Pharmacology Watch: FDA - No Approval for Pleconaril; Side Effects Cited
May 1, 2002 6 minutes read
FDA: No Approval for Pleconaril; Side Effects Cited
Editor’s note: 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. Telephone: (404) 262-5517. E-mail: [email protected]. 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.
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The world will have to wait a while longer for a cure for the common cold. In mid March, the FDA’s Antiviral Drugs Advisory Committee voted to not endorse the approval of pleconaril, ViroPharma and Adventis’ antiviral drug for inhibiting picornaviruses, the most common cause of the common cold. The drug has been available on an open-label basis since 1996 to treat severe infections caused by picornaviruses. But studies have shown that the effect on the common cold is modest, shortening the duration of symptoms only 0.5 to 1.5 days. More importantly, the drug has been shown to have significant side effects, including increase menstrual bleeding and the drug interactions with some asthma medications. Finally, the committee was also concerned about the selection of resistant viruses with overuse of the drug. ViroPharma may continue research with the drug to establish a safety profile, and try resubmitting in the future.
Statins Reduce Fracture Risk in Elderly
A new study shows that statins are associated with a reduction in fracture risk in older women, even though the drugs do not seem to increase bone mineral density (BMD). Researchers in Australia look at the history of statin use in 1573 women with a history of fractures and 800 matched women without fracture with an average age of 70 years old. After controlling for medication use and lifestyle factors, statin use resulted in odds ratio for fracture of 0.40. Even after adjusting for BMD at the femoral neck, spine, and whole body, the odds ratios were essentially unchanged. The reason for these findings is unclear, but the researchers suggest that statins may have an effect on bone architecture or may reduce the rate of fracture by some other, yet unknown, mechanism (Arch Intern Med. 2002;162:537-540).
Levofloxacin Resistance Shown in Study
Levofloxacin is quickly becoming one of the most widely used antibiotics in the country for the treatment of community-acquired pneumonia. Almost predictably, Canadian researchers have recently identified 4 adult patients who failed treatment with levofloxacin and eventually grew levofloxacin-resistant Streptococcus pneumoniae from sputum or blood cultures (N Engl J Med. 2002;346:722, 747-750). Pneumococcal resistance has also become a serious problem in children as well. Surveillance of pneumococcal isolates from children between 1993 and 1999 showed a marked increase in resistance to several antibiotics over those 6 years. Penicillin resistance increased from 4% to 15% while resistance to ceftriaxone increased from 0.5% to 2%. One-third of children had received antibiotic in the 30 days prior to diagnoses with resistant pneumococcal disease.
Claritin Could Become OTC
Loratadine (Claritin) may be available over-the-counter (OTC) before the end of the year. In a dramatic shift from the company’s previous stance, Schering-Plough has asked the FDA for permission to market all strengths of loratadine as over-the-counter products. Less than 1 year ago, the FDA independently considered moving loratadine, as well as 2 other nonsedating antihistamines, to OTC status, a move that Schering-Plough vigorously opposed. However, the drug now faces an impending patent expiration in December. Claritin generated $3.2 billion in sales for Schering-Plough last year, which represented about a third of the company’s total sales. The company, in hopes of recovering much of that lost revenue, has also introduced desloratadine, the active metabolite of loratadine to great fanfare under the trade name Clarinex. If desloratadine is a winner, the company hopes to control both the prescription market with its new product, and the OTC market with loratadine. Meanwhile, generic houses are lining up to produce a generic version of loratadine, which could be available as early as December 2002.
Ramipril Might Have Additional Benefits
The ACE inhibitor ramipril may have benefits beyond blood pressure lowering in patients who are at risk for stroke. A review of more than 9000 patients in the Heart Outcomes Prevention Evaluation (HOPE) trial revealed that patients treated with ramipril were 32% less likely to experience a stroke than those who received placebo. Patients in the trial were all at high risk for cerebrovascular disease, having pre-existing cardiovascular disease or diabetes plus other risk factors. Patients were randomized to either placebo or ramipril 10 mg per day, after a run-in period of several weeks, and they were followed for 4.5 years. Not only was the rate of stroke reduced by one third, but also ramipril resulted in a decreased risk of fatal stroke of nearly two thirds (61%). Curiously, patients in the ramipril group showed only modest blood pressure lowering (3.8 mm Hg systolic and 2.8 mm Hg diastolic), and the authors and others conjecture that the protective effective ramipril may go beyond its blood pressure lowering properties. The authors also suggest that this may be a class effect of ACE inhibitors. An accompanying editorial conjectures that ACE inhibitors may decrease oxidative stress and decrease proliferative and inflammatory responses in atherosclerotic plaques. They also suggest that the effect of ACE inhibitors is additive to that of aspirin in preventing stroke (BMJ. 2002;324:699-702, 687-688).
Losartan More Effective Than Atenolol
In a head-to-head study of losartan vs. atenolol, the angiotensin II receptor blocker losartan was shown to be more effective at reducing cardiovascular mortality and morbidity than the beta-blocker atenolol. In a multinational trial of more than 9000 patients aged 55-80 with hypertension and left ventricular hypertrophy (LVH), patients were randomized to losartan or atenolol-based antihypertensive treatments for 4 years. The blood pressure lowering effect of both medications was similar, approximately 30 mm HG drop in systolic pressure and a 16.5 mm Hg drop in diastolic pressure for both drugs. The primary composite end point (cardiovascular death, myocardial infarction, or stroke) was lower in the losartan group (23.8 per 1000) compared with the atenolol group (27.9 per 1000). The death rate and rate of nonfatal or fatal stroke was lower with losartan, while the rate of myocardial infarction was slightly higher with losartan although not statistically significant. Interestingly, the rate of new onset diabetes was 25% lower in patients taking losartan. The authors point out that this study does not condemn beta-blockers, with studies showing the drugs reduce cardiovascular event by 45% vs. placebo. They also point out that the beneficial effects of losartan may be incremental and additive to the benefits of beta-blockers in preventing cardiovascular disease, and that the drugs may, and perhaps should, be used together in these patients. However, the study also showed that losartan was better tolerated than atenolol (Lancet. 2002;359:995-1003). A related study from the same journal compared losartan to atenolol in patients with hypertension and diabetes. Nearly 1200 patients with diabetes, hypertension, and LVH were randomized to losartan or atenolol-based treatment regimens. Again, a pressure reduction was similar in both groups. The primary end points (cardiovascular disease, stroke, or myocardial infarction) occurred in 103/586-losartan group vs. 139/609 atenolol group (relative risk, 0.76). All-cause mortality was significantly lower in the losartan group, as was cardiovascular mortality (relative risk, 0.63 and 0.61, respectively). The authors of the study conclude that losartan is more effective than atenolol in reducing cardiovascular morbidity and mortality in patients with hypertension and diabetes with LVH. As in the previous study, the authors also conclude that the benefits of losartan seem to be more than just an antihypertensive effect (Lancet. 2002;359:1004-1010).
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