 22, 2010 HPV Vaccine – Gardasil UPDATE The FDA 

approved vaccination in people ages 9 through 26 years for 

the prevention of anal cancer and associated precancerous 

lesions due to human papillomavirus (HPV) types 6, 11, 16, 

and 18. Gardasil was studied in a randomized, controlled trial 

of men who self-identified as having sex with men (MSM). 

This population was studied because it has the highest 

incidence of anal cancer. At the end of the study period, 

Gardasil was shown to be 78 percent effective in the 

prevention of HPV 16- and 18-related AIN. Because anal 

cancer is the same disease in both males and females, the 

effectiveness data was used to support the indication in 

females as well. (N Engl J Med 2011; 364:401-411) 

PPI’s and Fracture Risk 

• May 25, 2010 FDA Safety Alert PPI’s and Fracture Risk FDA is 

revising the prescription and over-the-counter (OTC) labels for 

a class of drugs called proton pump inhibitors to include new 

safety information about a possible increased risk of fractures 

of the hip, wrist, and spine with the use of these medications. 

– Six epidemiological studies that reported an increased risk of fractures 

of the hip, wrist, and spine with proton pump inhibitor use. Some 

studies found that those at greatest risk for these fractures received 

high doses of proton pump inhibitors or used them for one year or 

more. The majority of the studies evaluated individuals 50 years of age 

or older and the increased risk of fracture primarily was observed in 

this age group. 

– Individuals at risk for osteoporosis should have their bone status 

managed according to current clinical practice, and should take 

adequate vitamin D and appropriate calcium supplementation. (IE a 

soluble calcium salt like calcium citrate) 

Wayne Weart 





Bisphosphonates and Atypical Fractures 

Oct 13, 2010 FDA MedWatch Bisphosphonates (Osteoporosis 

Drugs): Label Change - Atypical Fractures Atypical 

subtrochanteric femur fractures are fractures in the bone just 

below the hip joint. 

These fractures are very uncommon and appear to account for 

less than 1% of all hip and femur fractures overall. The median 

BP treatment duration in patients with atypical subtrochanteric 

and femoral shaft fractures is 7 years. 

The FDA recommends: 

• Evaluate any patient who presents with new thigh or groin 

pain to rule out a femoral fracture. More than half of patients 

reported with atypical femoral fractures have had a prodrome of 

thigh or groin pain before suffering an overt break. 

Bisphosphonates and Atypical Fractures 

Educate physicians and patients about this symptom and for 

physicians to ask patients on BPs and other potent antiresorptive 

agents about thigh or groin pain. Complaints of thigh or groin 

pain in a patient on BPs require urgent radiographic evaluation 

of both femurs (even if pain is unilateral). 

• Discontinue potent antiresorptive medications (including 

bisphosphonates) in patients who have evidence of a femoral 

shaft fracture. anecdotal findings suggest that teriparatide 

therapy can improve or hasten healing of these fractures 

• Consider periodic reevaluation of the need for continued 

bisphosphonate therapy, particularly in patients who have been 

treated for over 5 years. Patients without a recent fracture and 

with femoral neck T scores > -2.5 after the initial therapeutic 

course, consideration may be given to a “drug holiday” 

Wayne Weart 





Pioglitazone and Bladder Cancer? 

• September 17, 2010 FDA Ongoing Safety Review of Actos 

(pioglitazone) and Potential Increased Risk of Bladder Cancer 

– After Two Years Exposure In preclinical carcinogenicity studies of 

pioglitazone, bladder tumors were observed in male rats receiving 

doses of pioglitazone that produced blood drug levels equivalent to 

those resulting from a clinical dose. 

– Additionally, results from two, three-year controlled clinical studies of 

Actos (the PROactive study and a liver safety study) demonstrated a 

higher percentage of bladder cancer cases in patients receiving Actos 

versus comparators 

– A ten-year, observational cohort study as well as a nested case-control 

study in patients with diabetes who are members of Kaiser 

Permanente Northern California (KPNC) health plan. 

• A planned five-year interim analysis was performed with data collected from 

January 1, 1997 through April 30, 2008, the risk of bladder cancer increased with 

increasing dose and duration of Actos use, reaching statistical significance after 24 

months of exposure 

Pioglitazone and Bladder Cancer? 

• Update 6-16-2011 The FDA warned that the diabetes drug 

Actos, known generically as pioglitazone, increases the risk of 

bladder cancer by at least 40% when used for more than a 

year or in higher cumulative doses. The agency said it will 

require changes in the label of the drug to reflect the new 

findings. 

• The FDA is not taking any further action against Actos until it 

receives further results from an ongoing study of the drug, 

but France has already suspended sales and Germany has 

warned physicians not to prescribe the drug to new patients. 

Wayne Weart 





Acetaminophen Update 

January 13, 2011 FDA Drug Safety Communication: Prescription 

Acetaminophen Products to be Limited to 325 mg Per Dosage 

Unit - The FDA is asking drug manufacturers to limit the strength 

of acetaminophen in prescription drug products, which are 

predominantly combinations of acetaminophen and opioids. This 

action will limit the amount of acetaminophen in these products 

to 325 mg per tablet, capsule, or other dosage unit, making 

these products safer for patients. 

• In addition, a Boxed Warning highlighting the potential for 

severe liver injury and a Warning highlighting the potential for 

allergic reactions (e.g., swelling of the face, mouth, and 

throat, difficulty breathing, itching, or rash) are being added 

to the label of all prescription drug products that contain 

acetaminophen. 

PPI’s and Low Serum Magnesium 

March 2, 2011 FDA Safety Communication: Proton Pump Inhibitor 

drugs (PPIs) - Low Magnesium Levels Can Be Associated With 

Long-Term Use 

• Prescription proton pump inhibitor (PPI) drugs may cause low 

serum magnesium levels (hypomagnesemia) if taken for 

prolonged periods of time (in most cases, longer than one 

year). Low serum magnesium levels can result in serious 

adverse events including muscle spasm (tetany), irregular 

heartbeat (arrhythmias), and convulsions (seizures); however, 

patients do not always have these symptoms. Treatment of 

hypomagnesemia generally requires magnesium supplements. 

In approximately one-quarter of the cases reviewed, 

magnesium supplementation alone did not improve low serum 

magnesium levels and the PPI had to be discontinued 

Wayne Weart 






March 24, 2011 Approval Letter – Zostavax for patients 

age 50-59 years 

• Compared with placebo, ZOSTAVAX significantly 

reduced the risk of developing zoster by 69.8% (95% 

CI [54.1 - 80.6%]) in 22,439 subjects 50 to 59 years of 

age. Data from the Shingles Prevention Study 

demonstrated 64% (95% CI 56-71%) efficacy in 

patients age 60-69 years and 41% (95% CI 28 -52%) 

efficacy for patients age 70-79 years and. only 18% 

(95% CI -29 – 48%) efficacy in patients age 80 and 

above. 

New Influenza Vaccine 

• MAY 10, 2011 The FDA has approved the first Fluzone 

Intradermal vaccine for adults 18 through 64 years old. It will 

be available for the 2011-12 influenza season. 

– Sanofi Pasteur's new product has a needle less than a 

tenth of an inch long, attached to a pre-filled syringe that 

holds a smaller amount of influenza vaccine than the 

company' standard flu shots. 

– patients have said they prefer the shorter, slimmer needles 

of the Fluzone Intradermal vaccine, but there's no data yet 

on whether they are less painful 

– Reactions around the injection site, including redness, 

swelling and itching, were more common with the new 

vaccine than with an intramuscular vaccine, company 

research found. 

Wayne Weart 





NIH Stops AIM-HIGH Trial 

• May 26, 2011 The AIM-HIGH trial, which stands for 

Atherothrombosis Intervention in Metabolic Syndrome with 

Low HDL/High Triglycerides: Impact on Global Health, enrolled 

3,414 participants with a history of cardiovascular disease 

who were taking a statin drug to keep their LDL cholesterol 

low. Study participants also had low HDL cholesterol and high 

triglycerides. Patients were randomly assigned to either high 

dose, extended-release niacin (Niaspan) in gradually 

increasing doses up to 2,000 mg per day (1,718 people) or a 

placebo treatment (1,696 people). All participants were 

prescribed simvastatin (Zocor), and 515 participants were 

given a second LDL cholesterol-lowering drug, ezetimibe 

(Zetia), in order to maintain LDL cholesterol levels at the 

target range between 40-80 mg/dL. 

NIH Stops AIM-HIGH Trial 

• The study’s DSMB concluded that high dose, extended-release 

niacin offered no benefits beyond statin therapy alone in 

reducing cardiovascular-related complications in this trial. 

The rate of clinical events was the same in both treatment 

groups, and there was no evidence that this would change by 

continuing the trial andthe DSMB recommended that the 

NHLBI end the study. 

• There was also a small and unexplained increase in ischemic 

stroke rates in the high dose, extended-release niacin group. 

– The Coronary Drug Project Trial with IR niacin found an increase in A 

Fib which might explain the stroke risk? 

Wayne Weart 





Recent FDA Approval 

• May 27, 2011 The FDA approved Dificid (fidaxomicin) tablets 

by Optimer Pharmaceuticals for the treatment of Clostridium 

difficile-associated diarrhea (CDAD). 

– The safety and efficacy of Dificid were demonstrated in two trials that 

included 564 patients with CDAD that compared Dificid with 

vancomycin, a common antibiotic used to treat CDAD. The clinical 

response was similar in the Dificid group compared with the 

vancomycin group in both studies. In some patients with CDAD, 

symptoms can return. In the Dificid trials, a greater number of patients 

treated with Dificid had a sustained cure three weeks after treatment 

ended versus those patients treated with vancomycin. 

– Dificid, a macrolide antibacterial, should be taken 200 mg two times a 

day for 10 days with or without food. Cost ~ $2,800.00 

– The most common side effects reported with Dificid included nausea, 

vomiting, headache, abdominal pain, and diarrhea. 

FDA Safety Update Simvastatin 

• SEARCH was a seven-year, randomized, double-blind clinical 

trial comparing the efficacy and safety of simvastatin 80 mg to 

simvastatin 20 mg, with or without vitamin B12 and folate, in 

survivors of myocardial infarction. 

• At the end of the trial, the incidence of major vascular events 

was 25.7% in the 20-mg group versus 24.5% in the 80-mg 

group [RR=0.094, 95% CI (0.88, 1.01); p=0.10]. Due in part to 

greater use of off-study LDL-C lowering medication in the 

simvastatin 20 mg group versus the 80-mg group, the 

difference in mean levels of LDL-C between the two treatment 

groups was 13 mg/dL instead of the expected difference of 20 

mg/dL. 

Wayne Weart 






• Fifty-two patients (0.9%) in the 80-mg group versus one 

patient (0.02%) in the 20-mg group developed myopathy 

(defined as unexplained muscle weakness or pain with a 

serum CK >10 times the upper limit of normal [ULN]). This was 

higher than the labeled risk (based on clinical trial data) of 

0.53%. 

• Twenty-two patients (0.4%) in the 80-mg group versus no 

patient in the 20-mg group developed rhabdomyolysis 

(defined as unexplained muscle weakness or pain with serum 

CK >40 times ULN). 

• The risks for myopathy and rhabdomyolysis with simvastatin 

80 mg were highest in the first 12 months of treatment, 5 per 

1000 person-years and 2 per 1000 person-years, respectively, 

and decreased to 1 per 1000 person-years and 0.4 per 1000 

person-years after that. 


6-8-2011 FDA Safety Update 

• Based upon data from the SEARCH Trial the FDA is 

recommending limiting the use of the highest 

approved dose of the cholesterol-lowering 

medication, simvastatin (80 mg) because of 

increased risk of muscle damage. 

• Simvastatin 80 mg should be used only in patients 

who have been taking this dose for 12 months or 

more without evidence of muscle injury (myopathy). 

• Simvastatin 80 mg should not be started in new 

patients, including patients already taking lower 

doses of the drug. 

Wayne Weart 






FDA is requiring changes to the simvastatin label to add new 

contraindications (should not be used with certain medications) 

and dose limitations for using simvastatin with certain 

medicines. 

• Contraindicated with : Itraconazole, Ketoconazole, 

Posaconazole (New), Erythromycin, Clarithromycin, 

Telithromycin, HIV/HCV protease inhibitors, Nefazodone, 

Gemfibrozil (old 10mg), Cyclosporine (old 10 mg), and Danazol 

(old 10mg). 

• Maximum 10 mg simvastatin dose with: Amiodarone (old 

20mg), Verapamil (old 20mg) and Diltiazem (old 40 mg). 

• Maximum 20 mg simvastatin dose with: Amlodipine (New) 

and Ranolazine (New) 

Varenicline Safety Update 

6-16-2011 FDA safety update Chantix (varenicline) may increase 

the risk of certain cardiovascular adverse events in patients with 

cardiovascular disease 

FDA reviewed a randomized, double-blind, placebo-controlled 

clinical trial designed to assess the efficacy and safety of Chantix 

for smoking cessation in 700 patients aged 35 to 75 years with 

stable, documented cardiovascular disease (other than, or in 

addition to, hypertension) that had been diagnosed at least two 

months prior to the screening visit. Patients were randomized to 

treatment with Chantix 1 mg twice daily (n=350) or placebo 

(n=350). The study consisted of a 12-week treatment period that 

was followed by a 40-week non-treatment period. 

Wayne Weart 






Adjudicated Cardiovascular Events During the 52-Week 

Study Period (1% in any group) Rigotti et al Circulation 

2011;121:221-229 

Varenicline N=353* n (%) Placebo N=350 n (%) 

Nonfatal myocardial infarction 7 (2.0) 3 (0.9) 

Need for coronary 

revascularizaon† 

8 (2.3) 3 (0.9) 

Hospitalization for angina pectoris 8 (2.3) 8 (2.3) 

New diagnosis of peripheral 

vascular disease (PVD) or 

admission for a procedure for the 

treatment of PVD 

5 (1.4) 3 (0.9) 

The FDA recommends providers weigh the known benefits of Chantix against its 

potential risks when deciding to use the drug in smokers with cardiovascular disease. 

They also are working with the manufacturer to gain further data and plan on further updates. 


• A recent meta-analysis (early release CMAJ 7-4-2011) 

of 14 double blind randomized controlled trials 

involving 8216 participants. The trials ranged in 

duration from 7 to 52 weeks. Varenicline was 

associated with a significantly increased risk of 

serious adverse cardiovascular events compared with 

placebo (1.06% [52/4908] in varenicline group v. 

0.82% [27/3308] in placebo group; Peto odds ratio 

[OR] 1.72, 95% confidence interval [CI] 1.09–2.71. 

RRI 72%; ARI 0.24%; NNH ~400 

– 57.3% of the weight of this meta-analysis comes from the 

recent Circulation data by Rigotti 

Wayne Weart 





Citalopram hydrobromide (Celexa) 

Safety Alert 

August 24, 2011 FDA Drug Safety 

Communication: Abnormal heart rhythms 

associated with high doses of citalopram. 

• Previously doses up to 60 mg per day were 

FDA approved but based upon new data and 

case reports of dose related QT interval 

prolongation, leading to an abnormal heart 

rhythm (including Torsade de Pointes), 

citalopram should no longer be used at doses 

greater than 40 mg per day. 

Citalopram hydrobromide (Celexa) 

Safety Alert 

• Patients at particular risk for developing prolongation 

of the QT interval include those with underlying 

heart conditions and those who are predisposed to 

low levels of potassium and magnesium in the blood. 

• Studies have not shown a benefit in the treatment of 

depression at doses higher than 40 mg per day. 

• Citalopram and sertraline are the recommended 

agents of choice for patients with depression and 

CVD according to the AHA/APA 

– Circulation 2008;118:1768-75 

Wayne Weart 





American Diabetes Association 

ADA/EASD Guidelines 2008 Update (Diabetes Care 2009; 32:193–203) 

Avoid Use of Glyburide? 

In-hospital mortality in patients on sulfonylureas before admission (n = 459) according to the type of sulfonylureas and stratified by 

specific subgroups (J Clin Endocrinol Metab, November 2010, 95(11):4993–5002) 

Wayne Weart 





Proposed Recommendations for Use of 

Metformin Based on e-GFR 

Diabetes Care 2011;34:1435 

eGFR (ml/min per 1.73m2) 

Action 

>60 No renal contraindication to metformin 

>45 Continue use 

Increase monitoring of renal function (every 3–6 

months) 

30 Prescribe metformin with caution 

Use lower dose (e.g., 50%, or half-maximal dose) 

Closely monitor renal function (every 3-6 months) Do 

not start new patients on metformin 




Liraglutide – Victoza 


LEAD 6 Trial (Lancet 2009; 374:39-47) 

• Inadequately controlled type 2 diabetes patients on 

maximally tolerated doses of metformin, sulfonylurea, or 

both, were stratified by previous oral antidiabetic therapy 

and randomly assigned to receive additional liraglutide 1·8 

mg once a day (n=233) or exenatide 10 g twice a day 

(n=231) in a 26-week open-label study. 

• Liraglutide reduced mean HbA1c significantly more than did 

exenade (1·12% vs 0·79%; esmated treatment 

dierence 0·33; 95% CI 0·47 to 0·18; p





Risk of Thyroid C-cell Tumors BLACK BOX WARNING 

• Liraglutide causes dose-dependent and treatmentduration-dependent 

thyroid C-cell tumors 

(adenomas and/or carcinomas) at clinically relevant 

exposures in both genders of rats and mice. 

• In the clinical trials, there have been 4 reported cases 

of thyroid C-cell hyperplasia among Victoza-treated 

patients and 1 case in a comparator-treated patient 

(1.3 vs. 0.6 cases per 1000 patient-years). 

– a 5 year epidemiological study using a large healthcare 

claims database to compare the development of thyroid 

cancer among patients with T2DM who use Victoza to 

those who are not using this medicine. 

– develop a medullary thyroid cancer registry to monitor 

how many cases of medullary thyroid cancer occur each 

year for at least 15 years 


• It is unknown whether Victoza will cause 

thyroid C-cell tumors, including medullary 

thyroid carcinoma (MTC), in humans 

• Counsel patients regarding the risk for MTC 

and the symptoms of thyroid tumors (e.g. a 

mass in the neck, dysphagia, dyspnea or 

persistent hoarseness). 

Wayne Weart 






Pancreatitis: Warnings and Precautions 

• In five clinical trials including more than 3,900 

people, there were seven cases of pancreatitis in 

patients using liraglutide and one case in a patient 

using another diabetes medicine. This constituted a 

4:1 imbalance of pancreatitis cases, when 

considering the number of patient exposures (2.2 vs. 

0.6 cases per 1000 patient-years). 

• Patients taking liraglutide should be aware of the 

symptoms of pancreatitis, such as severe abdominal 

pain that may also radiate into the back, possibly 

with nausea, and vomiting. 


Adverse Effects in Clinical Trials %__ 

• Nausea 28.4 

• Diarrhea 17.1 

• Vomiting 10.9 

• Constipation 9.9 

• Upper Respiratory Tract Infection 9.5 

Wayne Weart 






Linagliptin – Tradjenta 

by Boehringer Ingelheim and Lilly 

• A dipeptidyl peptidase-4 

(DPP-4) inhibitor indicated 

as an adjunct to diet and 

exercise to improve 

glycemic control in adults 

with type 2 diabetes 

mellitus 

• The recommended dose of 

linagliptin is 5 mg once daily 

with or without food. 

• Cost $243.60/30 

tablets AWP 

Wayne Weart 






• Linagliptin is an inhibitor of DPP-4, an enzyme that 

degrades the incretin hormones glucagon-like 

peptide-1 (GLP-1) and glucose-dependent 

insulinotropic polypeptide (GIP). Thus, linagliptin 

increases the concentrations of active incretin 

hormones, GLP-1 and GIP which both increase 

glucose stimulated insulin biosynthesis and secretion 

from pancreatic beta cells. Furthermore, GLP-1 also 

reduces glucagon secretion from pancreatic alpha 

cells, resulting in a reduction in hepatic glucose 

output. 


• The effective half-life for accumulation of linagliptin, 

as determined from oral administration of multiple 

doses of linagliptin 5 mg, is approximately 12 hours. 

• Following administration of an oral [14C]-linagliptin 

dose to healthy subjects, approximately 85% of the 

administered radioactivity was eliminated via the 

enterohepatic system (80%) or urine (5%) within 4 

days of dosing. 

• No dose adjustment is recommended in patients 

with renal impairment. 

Wayne Weart 





Drug Interactions 


• Linagliptin is a weak to moderate inhibitor of CYP isozyme 

CYP3A4, but does not inhibit other CYP isozymes and is not an 

inducer of CYP isozymes. 

• Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P- 

gp mediated transport of digoxin at high concentrations. 

Based on the results of limited drug interaction studies, 

linagliptin is considered unlikely to cause interactions with 

P-gp substrates at therapeutic concentrations. 

• Inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure 

to linagliptin to subtherapeutic and likely ineffective 

concentrations. For patients requiring use of such drugs, an 

alternative to linagliptin is strongly recommended. 


Clinical Trials Monotherapy: 

• 496 patients mean A1c 8.0 treated with 

linagliptin 5 mg QD vs. placebo for 24 weeks 

– A1c -0.4% linagliptin (L) vs. +0.3% placebo (P) 

(difference from placebo -0.7%) 

– Patients achieving A1c





Add on to Metformin: 

• 701 patients on at least 1500 mg/d metformin and 

not at goal A1c (mean baseline 8.1 and 8.0%) had 

either linagliptin 5 mg or placebo added for 24 weeks 

– A1c -0.5% L vs. +0.15% P (difference from placebo -0.6%) 

– Patients achieving A1c





Add on to pioglitazone (30mg) for 24 weeks 

• 389 patients (baseline A1c 8.6%) linagliptin 5 mg plus 

pioglitazone 30mg (LP) vs. piogltazone plus placebo (PP) 

(patients who did not get to goal could have rescue therapy 

with metformin added) 

– A1c -1.1% LP vs. -0.6% PP 

– FPG -32.6 mg/dl LP vs. -18.4 mg/dl PP 

– Metformin rescue was added on 7.9% with LP vs. 14.1% PP 

– Weight changes +2.3 Kg LP and +1.2 Kg PP 

• Diabetes Obes Metab. 2011;13(7):653-661. 10.111/j.1463- 

1326.2011.01391.x. 


Contraindication: 

• Linagliptin is contraindicated in patients with a history of hypersensitivity 

reactions (eg, urticaria, angioedema, bronchial hyperreactivity). 

Adverse Effects: 

• In the clinical trial program, pancreatitis was reported in 8 of 4687 

patients (4311 patient years of exposure) while being treated with 

linagliptin compared with 0 of 1183 patients (433 patient years of 

exposure) treated with placebo. Three additional cases of pancreatitis 

were reported following the last administered dose of linagliptin 

• When linagliptin was administered in combination with metformin and a 

sulfonylurea, 181 of 791 (22.9%) of patients reported hypoglycemia 

compared with 39 of 263 (14.8%) of patients administered placebo in 

combination with metformin and a sulfonylurea 

– When used in combination with an insulin secretagogue (e.g., sulfonylurea), a lower 

dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia 

Wayne Weart 






• There have been no clinical studies 

establishing conclusive evidence of 

macrovascular or microvascular risk reduction 

with linagliptin 

• Linagliptin has not been studied in 

combination with insulin 

• Linagliptin is an alternative to sitagliptin and 

saxagliptin for the treatment of patients with 

type 2 diabetes and it does not need a dosage 

reduction in patients with renal dysfunction. 

Pancreatitis, Pancreatic, and Thyroid 

Cancer With Glucagon-Like 

Peptide-1–Based Therapies 

GASTROENTEROLOGY 2011;141:150–156 

• US Food and Drug Administration’s database of reported 

adverse events for those associated with the dipeptidyl 

peptidase4 inhibitor sitagliptin and the glucagon-like peptide- 

1 mimetic exenatide, from 2004-2009; data on adverse events 

associated with 4 other medications were compared as 

controls.(rosiglitazone, nateglinide, repaglinide and glipizide) 

• The primary outcomes measures were rates of reported 

pancreatitis, pancreatic and thyroid cancer, and all cancers 

associated with sitagliptin or exenatide, compared with other 

therapies. 

Wayne Weart 





Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon- 

Like Peptide-1–Based Therapies 


Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon- 

Like Peptide-1–Based Therapies 


Wayne Weart 





Pancreatitis, Pancreatic, and Thyroid Cancer With 

Glucagon-Like Peptide-1–Based Therapies 


• “In conclusion, analysis of the FDA adverse event reporting 

database suggests that the GLP-1 class of drugs being widely 

promoted for treatment of type 2 diabetes could have serious 

unintended and unpredicted side effects.” 

• “Pancreatitis is 6-fold more likely to be reported in association 

with sitagliptin or exenatide than other therapy” 

• “We have a concern that there is a significantly increased 

association of thyroid cancer and pancreatic cancer with these 

therapies.” 

• “The most obvious conclusion from these studies is that careful 

long-term monitoring of patients treated with GLP-1 mimetics 

or DPP-4 inhibitors is required.” 

Pancreatitis, Pancreatic, and Thyroid Cancer With 

Glucagon-Like Peptide-1–Based Therapies 


• “For now this analysis of the FDA data base 

does not establish that pancreatitis, 

pancreatic and thyroid cancer are caused 

by GLP-1based therapy. It simply raises the 

level of concern that they may be and that 

the appropriate prospective studies are 

required to rule them out.” 

Wayne Weart 





GLP-1–Based Therapies: The Dilemma of 

Uncertainty 

Gastroenterology 2011; 141:20-23 

• The accompanying editorial states “…more reliable studies 

must be performed. Until then, the questions about the 

potential link between GLP-1–based therapies and 

pancreatitis and tumorigenesis remain open. The fact that 

GLP-1–based therapies have no record of lowering clinical 

endpoints (ie, mortality, stroke, myocardial infarction) 

does not inspire confidence and more informative 

prospective randomized trials with such patient-relevant 

clinical endpoints are urgently required.” 

• “For the sake of patients, history will hopefully not repeat 

itself in the case of GLP-1–based drugs. Two thoughts 

remain: primum non nocere and “vigilance equals 

avoidance.” 

Dabigatran- Pradaxa 

by Boehringer Ingelheim 

Wayne Weart 





Dabigatran - Pradaxa 

• A direct thrombin 

inhibitor indicated to 

reduce the risk of stroke 

and systemic embolism 

in patients with nonvalvular 

atrial fibrillation 

• 75 mg and 150 mg 

capsules BID $253.00/60 

• No need to monitor INR 

• Not reversible with 

vitamin K or FFP 

(consider factor 

concentrates or dialysis) 


RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), 

a randomized trial comparing two blinded doses of dabigatran (110 

mg twice daily and 150 mg twice daily) with open-label warfarin 

(dosed to target INR of 2 to 3) in 18,113 patients with non-valvular, 

persistent, paroxysmal, or permanent atrial fibrillation and one or 

more of the following additional risk factors: 

• Previous stroke, transient ischemic attack (TIA), or systemic 

embolism 

• Left ventricular ejection fraction





Table 1: Event rates by INR time in range vs dabigatran 110 BID and 150 mg BID 

Event %/yr 

Stroke* + 

SEE 

Warf 

n=6022 

Warf Q 4 

TTR < 53% 

Warf Q 1-2 

TTR > 67% 

Dabig 110 

n=6015 

Dabig 150 

n=6076 

1.69 2.2 1.3 1.53 1.11** 

NNT 173 

Maj Bld 3.36 4.6 2.7 2.71** 3.11 

MI 0.53 Na Na 0.72 0.74** 

NNH 476 

Comp. 7.64 11.9 5.3 7.09 6.91 

*"Stroke" includes hemorrhagic stroke, **stat. sig. vs warfarin in original report. 

Comp = Stroke, systemic embolism, MI, PE, death, major bleeding. Warf 4th quartile = ITTR < 53.4%, 

1st & 2nd quartile = ITTR > 67.1%. 

N Engl J Med 2009; 361:1139-1151 


Risk of extracranial and intracranial bleeding (% per year) by age 

End point 

Warfarin 

(%) 

Dabigatran 110 

mg (%) 

Dabigatran 150 

mg (%) 

P 

Extracranial bleeding 

Age 75 3.44 4.10 4.68 0.001 

Intracranial bleeding 

Age 75 1.00 0.37 0.41 0.28 

Circulation 2011;123:2363-2372 

Wayne Weart 






• Compared to warfarin, both doses of dabigatran 

were associated with a significantly lower rate of 

haemorrhagic stroke, life-threatening bleeds, and 

intracranial haemorrhage (ICH) with and without 

haemorrhagic stroke; dabigatran 110 mg also 

showed a significant reduction in major bleeding 

compared to warfarin 

• Warfarin has statistically significantly fewer GI bleeds 

compared to both doses of dabigatran, and 

significantly fewer major GI bleeds and lifethreatening 

GI bleeds than dabigatran 150 mg 


• The rates of adverse reactions leading to treatment 

discontinuation in RE-LY were 21% for dabigatran 150 mg and 

16% for warfarin. The most frequent adverse reactions 

leading to discontinuation of dabigatran were bleeding and 

gastrointestinal events (i.e., dyspepsia, nausea, upper 

abdominal pain, gastrointestinal hemorrhage, and diarrhea). 

– NNH 20 patients 

• Drug Interactions 

– The concomitant use of dabigatran with P-gp inducers 

(e.g., rifampin) reduces exposure to dabigatran and should 

generally be avoided 

– P-gp inhibitors ketoconazole, verapamil, amiodarone, 

quinidine, and clarithromycin do not require dose 

adjustments 

Wayne Weart 






ACCF/AHA/HRS 2011 Focused Update 

Recommendation Class I 

“Dabigatran is useful as an alternative to warfarin for 

the prevention of stroke and systemic 

thromboembolism in patients with paroxysmal to 

permanent AF and risk factors for stroke or systemic 

embolization who do not have a prosthetic heart valve 

or hemodynamically significant valve disease, severe 

renal failure (creatinine clearance 50 mL/min, start warfarin 3 days before 

discontinuing dabigatran. 

– For CrCl 31-50 mL/min, start warfarin 2 days before 


– For CrCl 15-30 mL/min, start warfarin 1 day before 


Wayne Weart 






• DOSING: Recommended Dose for patients with creatinine 

clearance (CrCl) >30 mL/min, the recommended dose of 

dabigatran is 150 mg taken orally, twice daily, with or without 

food. For patients with CrCl 15-30 mL/min, or patients 75 years 

of age or older the recommended dose is 75 mg twice daily 

• 

– Instruct patients to swallow the capsules whole. Breaking, 

chewing, or emptying the contents of the capsule can result 

in increased exposure. 

– Pradaxa capsules will hydrolyze over time when exposed to 

humidity, causing a breakdown of active ingredient, and 

rendering the medication less effective. Pradaxa is 

packaged in a 30-day supply bottle with a desiccant cap or 

in unit-of-use blister packaging to minimize product 

breakdown from moisture. 

Rivaroxaban – Xarelto 

by Bayer HealthCare AG and Janssen Pharmaceuticals 

Rivaroxaban exhibits a linear pharmacokinetic 

relationship with a rapid onset of action, resulting 

in maximal factor Xa inhibition in approximately 3 

hours. Maintenance of the anti–factor Xa effect 

lasted 8 to 12 hours, depending on the dose of 

rivaroxaban. 

Terminal half-life of rivaroxaban is approximately 9 

hours in adults and 12 hours in elderly patients 

(older than 65 years of age). Elimination of 

rivaroxaban occurs by multiple routes: renal (onethird 

is excreted unchanged), biliary/fecal, and 

hepatic (through CYP-450 3A4). Renal function 

impairment may influence elevated plasma 

concentrations and increased anti-Xa activity; 

therefore, dose adjustments may be required 

Wayne Weart 





Rivaroxaban - Xarelto 

• July 5, 2011 The FDA approved rivaroxaban a factor Xa 

inhibitor indicated for the prophylaxis of deep vein 

thrombosis (DVT) which may lead to pulmonary embolism 

(PE) in patients undergoing knee or hip replacement. 

• The recommended dose of is 10 mg taken orally once daily 

with or without food. The initial dose should be taken at least 

6 to 10 hours after surgery once hemostasis has been 

established. 

– For patients undergoing hip replacement surgery, 

treatment duration of 35 days is recommended. 

– For patients undergoing knee replacement surgery, 

treatment duration of 12 days is recommended. 


RECORD is a global program involving more than 12,500 patients, 

comparing rivaroxaban 10 mg QD with SC enoxaparin in patients 

following either total hip or knee replacement surgery. 

• RECORD comprised four pivotal Phase III clinical 

– RECORD 1 and 2: total hip replacement surgery 

• RECORD 1: Both treatments continued for 35+/-4 days (N Engl J Med. 2008;358:2765- 

2775) 

• RECORD 2: Rivaroxaban continued for 35+/-4 days; enoxaparin 10-14 days (Lancet. 

2008;372:31-39) 

– RECORD 3 and 4: total knee replacement surgery 

• RECORD 3: Both treatments continued for 10-14 days (N Engl J Med. 2008;358:2776- 

2786) 

• RECORD 4: Both treatments continued for 10–14 days (Lancet 2009;373:1673-80) 

– Results of a pre-specified pooled analysis of RECORD1, 2 and 3 showed 

that rivaroxaban significantly reduced the composite of symptomatic VTE 

and all-cause mortality during the 2-week active controlled period by 56% 

compared with enoxaparin (0.4% versus 0.8%, respectively; odds ratio: 

0.44; p=0.005) while maintaining a similar safety profile. 

Wayne Weart 






• RECORD 1 (Hip) R=1.1% vs. E=3.9%, RRR 71%, 

ARR 2.8%, NNT=36 

• RECORD 2 (Hip) R=2.0% vs. E=8.4%, RRR 76%, 

ARR 6.4%, NNT=16 

• RECORD 3 (Knee) R=9.7% vs. E=18.8%, 

RRR 48%, ARR 9.1%, NNT=11 

• RECORD 4 (Knee) R=6.9% vs. E=10.1%, 

RRR 31%, ARR 3.19%, NNT=32 


• Additional Clinical Trials completed or under 

way include: (NOT FDA Approved!) 

– EINSTEIN: VTE treatment (Phase III) (N Engl J Med 

2010; 363:2499-2510) 

– ROCKET AF: Stroke prevention in patients with 

atrial fibrillation (Phase III) (N Engl J Med 

2011;365:883-91) 

– MAGELLAN: VTE prevention in hospitalized, 

medically ill patients (Phase III) 

– ATLAS ACS TIMI 46: Secondary prevention of acute 

coronary syndrome (Phase II) (Lancet 2009; 374: 29 – 

38) 

Wayne Weart 






• BOX WARNING: SURGICAL SETTINGS--SPINAL/EPIDURAL 

HEMATOMA: Epidural or spinal hematomas may occur in 

patients who are anticoagulated and are receiving neuraxial 

anesthesia or undergoing spinal puncture. These hematomas 

may result in long-term or permanent paralysis. Consider 

these risks when scheduling patients for spinal procedures. 

Factors that can increase the risk of developing epidural or 

spinal hematomas in these patients include: 

– use of indwelling epidural catheters 

– concomitant use of other drugs that affect hemostasis, such as 

nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, 

other anticoagulants 

– a history of traumatic or repeated epidural or spinal punctures 

– a history of spinal deformity or spinal surgery. 


• Avoid concomitant administration of rivaroxaban 

with combined P-gp and strong CYP3A4 inhibitors 

(e.g., ketoconazole, itraconazole, lopinavir/ritonavir, 

ritonavir, indinavir/ritonavir, and conivaptan) which 

cause significant increases in rivaroxaban exposure 

that may increase bleeding risk. 

• When clinical data suggest a change in exposure is 

unlikely to affect bleeding risk (e.g., clarithromycin, 

erythromycin), no precautions are necessary during 

coadministration with drugs that are combined P-gp 

and CYP3A4 inhibitors. 

Wayne Weart 






• Patients with any degree of renal impairment with 

concurrent use of P-gp and weak to moderate 

CYP3A4 inhibitors may have significant increases in 

exposure which may increase bleeding risk 

• Avoid concomitant use of rivaroxaban with drugs 

that are combined P-gp and strong CYP3A4 inducers 

(e.g., carbamazepine, phenytoin, rifampin, St. John’s 

wort). Consider increasing the rivaroxaban dose if 

these drugs must be co-administered 


• Avoid the use of rivaroxaban in patients with severe 

renal impairment (CrCl






Wayne Weart 





ROCKET-AF Trial 

• The ROCKET AF study was a multicenter, doubleblind, 

randomized trial of once-daily oral rivaroxaban 

20 mg or 15 mg daily in patients with a creatinine 

clearance of 30 to 49 ml per minute) compared with 

dose-adjusted warfarin (INR 2-3) in moderate-tohigh-risk 

patients with nonvalvular AF. The authors 

hypothesized that rivaroxaban is noninferior to 

warfarin at preventing the composite of stroke 

(ischemic and hemorrhagic) and systemic embolism. 

The 14,264 enrolled patients (median age, 73; 40% 

women) had a mean CHADS2 score of 3.5; about half 

had a CHADS2 score of 4. 

– N Engl J Med 2011;365:883-91. 


• Median follow-up was 707 days. 

• In the warfarin group, the overall mean proportion of 

time in therapeutic international normalized ratio 

range was 55%. 

– N Engl J Med 2011;365:883-91. 

• On Sept 9, 2011 the FDA Cardiovascular and Renal 

Drugs Advisory Committee recommended approval 

of rivaroxaban for the prevention of stroke and 

systemic embolism in patients with non-valvular 

atrial fibrillation (AF) by a 9-2 vote. 

– The FDA had expressed concern over the low rate of 

desired INR’s) 

Wayne Weart 





Outcome 


Rivaroxaban 

(n=7081) 

Warfarin 

(n=7090) 

N Egl J Med 2011;365:883-91. 

Hazard ratio 

(95% CI) p 

Primary end point, 

noninferiority 

Primary end point, on 

treatment superiority 

Primary end point, 

intention-to-treat 

superiority 

Vascular death, 

stroke, 

embolism 

1.71 2.16 0.79 (0.66-0.96) 

NNT 222 

2 g/dL hemoglobin 

drop 

2.77 2.26 1.22 (1.03-1.44) 

NNH 197 

Transfusion 1.65 1.32 1.25 (1.01-1.55) 

NNH 304 

Critical organ 

bleeding 

Bleeding causing 

death 

Intracranial 

hemorrhage 

0.82 1.18 0.69 (0.53-0.91) 

NNT 278 

0.24 0.48 0.50 (0.31-0.79) 

NNT 455 

0.49 0.74 0.67 (0.47-0.94) 

NNT 400 

0.019 

0.044 

0.007 

0.003 

0.019 

Wayne Weart 






• 9/22/2011 Advisors for the European Medicines 

Agency (EMA) have paved the way for two new 

indications for rivaroxaban in Europe. The EMA's 

Committee for Medicinal Products for Human 

Use (CHMP) issued two "positive opinions" for 

the oral factor Xa inhibitor: one in the setting of 

the prevention of stroke and systemic embolism 

in nonvalvular atrial fibrillation (AF) and one for 

the treatment of venous thromboembolism 

(VTE), deep vein thrombosis (DVT), and 

pulmonary embolism (PE) 

Ticagrelor – Brilinta 

by Astra Zeneca 

90 mg tablets Loading dose 180 mg then 90 mg BID 

$217.20 per month WAC 

Wayne Weart 





Ticagrelor - Brilinta 

• Ticagrelor and its major metabolite reversibly 

interact with the platelet P2Y12 ADP-receptor to 

prevent signal transduction and platelet 

activation. Ticagrelor and its active metabolite 

are approximately equipotent. 

• Transitioning from clopidogrel to ticagrelor 

resulted in an absolute inhibition of platelet 

inhibition (IPA) increase of 26.4% and from 

ticagrelor to clopidogrel resulted in an absolute 

IPA decrease of 24.5%. Patients can be 

transitioned from clopidogrel to ticagrelor 

without interruption of antiplatelet effect 

Mean inhibition of platelet aggregation (±SE) following 

single oral doses of placebo, 180 mg ticagrelor, or 600 

mg clopidogrel 

Wayne Weart 






• Metabolism: CYP3A4 is the major enzyme responsible 

for ticagrelor metabolism and the formation of its 

major active metabolite. Ticagrelor and its major active 

metabolite are weak P-glycoprotein substrates and 

inhibitors. 

• The mean t1/2 is approximately 7 hours for ticagrelor 

and 9 hours for the active metabolite. 

• The mean absolute bioavailability of ticagrelor is about 

36%, (range 30%-42%) and it can be taken without 

regard to meals. 

• The effects of age, gender, ethnicity, renal impairment 

and mild hepatic impairment on the pharmacokinetics 

of ticagrelor are modest and do not require dose 

adjustment. 


Effects of Other Drugs on Ticagrelor 

• CYP3A4 is the major enzyme responsible for ticagrelor 

metabolism and the formation of its major active 

metabolite. 

– Strong CYP3A inhibitors (e.g., atazanavir, clarithromycin, 

indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 

ritonavir, saquinavir, telithromycin and voriconazole) 

substantially increase ticagrelor exposure and are not 

recommended 

– Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem 

and verapamil) and do not require a dosage adjustment 

– CYP3A inducers (e.g., rifampin, dexamethasone, phenytoin, 

carbamazepine, and phenobarbital) substantially reduce 

ticagrelor blood levels and are not recommended 

Wayne Weart 






Effects of Ticagrelor on Other Medications: 

• Patients receiving more than 40 mg per day of 

simvastatin or lovastatin may be at increased risk of 

statin-related adverse effects. 

• Monitor digoxin levels with initiation of or any change 

in ticagrelor because of P-glycoprotein transporter 

inhibition 

Concomitant Aspirin Maintenance Dose: In PLATO, use of 

ticagrelor with maintenance doses of aspirin above 100 

mg decreased the effectiveness of ticagrelor. Therefore, 

after the initial loading dose of aspirin (usually 325 mg), 

use ticagrelor with a maintenance dose of aspirin of 75- 

100 mg 


N Engl J Med 2009;361:1045-57 

• PLATO Trial, a randomized double-blind study comparing 

ticagrelor (180 mg LD then 90 mg BID)(N=9333) to 

clopidogrel (300mg LD then 75 mg QD) (N=9291), both 

given in combination with aspirin (75-100 mg QD but 

higher doses were allowed per investigator) and other 

standard therapy, in patients with acute coronary 

syndromes (ACS). Patients were treated for at least 6 

months and for up to 12 months. 

– Patients were predominantly male (72%) and Caucasian (92%). 

About 43% of patients were >65 years and 15% were >75 years. 

– Primary endpoint was the composite of first occurrence of 

cardiovascular death, non-fatal MI (excluding silent MI), or nonfatal 

stroke. The components were assessed as secondary 

endpoints 

– Median exposure to study drug was 277 days 

Wayne Weart 






N Engl J Med 2009;361:1045-57 

Endpoint 

Primary Composite 

(CV death, MI, CVA) 

Secondary Endpoints 

Ticagrelor 

N=9333 

Clopidogrel 

N=9291 

Hazard Ratio 

(95% CI) 

9.8% 11.7% 0.84 

(0.77-0.92) 

CV death 4.0% 5.1% 0.79 

(0.69-0.91) 

MI 5.8% 6.9% 0.84 

(0.75-0.95) 

Stroke 1.5% 1.3% 1.17 

(0.91-1.52) 

All cause mortality 4.5% 5.9% 0.78 

(0.69-0.89) 

In-stent thrombosis 

(11,289 pts with 

PCI/stenting) 

1.3% 1.9% 0.67 

(0.50-0.91) 

P-value ARR/NNT 

0.0003 1.9%/53 

0.0013 1.1%/91 

0.0045 1.1%/91 

0.22 

0.0003 1.4%/72 

0.0091 0.6%/167 


N Engl J Med 2009;361:1045-57. 

• No significant difference in the rates of major bleeding 

was found between the ticagrelor and clopidogrel 

groups (11.6% and 11.2%, respectively; P = 0.43) 

• Ticagrelor was associated with a higher rate of major 

bleeding not related to coronary-artery bypass grafting 

(4.5% vs. 3.8%, P = 0.03, ARI = 0.7%, NNH = 143) 

including more instances of fatal intracranial bleeding 

and fewer of fatal bleeding of other types. 

• In a genetic substudy of PLATO (n=10,285), the effects 

of ticagrelor compared to clopidogrel on thrombotic 

events and bleeding were not significantly affected by 

CYP2C19 genotype. 

Wayne Weart 





PLATO: CV Death, MI, Stroke by 

maintenance aspirin dose in the US and 

outside the US 


N Engl J Med 2009;361:1045-57 

Wayne Weart 






• Dyspnea was usually mild to moderate in intensity and often 

resolved during continued treatment. If a patient develops new, 

prolonged, or worsened dyspnea during treatment with ticagrelor, 

exclude underlying diseases that may require treatment. If dyspnea 

is determined to be related to ticagrelor, no specific treatment is 

required; continue ticagrelor without interruption 

• Serum Uric Acid: Serum uric acid levels increased approximately 0.6 

mg/dL from baseline on ticagrelor and approximately 0.2 mg/dL on 

clopidogrel in PLATO. The difference disappeared within 30 days of 

discontinuing treatment. Reports of gout did not differ between 

treatment groups in PLATO (0.6% in each group). 

• Serum Creatinine: In PLATO, a >50% increase in serum creatinine 

levels was observed in 7.4% of patients receiving ticagrelor 

compared to 5.9% of patients receiving clopidogrel. The increases 

typically did not progress with ongoing treatment and often 

decreased with continued therapy. 


BOX WARNING: BLEEDING RISK 

• BRILINTA, like other antiplatelet agents, can cause significant, sometimes 

fatal, bleeding . 

• Do not use BRILINTA in patients with active pathological bleeding or a 

history of intracranial hemorrhage. 

• Do not start BRILINTA in patients planned to undergo urgent coronary 

artery bypass graft surgery (CABG). When possible, discontinue BRILINTA 

at least 5 days prior to any surgery. 

• Suspect bleeding in any patient who is hypotensive and has recently 

undergone coronary angiography, percutaneous coronary intervention 

(PCI), CABG, or other surgical procedures in the setting of BRILINTA. 

• If possible, manage bleeding without discontinuing BRILINTA. Stopping 

BRILINTA increases the risk of subsequent cardiovascular events. 

• WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS 

• Maintenance doses of aspirin above 100 mg reduce the effectiveness of 

BRILINTA and should be avoided. After any initial dose, use with aspirin 

75-100 mg per day 

Wayne Weart 






DOSAGE AND ADMINISTRATION: 

• Initiate ticagrelor treatment with a 180 mg (two 

90 mg tablets) loading dose and continue 

treatment with 90 mg twice daily with or without 

food 

• After the initial loading dose of aspirin (usually 

325 mg), use ticagrelor with a daily maintenance 

dose of aspirin of 75-100 mg (typically 81mg) 

COST: $7.24 per day or $217.20 per month WAC 

Dronedarone – Multaq 

by Sanofi Aventis 

• Indicated to reduce the 

risk of cardiovascular 

hospitalization in patients 

with paroxysmal or 

persistent atrial fibrillation 

(AF) or atrial flutter (AFL), 

with a recent episode of 

AF/AFL and associated 

cardiovascular risk factors 

• Dose 400 mg tablets BID 

with food $297.00/60 

Wayne Weart 





Dronedarone - Multaq 

• ATHENA was a double blind, and randomized placebocontrolled 

study of dronedarone in 4628 patients with a 

recent history of AF/AFL who were in sinus rhythm or who 

were to be converted to sinus rhythm. 

– The objective of the study was to determine whether dronedarone 

could delay death from any cause or hospitalization for cardiovascular 

reasons. 

– Subjects were randomized and treated for up to 30 months (median 

follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 

patients) or placebo (2327 patients), in addition to conventional 

therapy for cardiovascular diseases that included beta-blockers (71%), 

ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin 

(14%), calcium antagonists (14%), statins (39%), oral anticoagulants 

(60%), aspirin (44%), other chronic antiplatelet therapy (6%) and 

diuretics (54%). 

ATHENA Results: 


• Primary endpoint (median follow up 22 months) 

– Cardiovascular hospitalization or death from any cause 913 

(39.2%) placebo vs 727 (31.6%) dronedarone HR 0.76 or 

24% RRR, 7.6% ARR, NNT=14, p





ANDROMEDA Study (Increased Mortality in Patients with Severe 

Heart Failure) 

• Patients recently hospitalized with symptomatic heart failure 

and severe left ventricular systolic dysfunction were 

randomized to either MULTAQ 400 mg twice daily or matching 

placebo, with a primary composite end point of all-cause 

mortality or hospitalization for heart failure. 

• After enrollment of 627 of 1000 planned patients (310 and 

317 in the dronedarone and placebo groups, respectively), 

and a median follow-up of 63 days, the trial was terminated 

because of excess mortality in the dronedarone group. 

Twenty-five (25) patients in the dronedarone group (8.1%) 

versus 12 patients in the placebo group (3.8%) had died, 

hazard ratio 2.13; 95% CI: 1.07 to 4.25; p=0.027. ARI 4.3%, 

NNH = 26. 


BOX WARNING: HEART FAILURE 

• MULTAQ is contraindicated in patients with NYHA Class IV 

heart failure, or NYHA Class II - III heart failure with a recent 

decompensation requiring hospitalization or referral to a 

specialized heart failure clinic 

• Contraindications: 

– Second- or third-degree atrioventricular (AV) block or sick sinus 

syndrome (except when used in conjunction with a functioning 

pacemaker) 

– Bradycardia less than 50 bpm 

– Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, 

itraconazole, voriconazole, cyclosporine, telithromycin, 

clarithromycin, nefazodone, and ritonavir 

– Concomitant use of drugs or herbal products that prolong the QT 

interval and might increase the risk of Torsade de Pointes, such as 

phenothiazine anti-psychotics, tricyclic antidepressants, certain oral 

macrolide antibiotics, and Class I and III antiarrhythmics 

Wayne Weart 






• DIONYSOS Trial evaluating the efficacy and safety of 

dronedarone versus amiodarone for the 

maintenance of sinus rhythm in 504 patients with 

persistent Atrial Fibrillation (AF) for a short 

treatment duration (mean follow up of 7 months). 

– AF recurrence or premature drug discontinuation for 

intolerance or lack of efficacy). There were 184 patients 

(73.9%) who reached the primary endpoint in the 

dronedarone arm as compared to 141 (55.3%) in the 

amiodarone arm (p





Recommendation for Rate Control During Atrial Fibrillation 

• 2011 Focused Update Recommendation Comments Class III–No Benefit 

• Treatment to achieve strict rate control of heart rate (





New Safety Concern July 7, 2011 Paris, France 

Sanofi, maker of dronedarone (Multaq), has 

suspended its phase 3b trial of its 

antiarrhythmic drug due to a significant increase 

in cardiovascular events seen in patients 

randomized to dronedarone. The PALLAS trial 

(begun 7-2010) was testing the drug in ~10,000 

patients with permanent atrial fibrillation and at 

least one other cardiovascular disease risk 

factor; at present, dronedarone is approved in 

patients with nonpermanent AF. 

Events during the PALLAS study as of 

June 30, 2011.(FDA MedWatch 7-21-2011) 

CV Death, Myocardial 

Infarction, Stroke, Systemic 

Embolism* 

Death, Unplanned CV 

Hospitalization* 

Multaq 

N=1572 

n (%) 

Placebo 

N=1577 

n (%) 

Hazard 

Ratio/NNH 

32 (2) 14 (0.9) 2.3/91 0.009 

118 (7.5) 81 (5.1) 1.5/42 0.006 

Death 16 (1) 7 (0.4) 2.3 0.065 

Myocardial Infarction 3 (0.2) 3 (0.2) 1.0 1 

Stroke 17 (1.1) 7 (0.4) 2.4/143 0.047 

Heart Failure Hospitalization 34 (2.2) 15 (1) 2.3/84 0.008 

*coprimary endpoints 

p-value 

Wayne Weart 






Sept 22, 2011 The European Medicines Agency 

(EMA) recommends restricting the use of the 

antiarrhythmic medication dronedarone. The 

committee states that because of the increased 

risk of liver, lung, and cardiovascular adverse 

events, dronedarone "should only be prescribed 

after alternative treatment options have been 

considered." Patients currently taking 

dronedarone should have their treatment 

reassessed by their physician at their next 

scheduled visit 

Pitavastatin - Livalo 

by Kowa and Lilly 

• A synthetic competitive 

lipophilic 3-hydroxy-3- 

methylglutaryl-coenzyme A 

(HMG-CoA) reductase 

inhibitor. 

• Pitavastatin elimination 

half-life is 10 to 12 hours 

• The effect of pitavastatin 

on cardiovascular morbidity 

and mortality has not been 

determined. 

• Pitavastatin is 

administered orally once 

daily, with or without 

food, at any time of day. 

The dosage range is 1 to 

4 mg once daily. The 

maximum dosage is 4 mg 

per day. 

Wayne Weart 






• Mean Change from Baseline to Week 12 

Treatment LDL-C Apo B TC TG HDL-C 

Pitavastatin 2 mg (n= 307) -39% -30% -28% -16% 6% 

Pitavastatin 4 mg (n= 319) -44% -35% -32% -17% 6% 

Simvastatin 20 mg (n= 107) -35% -27% -25% -16% 6% 

Simvastatin 40 mg (n= 110) -43% -34% -31% -16% 7% 

The most frequent adverse effects, occurring in at least 2% of patients 

receiving one of the available doses, were myalgia, back pain, diarrhea, 

constipation, and pain in extremity. 


• DRUG INTERACTIONS: Several agents 

(cyclosporine-avoid, rifampin-max 2mg, 

eryrthromycin-max 1 mg, gemfibrozil and 

lopinovir/retonavir-caution) have the 

potential to interact with the organic anion 

transporting polypeptide–mediated uptake of 

pitavastatin. 

• 1, 2, and 4 mg tablets supplied in bottles of 

90 tablets. The cost for all three doses is 

$119.00/30 AWP. 

Wayne Weart 





Denosumab – Prolia 

by Amgen 

Dosage 60 mg Sub Q every 6 months $990.00/dose AWP 

Denosumab - Prolia 

• A fully human 

monoclonal antibody to 

the receptor activator of 

nuclear factor-kappa B 

ligand (RANKL) 

. 

• Prevention of the 

RANKL/RANK 

interaction inhibits 

osteoclast formation, 

function, and survival, 

thereby decreasing 

bone resorption and 

increasing bone mass 

and strength in both 

cortical and trabecular 

bone. 

FDA approved for the treatment of 

postmenopausal women with 

osteoporosis at high risk for fracture, 

defined as a history of osteoporotic 

fracture, or multiple risk factors for 

fracture; or patients who have failed or 

are intolerant to other available 

osteoporosis therapy 

Wayne Weart 






• FREEDOM Trial 

– 7868 women between the ages of 60 and 

90 years who had a bone mineral density T 

score of less than 2.5 but not less than 

4.0 at the lumbar spine or total hip. 

– Subjects were randomly assigned to 

receive either 60 mg of denosumab or 

placebo subcutaneously every 6 months 

for 36 months 

– The primary end point was new vertebral 

fracture. Secondary end points included 

nonvertebral and hip fractures 


• FREEDOM Trial results at 3 years 

Fracture Type Placebo Denosumab RRR ARR NNT 

Vertebral 7.2% 2.3% 68% 4.9% 21 

Non-vertebral 8.0% 6.5% 20% 1.5% 67 

Hip 1.2% 0.7% 40% 0.5% 200 

Eczema and increased rates of hospitalization for cellulitis were the 

only two statistically significant adverse effects reported in this trial 

along with an increase in flatulence. 

N Engl J Med 2009;361:756-65 

Wayne Weart 





FREEDOM Trial 5 Year Data 

• May 2, 2011 (San Diego, California) — Results from the first 2 years of the 

international multicenter (FREEDOM) trial 10 year extension, in 4550 

postmenopausal women with osteoporosis, showed that the drug 

maintains its efficacy in improving bone mineral density (BMD) and 

reducing the incidence of fractures over 5 years without any increase in 

adverse events, according to researchers here at the American Association 

of Clinical Endocrinologists 20th Annual Meeting and Clinical Congress. 

– In the fourth and fifth year of denosumab treatment, those in the original intervention 

group (2342 women) experienced further benefits in BMD of the lumbar spine and hip. 

In the fourth year, BMD of the lumbar spine increased by 1.9% in the long-term 

treatment group and BMD of the hip increased by 0.7%. In the fifth year of treatment, 

BMD of the lumbar spine increased by 1.7% in the long-term treatment group and BMD 

of the total hip increased by 0.6%. 

– The de novo group (2207 women) in the extension trial experienced improvements in 

BMD similar to those seen in the intervention group in the first 2 years of the original 

FREEDOM trial. In the first 2 years of their treatment, the crossover group experienced a 

7.9% increase in lumbar spine BMD and a 4.1% increase in total hip BMD (P < .0001, 

compared with baseline). 

FREEDOM Trial 5 Year Data 

• The yearly incidence of new vertebral fractures was 1.4% in 

the long-term denosumab group and 0.9% in the crossover 

group. Rates of new nonvertebral fractures were also low, 

with a yearly incidence of 1.4% in the fourth year and 1.1% in 

the fifth year for the long-term treatment group. In contrast, 

the yearly incidence rate of new nonvertebral fractures in the 

crossover group was 2.4% in the first year of treatment and 

1.7% in the second year of treatment 

• The incidence of serious adverse events were low, with just 2 

cases of osteonecrosis of the jaw and 1 case of cellulitis in the 

crossover group of the extension trial. Three subjects in the 

long-term treatment group experienced cellulitis. 

Wayne Weart 






Risedronate – Atelvia 

by Warner Chilcott 

• Like other oral agents in this 

class the oral bioavailabilty is 

very poor ~0.063% 

• Dosage of delayed-release 

risedronate is 35 mg once 

weekly, taken in the morning 

immediately following 

breakfast with at least 4 

ounces of plain water. 

– The tablets should be 

swallowed whole while the 

patient is in an upright 

position. Patients should 

be instructed not to lie 

down for 30 minutes. 

Cost: Dosepak of 4 tablets of 35mg 

for $121.78 AWP. 

Wayne Weart 





Risedronate - Atelvia 

• The efficacy of Atelvia 35 mg once-a-week in the 

treatment of postmenopausal osteoporosis was 

demonstrated in a randomized, double-blind, activecontrol 

trial of approximately 900 subjects. 

• All patients in this study received supplemental 

calcium (1000 mg/day) and vitamin D (800 – 1000 

IU/day). 

• The primary efficacy endpoint was percent change in 

lumbar spine bone mineral density at 1 year. 

• Atelvia 35 mg once-a -week administered after 

breakfast was shown to be non-inferior to 

risedronate sodium immediate-release 5 mg daily 

(3.3% vs. 3.1% increase in lumbar spine BMD) 


HIP Trial (NEJM 2001;344:333-340) 

• 5445 women 70 to 79 years old who had osteoporosis 

(indicated by a T score for BMD at the femoral neck that was 

more than 4 SD below the mean peak value in young adults 

or lower than -3 plus a nonskeletal risk factor for hip 

fracture, such as poor gait or a propensity to fall) and 3886 

women at least 80 years old who had at least one 

nonskeletal risk factor for hip fracture or low bone mineral 

density at the femoral neck (T score, lower than -4 

• Patients were randomly assigned to receive treatment with 

oral risedronate (2.5 or 5.0 mg daily) or placebo for three 

years. 

• The primary end point was the occurrence of hip fracture. 

Wayne Weart 






HIP Trial results: (NEJM 2001;344:333-340) 

• Hip fractures 

Group Placebo n % Fx Drug n % Fx RRR P Value ARR NNT 

Overall 3134 3.9% 6197 2.8% 30% 0.02 1.1% 91 

Age 70-79 1821 3.2% 3624 1.9% 40% 0.009 1.3% 77 

+Hx Vert Fx 575 5.7% 1128 2.3% 60% 0.003 3.4% 30 

-Hx Vert Fx 875 1.6% 1773 1.0% 40% 0.14 ns 

Age 80+* 1313 5.1% 2573 4.2% 20% 0.35 ns 

*Women 80 and older did not have to have documented osteoporosis on the 

basis of low T-scores only one or more clinical risk factors, BMD is a better 

predictor of fracture risk than clinical risk factors in the absence of a history of fracture. 

Non-vertebral fractures (overall) 

11.2% placebo vs. 9.4% risedronate RRR 20% (P=0.03); 

ARR 2.8%; NNT 33 


Table 4. Adverse Reactions Occurring in 3% of Patients With Delayed-Release 

vs Immediate-Release Risedronate 

Delayed-Release 35 mg Weekly 

After Breakfast (n = 307) 

Immediate-Release 5 mg Daily 

Before Breakfast (n = 307) 

Diarrhea 8.8% 4.9% 

Influenza 7.2% 6.2% 

Arthralgia 6.8% 7.8% 

Back pain 6.8% 5.9% 

Abdominal pain 5.2% 2.9% 

Constipation 4.9% 2.9% 

Vomiting 4.9% 1.6% 

Bronchitis 3.9% 4.2% 

Dyspepsia 3.9% 3.9% 

Wayne Weart 





Vilazodone HCl - Viibryd 

by Trovis/Forest 

• Approved for the treatment of 

adults with major depressive 

disorder (MDD). 

• An SSRI and partial serotonin 

5-HT1A receptor agonist. 

• It is not clear what role the 

partial agonist activity 

contributes to the clinical 

activity of vilazodone.(like 

adding buspirone to an SSRI?) 

• Metabolized by CYP 3A4 and 

has a T1/2 of about 25 hours 

• 10, 20 and 40 

mg tablets 


• A randomized, double-blind, placebo-controlled trial with 

an 8-week treatment duration enrolled 410 adults 18 to 

65 years of age diagnosed with a single or recurrent 

episode of MDD lasting for periods between 4 weeks 

and 2 years with a score of at least 22 on the 17-item 

Hamilton Rating Scale for Depression (HAM-D-17) and a 

score of at least 2 on the HAM-D-17 item 1 (depressed 

mood). (J Clin Psychiatry. 2009;70(3):326-333) 

– Patients were randomized (1:1) to receive placebo or vilazodone 

10 mg/day in week 1. The dosage was increased to 20 mg/day in 

week 2, and then to 40 mg/day for the remainder of the 8-week 

study. 

Wayne Weart 






• The primary outcome of the study was mean change 

from baseline to week 8 (end of treatment) on the 

Montgomery-Asberg Depression Rating Scale (MADRS) 

total score. 

– Mean change from baseline to week 8 in MADRS total score 

was 12.9 with vilazodone compared with 9.6 with placebo (P = 

0.001). 

– Vilazodone also resulted in significant reductions in the HAM-D- 

17 (10.4 vs 8.6, P = 0.022), 

– Response, defined as a 50% or greater reduction in total score 

from baseline to week 8 on the MADRS or HAM-D-17 total 

scores, or a score of 1 or 2 on the CGI-I, was achieved in 40% to 

48% of vilazodone-treated patients compared with 28% to 32% 

of placebo recipients. 

– The discontinuation rate in the vilazodone arm was 9.3% 

compared with 4.9% in the placebo group (primarily diarrhea) 


WARNINGS AND PRECAUTIONS 

• Vilazodone labeling includes class cautions regarding 

clinical worsening and suicide risk (Box Warning), 

serotonin syndrome, neuroleptic malignant–like 

syndrome, seizures, abnormal bleeding, activation of 

mania/hypomania, and hyponatremia 

• A gradual dosage reduction is recommended to minimize 

discontinuation symptoms 

• The vilazodone dose should be reduced to 20 mg when 

coadministered with strong CYP3A4 inhibitors. 

• Coadministration of vilazodone with CYP3A4 inducers 

can result in reduced vilazodone concentrations, and 

may reduce its effectiveness. 

Wayne Weart 






Table 3. Most Common Adverse Events With Vilazodone Reported 

in Placebo-Controlled Depression Studies in Patients With MDD 

Vilazodone 40 mg/day (n = 436) Placebo (n = 433) 

Diarrhea 28% 9% 

Nausea 23% 5% 

Dizziness 9% 5% 

Dry mouth 8% 5% 

Insomnia 6% 2% 

Vomiting 5% 1% 

Fatigue 4% 3% 

Abnormal dreams 4% 1% 

Libido decreased 4% < 1% 

Somnolence 3% 2% 

Orgasm abnormal 3% 0% 


Dosing: 

• The recommended dosage of vilazodone is 40 mg once 

daily. Therapy should be initiated with a dosage of 10 mg 

once daily for 7 days, then 20 mg once daily for an 

additional 7 days, and then increased to 40 mg once 

daily. When discontinuing therapy, the dosage should be 

reduced gradually. 

• Vilazodone should be taken with food. Administration 

without food may result in inadequate absorption and 

reduced effectiveness. 

• Cost $144.00/30 x 40 mg tabs WAC 

Wayne Weart 





Roflumilast - Daliresp 

by Forest Labs • Dose 500 mcg QD with 

or without food 

• Indicated as a treatment to 

reduce the risk of COPD 

exacerbations in patients with 

severe COPD associated with 

chronic bronchitis and a 

history of exacerbations 

• Neutrophils, eosinophils, and 

monocytes contain PDE4. 

Roflumilast is believed to 

exert an anti-inflammatory 

effect through inhibition of 

PDE4 in these cell types 

• Cost $211.50/30 tabs 

WAC 


• The pharmacologically active N-oxide metabolite is 

estimated to account for about 90% of roflumilast’s 

overall pharmacologic effects. The elimination halflife 

of the N-oxide metabolite is approximately 21 to 

27 hours. Roflumilast N-oxide is predominantly 

metabolized via CYP3A4 

• Drug Interactions: Use with strong cytochrome P450 

enzyme inducers (e.g. rifampicin, phenobarbital, 

carbamazepine, phenytoin) is not recommended. 

• CYP3A4 inhibitors or dual inhibitors that inhibit both 

CYP3A4 and CYP1A2 simultaneously (e.g., 

erythromycin, ketoconazole, fluvoxamine, enoxacin, 

cimetidine) may increase roflumilast systemic 

exposure and may result in increased adverse 

reactions. The risk of such concurrent use should be 

weighed carefully against benefit. 

Wayne Weart 






• 3 placebo controlled trials in patients with COPD and 

at least 1 exacerbation requiring steroids in the last 

year randomized to either roflumilast 500 mcg or 

placebo QD for 52 weeks. 

– Change in postbrochodilator FEV ranged from 

39-61 ml increase with roflumilast vs. placebo 

– Minimal reduction in moderate to severe 

exacerbations in 2 of the 3 trials- RR 0.85 and 0.82 

(RRR 15 and 18%) (0.19 and 0.28 exacerbations 

per year) 


• Roflumilast 500 mcg plus salmeterol in patients with 

moderate to severe COPD vs. placebo plus 

salmeterol for 24 weeks. 

– Change in postbrochodilator FEV 1 60 ml increase 

with roflumilast vs. placebo 

– Non-significant reduction in mild, moderate or 

severe exacerbations with roflumilast vs. placebo 

RR 0.79 (P=0.1408) 2.4 VS. 1.9 exacerbations per 

year 

– Proportion of patients with a moderate or severe 

exacerbation RR 0.6 (P=0.0015) 18% vs. 11% 

– ARR 7%, NNT ~15 

Wayne Weart 






• Roflumilast 500 mcg plus tiotropium in patients with 

moderate to severe COPD vs. placebo plus 

tiotropium for 24 weeks. 

– Change in postbronchodilator FEV 1 

81 ml 

increase with roflumilast vs. placebo 

– Non-significant reduction in number of mild, 

moderate or severe exacerbations with roflumilast 

vs. placebo RR 0.84 (P=0.357) 2.2 vs. 1.8 

exacerbations per year 

– Proportion of patients with a moderate or severe 

exacerbation RR 0.73 NS (P=0.0867) 


Warnings and Precautions; 

• Acute bronchospasm: Do not use for the relief of acute 

bronchospasm. 

• Psychiatric Events including Suicidality: Advise patients ,their 

caregivers, and families to be alert for the emergence or worsening of 

insomnia, anxiety, depression, suicidal thoughts or other mood 

changes, and if such changes occur to contact their healthcare 

provider. Carefully weigh the risks and benefits of treatment with 

roflumilast in patients with a history of depression and/or suicidal 

thoughts or behavior. In 8 controlled clinical trials 5.9% (263) of 

patients treated with roflumilast 500 mcg daily reported psychiatric 

adverse reactions compared to 3.3% (137) treated with placebo 

• Weight Decrease: Monitor weight regularly. If unexplained or clinically 

significant weight loss occurs, evaluate weight loss and consider 

discontinuation of roflumilast. In the clinical trials weight loss was 

reported in 7.5% (331) of patients treated with roflumilast 500 mcg 

once daily compared to 2.1% (89) treated with placebo and in the trials 

that lasted 1 year 20% of patients receiving roflumilast experienced 

moderate weight loss (defined as between 5-10% of body weight) 

compared to 7% of patients who received placebo. 

Wayne Weart 






Indacaterol – Arcapta Neohaler 

by Novartis 

Wayne Weart 






• A long acting beta 2 agonist that increases cyclic AMP levels 

which causes relaxation of bronchial smooth muscle. FDA 

approved for the long term, once-daily maintenance 

bronchodilator treatment of airflow obstruction in patients 

with chronic obstructive pulmonary disease (COPD), including 

chronic bronchitis and/or emphysema 

• Not indicated to treat acute deteriorations of chronic 

obstructive pulmonary disease 

– In vitro studies have shown that indacaterol has more than 24-fold 

greater agonist activity at beta 2-receptors compared to beta 1- 

receptors and 20-fold greater agonist activity compared to beta 3- 

receptors. This selectivity profile is similar to formoterol. 

– The effective half-life, calculated from the accumulation of indacaterol 

after repeated dosing with once daily doses between 75 mcg and 600 

mcg ranged from 40 to 56 hours which is consistent with the observed 

time-to-steady state of approximately 12-15 days. 


BOX WARNING: ASTHMA-RELATED DEATH 

• Long-acting beta2-adrenergic agonists (LABA) increase the risk 

of asthma-related death. Data from a large placebo-controlled 

US study that compared the safety of another long-acting 

beta2-adrenergic agonist (salmeterol) or placebo added to 

usual asthma therapy showed an increase in asthma-related 

deaths in patients receiving salmeterol. This finding with 

salmeterol is considered a class effect of LABA, including 

indacaterol, the active ingredient in ARCAPTA NEOHALER. The 

safety and efficacy of ARCAPTA NEOHALER in patients with 

asthma have not been established. ARCAPTA NEOHALER is not 

indicated for the treatment of asthma. 

Wayne Weart 






Table 2. Pharmacokinetic Parameters for Inhaled Long-Acting 

Beta-2 Agonists Administered Using a Portable Inhaler 

Pharmacokinetic 

Parameter 

Formoterol Indacaterol Salmeterol 

C max 5 min 15 min 20 min 

Half-life 7 to 10 h 30 h 5.5 h 

Exchanged in the 

urine 

2% to 18% < 1% NS 

The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the 

contents of one 75 mcg capsule using the NEOHALER inhaler. The dose should be 

administered once daily every day at the same time of the day by the orally inhaled route 

only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do 

not use ARCAPTA NEOHALER more than one time every 24 hours. 

ARCAPTA capsules must always be stored in the blister, and only removed 

IMMEDIATELY BEFORE USE 


Wayne Weart 






Dose-ranging in COPD 

• A 2-week, randomized, double-blinded, placebo-controlled 

design that enrolled 552 patients with a clinical diagnosis of 

COPD, who were 40 years or older, had a smoking history of at 

least 10 pack years, had a post-bronchodilator FEV1 less than 

80% and at least 30% of the predicated normal value and a 

post-bronchodilator ratio of FEV1 over forced vital capacity 

(FEV1/FVC) of less than 70%. The trial compared doses of 

18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active 

control group, and placebo. The trial showed that the effect 

on FEV1 in patients treated with 18.75 mcg dose was lower 

compared to patients treated with other indacaterol doses. 

– Although a dose-response relationship was observed at Day 1, the 

effect did not clearly differ among the 37.5, 75 and 150 mcg doses by 

Day 15 


Like other beta2-agonists, indacaterol can produce a clinically significant cardiovascular 

effect in some patients as measured by increases in pulse rate, systolic or diastolic blood 

pressure, or symptoms. In addition, beta-agonists have been reported to produce ECG 

changes, such as flattening of the T wave, prolongation of the QTc interval, and ST 

segment depression, although the clinical significance of these findings is unknown 

Wayne Weart 





Buprenorphine Transdermal System - Butrans 

by Purdue Pharma 

• Indicated for the management 

of moderate to severe chronic 

pain in patients requiring a 

continuous, around-the-clock 

opioid analgesic for an 

extended period of time. 

• A morphine alkaloid. It is a 

partial agonist at mu-opioid 

receptors, which mediate 

analgesia, and an antagonist at 

kappa-opioid receptors which 

may reduce abstinenceinduced 

dysphoria? 


• The transdermal system is designed to deliver 

buprenorphine continuously for 7 days. 

– It is designed with 5 layers: a beige-colored web backing layer, 

an adhesive rim without buprenorphine, a separating layer over 

the buprenorphine-containing adhesive matrix, a buprenorphinecontaining 

adhesive matrix, and a peel-off release liner. The skin 

is the limiting barrier to diffusion into the systemic circulation. 

– Steady state is achieved by day 3 during the first application. 

The 5, 10, and 20 mcg/h patches provide dose-proportional total 

buprenorphine exposure (area under the curve) following 7-day 

application. 

– Following removal of transdermal buprenorphine, the mean 

buprenorphine concentration decreases approximately 50% in 

12 hours (range, 10 to 24 hours), with an apparent terminal halflife 

of approximately 26 hours. 

Wayne Weart 






• Transdermal buprenorphine was assessed in a study enrolling 1,160 

patients with chronic low back pain currently receiving long-term 

opioid therapy (morphine 30 to 80 mg equivalent per day). Patients 

entered an open-label, dose-titration period with transdermal 

buprenorphine for up to 3 weeks following tapering of prior opioids. 

Buprenorphine therapy was initiated with the 10 mcg/h dosage for 3 

days and then increased to 20 mcg/h for up to 18 days. Patients with 

adequate analgesia and tolerable adverse effects at the 20 mcg/h 

dosage were randomized to remain on buprenorphine 20 mcg/h or 

were switched to low-dosage control (buprenorphine 5 mcg/h) or an 

active control (not specified). 

– At least a 30% reduction in pain score from screening to end point was achieved 

in 49% of patients treated with the 20 mcg/h dosage compared with 33% of 

patients treated with the 5 mcg/h dosage 


• 588 patients with persistent non–cancer-related pain 

previously treated with oral opioid combination agents 

received transdermal buprenorphine during a 7- to 21- 

day open-label titration phase; those achieving stable 

pain control (267 patients) were randomized to receive 

up to 14 days of buprenorphine at the titrated dose or 

placebo. 

– Treatment was judged ineffective (requiring more than 

acetaminophen 1 g as escape medication on any day of the 

double-blind phase, requiring a change in study drug or dose, 

having difficulty keeping the patch affixed, or discontinuing 

treatment because of a lack of efficacy) in 51.2% of 

buprenorphine-treated patients compared with 65% of patients 

treated with placebo. The odds of ineffective treatment were 1.79 

times greater with placebo than with buprenorphine (P = 0.022). 

Wayne Weart 






CONTRAINDICATIONS: 

• Transdermal buprenorphine is contraindicated in patients 

who have significant respiratory depression, patients 

with severe bronchial asthma, patients who have or are 

suspected of having paralytic ileus, and patients with 

known hypersensitivity to any of the product’s 

ingredients 

• Transdermal buprenorphine is also contraindicated in the 

management of acute pain, postoperative pain, mild 

pain, and intermittent pain, and in patients who require 

short-term opioid analgesic therapy 


WARNINGS AND PRECAUTIONS: 

• Box warning regarding proper patient selection, potential for abuse, 

and dose limitations. Transdermal buprenorphine should only be 

used in the management of moderate to severe pain in patients 

requiring a continuous, around-the-clock opioid analgesic for an 

extended period of time. 

• Transdermal buprenorphine should be used with extreme caution in 

patients at risk of respiratory depression, particularly patients with 

significant chronic obstructive pulmonary disease or cor pulmonale; 

patients at risk of substantially decreased respiratory reserve (eg, 

asthma, severe obesity, sleep apnea, myxedema, clinically 

significant kyphoscoliosis, CNS depression); and patients with 

hypoxia, hypercapnia, or preexisting respiratory depression. 

• Buprenorphine is a schedule III controlled substance. Clinical risks 

for abuse or addiction should be assessed prior to prescribing the 

agent. 

Wayne Weart 






Table 2. Adverse Events of Buprenorphine vs Placebo in Patients Being Treated for Chronic Pain 

With a Dose That Was Titrated to Effect 

Adverse Events 

Buprenorphine 

(n = 392) 

Placebo 

(n = 261) 

Nausea 23% 8% 

Dizziness 16% 8% 

Headache 16% 11% 

Application-site pruritus 15% 12% 

Constipation 14% 5% 

Somnolence 14% 5% 

Vomiting 11% 2% 

Peripheral edema 7% 3% 

Application-site erythema 7% 2% 

Dry mouth 7% 2% 

Application-site rash 6% 6% 

Fatigue 5% 1% 

Fall 4% 2% 

Hyperhidrosis 4% 1% 

Pruritus 4% 1% 


DOSING: 

• The transdermal system (patch) is applied every 7 days to the upper 

outer arm, upper chest, upper back, or side of the chest on either 

side of the body. 

– Application should be rotated among these 8 sites and a 

minimum of 3 weeks should elapse before applying a patch to 

the same site. 

– The patch should be applied to a hairless or nearly hairless skin 

site. The hair at the site should be clipped, not shaven. 

– If there are adhesion problems with the patch, the edges may be 

taped down with first aid tape or covered with see-through 

adhesive dressing (eg, Bioclusive, Tegaderm). 

– If the patch falls off during the 7-day dosing interval, a new patch 

should be applied at a different skin site. 

– The buprenorphine transdermal system should not be cut. 

Wayne Weart 






DOSING: 

• In opioid-naive patients, the initial dosage should always 

be 5 mcg/h. The dosage should not be increased until the 

patient has been continuously exposed to the previous 

dosage for 72 hours. 

• Buprenorphine may precipitate withdrawal in patients 

who are already on opioids. 

– Prior to converting from another opioid to buprenorphine, the 

patient’s current around-the-clock opioid should be tapered to no 

more than morphine 30 mg or equivalent per day before beginning 

buprenorphine. 

– Following initiation of buprenorphine therapy, the dose may be 

titrated upward after at least 72 hours at the current dose. Individual 

dosage titration should be based on the patient’s requirement for 

supplemental short-acting analgesics. 

– The maximum transdermal buprenorphine dosage is one 20 mcg/h 

system because of potential dose-related QTc prolongation. 


Risk Evaluation and 

Mitigations Strategy 

(REMS) assessment plan 

stated in the FDA’s 

approval 

Including a surveillance 

and monitoring system to 

detect abuse, misuse, 

overdose, and addiction 

and any modifications in 

provider education and 

drug distribution if these 

problems exist 

The cost for 4 patches 

AWP is; 

5 mcg -$151.20 

10 mcg - $226.80 

20 mcg - $401.52 

Wayne Weart 





Azilsartan medoxomil - Edarbi 

by Takeda 

• Approved for the treatment of 

hypertension, alone or in 

combination with other 

antihypertensive agents. 

• No outcome data 

• A prodrug that is structurally 

related to candesartan. 

Azilsartan medoxomil is rapidly 

hydrolyzed to azilsartan in the 

GI tract. 

• T ½ ~ 11 hours 

• Cost $86.00 per 30 tablets 

drugstore.com 

• Usual dose 80 mg 

QD with or 

without food 


Wayne Weart 






First ARB in combination with chlorthalidone pending 

FDA approval 

Change in systolic blood pressure: 

End point 

Clinic SBP 

(change from baseline, mm 

Hg) 

Change in 24-h mean SBP 

(change from baseline, mm 

Hg) 

Azilsartan 

Chlorthalidon 

e 

40/25 (n=355) 

Azilsartan 

Chlorthalidone 

80/25 (n=352) 

Olmesartan 

HCTZ 

40/25 (n=364) 

- 42.5 - 44.0 - 37.1

New Drug Update 2010-2011 Faculty Disclaimer - CME Conferences

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