Pharmacology Watch

New, Shorter Treatment Regimen for Tuberculosis

In this issue: New treatment for TB; safety of dabigatran; quality of antidepressants; systolic hypertension treatment; and FDA actions.

Short course treatment for latent TB

Three months of two drugs administered once weekly is as effective as 9 months of daily isoniazid (INH) for the treatment of latent tuberculosis infection (LTBI), according to a new study. An international team of researchers randomized nearly 8000 patients with latent tuberculosis (TB) to 3 months of directly observed once-weekly therapy with rifapentine 900 mg plus INH 900 mg or 9 months of self-administered daily INH 300 mg. The primary endpoint was confirmed TB after 33 months of follow-up. In the modified intention-to-treat analysis, TB developed in 0.19% of the once-weekly combination group and in 0.43% of the INH only group. Rates of completion were much higher with the short course, once-weekly regimen (82.1% in the combination-therapy group and 69.0% in the INH only group, P < 0.001). Rates of hepatotoxicity were higher in the INH only group. The authors conclude that use of rifapentine plus INH given once a week for 3 months is as effective as 9 months of INH in preventing tuberculosis and has a higher treatment-completion rate (N Engl J Med 2011;365:2155-2166). Based on this study and others, the CDC has issued a new recommendation on the use of short-course combination therapy for latent TB infection. The recommendation states, "The new regimen is recommended as an equal alternative to the 9-month INH regimen for otherwise healthy patients ≥ 12 years who have LTBI and factors that are predictive of TB developing (e.g., recent exposure to contagious TB)." It also recommends that the new regimen may be considered for other categories of patients when it offers advantages. Daily INH continues to be the preferred regimen for children between the ages of 2 and 11 (MMWR Morb Mortal Wkly Rep 2011;60:1650-1653).

Bleeding concerns with dabigatran

Dabigatran (Pradaxa), Boehringer Ingelheim's blockbuster anticoagulant, is the subject of a December 7, 2011, Drug Safety Communication by the FDA regarding serious bleeding events. The FDA is evaluating postmarketing reports of serious bleeding events that may lead to serious or even fatal outcomes. Experts are working to determine whether the reports of bleeding associated with the drug are occurring more commonly than would be expected based on observations from large clinical trials. The drug was approved in October 2010 to reduce the risk of stroke in patients with non-valvular atrial fibrillation. More than a million prescriptions have been filled by nearly 400,000 patients since approval.

All antidepressants are created equal

When it comes to choosing an antidepressant, all modern drugs are roughly equivalent, according to a new study in the Annals of Internal Medicine. Researchers performed a large meta-analysis of 234 studies that looked at the treatment of major depressive disorder (MDD) with second-generation antidepressants. There were no differences among the drugs with regard to efficacy or effectiveness for the treatment of acute, continuation, and maintenance phases of MDD. There were also no significant differences when accompanying symptoms were taken into account or other factors such as age, sex, ethnicity, or comorbid conditions. There were differences among the drugs with regard to onset of action, adverse effects, and some quality-of-life issues. There was also a significant difference in cost and dosing convenience. Drugs considered in the study were bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxine. The authors suggest that familiarity with the broad spectrum of antidepressants is prudent given the difficulty of predicting which medication will be effective and tolerated by any given patient (Ann Intern Med 2011;155:772-785).

Benefits of treating systolic hypertension

Older adults with isolated systolic hypertension gained about 5 months of life when treated with chlorthalidone-based stepped care 2 decades after completion of the Systolic Hypertension in the Elderly Program (SHEP) trial. SHEP, conducted between 1985 and 1990, was a clinical trial of patients aged 60 years or older (mean age 72) with isolated systolic hypertension who were randomized to chlorthalidone-based antihypertensive therapy or placebo. Over a mean follow-up of 4.5 years, chlorthalidone-based therapy resulted in prevention of approximately 1 of 2 admissions for heart failure, 1 out of 3 fatal or nonfatal strokes, and 1 of 4 coronary heart disease events, but there was no effect on all-cause mortality or cardiovascular death. At the end of the trial, all participants were advised to receive active therapy. The new study reviewed cardiovascular death and all-cause mortality in SHEP trial participants 22 years after the study ended. Life expectancy gain between the active treatment group and placebo group was 105 days (95% confidence interval [CI], -39 to 242; P = 0.07) for all-cause mortality and 158 days (95% CI, 36-287; P = 0.009) for cardiovascular death. Each month of active treatment was associated with approximately 1 day extension in life expectancy. The authors conclude that treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up (JAMA 2011;306:2588-2593). This study may help convince older patients with systolic hypertension that compliance with diuretic-based hypertensive therapy is worth the effort as it will prolong their lives.

Aliskiren and ACEIs/ARBs don't mix

Aliskiren (Tekturna), Novartis' direct renin inhibitor, should not be combined with an ACE inhibitor or angiotensin receptor blocker (ARB) to treat hypertension, according to the manufacturer. Novartis recently terminated the ALTITUDE trial when it was found that patients with type 2 diabetes or impaired renal function who were given the combination of aliskiren with an ACEI or ARB had a higher incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension. More information can be found at

FDA actions

The FDA approved generic atorvastatin (Lipitor) on November 30, 2011. Ranbaxy Laboratories will make the first generic in 10, 20, 40, and 80 mg strengths. Atorvastatin as Lipitor was first marketed in 1997 and became the best-selling prescription medication in history with sales of more than $125 billion. It has dominated the statin market in recent years, representing nearly a quarter of Pfizer's annual revenue, and the giant pharmaceutical company aggressively defended their patent against multiple challenges. Ranbaxy has 180 days of exclusivity on generic atorvastatin after which time multiple manufacturers are expected to seek approval for their generic version of the drug.

The FDA has approved Prevnar 13 for adults age 50 and older to prevent pneumonia and invasive disease caused by Streptococcus pneumoniae. The vaccine was previously approved for children up to 5 years of age. The approval was based on head-to-head studies with Pneumovax 23 which is already approved for use in adults. According to the FDA, "for the 12 common serotypes, Prevnar 13-induced antibody levels were either comparable to or higher than the levels induced by Pneumovax 23." Prevnar 13 is manufactured by Wyeth Pharmaceuticals.

Dronedarone (Multaq) should not be prescribed to patients with permanent atrial fibrillation (AF), based on results from the PALLAS trial which showed that the drug doubles the risk for cardiovascular death, stroke, and heart failure in such patients. The FDA is requiring revised labeling for the antiarrhythmic drug and has issued a Drug Safety Communication after a safety review was completed. If dronedarone is to be prescribed, the FDA recommends ECGs every 3 months and immediately stopping the drug if the patient is found to be in AF. The drug is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (paroxysmal or persistent AF). Dronedarone is manufactured by Sanofi-Aventis.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: