FDA Issues Warning on Cisapride

By William T. Elliott, MD, FACP

The fda has issued a warning regarding "serious cardiac events" associated with the drug cisapride (Propulsid-Janssen) and has required the drug manufacturer to include a boxed warning on the package insert. Cisapride, a pro-motility agent, is used to treat gastroesophageal reflux disease. Janssen has issued a "Dr. Letter" warning about the incidence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Through May 1999, more than 270 cases of cardiac arrhythmias occurred spontaneously, including 70 fatalities. Almost all these cases occurred in patients with known risk factors. Coadministration of drugs that inhibit cytochrome P450 3A4 enzymes is a risk factor as is pre-existing cardiac disease. A partial list of drugs that should not be given with cisapride include: macrolides antibiotics (such as erythromycin, clarithromycin, and troleandomycin), antifungals (such as fluconazole, itraconazole, and ketoconazole), certain protease inhibitors, and phenothiazines. Other drugs that may cause potential interaction include class IA (quiniedine, procainamide) and class III (solatol) antiarrhythmics, tricyclic antidepressants, certain other antidepressants (such as nefazadone and maprotiline), certain antipsychotic medications, and other agents (such as bepridil, sparfloxacin, and grapefruit juice). Janssen is recommending that a 12-lead EKG be performed prior to administration of cisapride and that the drug should not be given if the QTc interval exceeds 450 ms†. Serum electrolytes and serum and creatinine tests should be performed prior to administration of cisapride.

Treatment for Helicobacter pylori may be getting more simple. Italian researchers have shown that a six-day course of treatment with three drugs has a 90% cure rate. The regimen includes ranitidine bismuth critrate, clarithromycin, and tinidazole all administered three times a day. This combination was safe and well-tolerated by patients. Cure rate was assessed by urea breath test. The study compared the six-day regimen to the same drugs used in a seven-day regimen. Adding an extra day of treatment only increased the cure rate to 92% (Dig Dis Sci 1999;44:2386-2389).

In a merger that will form the largest drug company in the world, British pharmaceutical giants Glaxo Wellcome and SmithKline Beecham announced in January that they are joining forces. The new company will be known as Glaxo SmithKline, and have a net worth of nearly $190 billion. This is the second time the two companies have attempted to merge; however, talks broke down two years ago without an agreement. The new company will have its headquarters in London and its new operational base in the United States. Glaxo’s top products include sumatriptan and antivirals including HIV drugs. SmithKline’s top products include the antibiotic amoxicillin/clavulantate (Augmentin) and the antidepressant paroxetine (Paxil).

Congress is getting serious about providing coverage for prescription drugs for Medicare beneficiaries. House Speaker Dennis Hastert (R-IL) has asked Republican members of the House Ways and Means Committee to begin working on a plan, an important first-step in what is sure to be a contentious bipartisan process, especially during an election year. House members are looking at a number of options, including a plan to provide coverage outside of Medicare. Both the House Ways and Means and Commerce Committees share jurisdiction over Medicare part B, which provides coverage for outpatient services. President Clinton has made it clear that the Medicare prescription drug plan along with a patient Bill of Rights are two of his primary objectives for his last year in office.

There is good and bad news for practitioners of alternative therapies. First, the bad news: Popular over-the-counter antidepressant St. John’s wort is increasingly being associated with photo-toxic reactions. In a recent study of the active ingredient, hypericin, given orally or intravenously for eight weeks to HIV-positive patients, 11 out of 23 patients developed severe cutaneous photo- toxicity (Ann Int Med 1999;130:510-514). St. John’s wort has also been associated with reduced absorption of digoxin, which may lead to a 30% reduction in serum levels of the drug after 10 days of combined therapy (Clin Pharm Ther 1999;66:338-345). Vitamin E also appears to be a bust in preventing cardiovascular disease. As part of the HOPE study, vitamin E 400 IU daily or placebo was randomly given to nearly 10,000 patients at high risk for cardiovascular disease. Throughout the 4.5 years of the study treatment, vitamin E had no effect on cardiovascular outcomes (N Engl J Med 2000;342:154-160). The good news: Chondroitin sulfate, available over-the-counter and commonly used for the treatment of osteoarthritis, may be beneficial in this role. A meta-analysis of seven randomized trials totaling 372 patients treated for at least three months showed that patients taking chondroitin sulfate exhibited reduction in pain and a reduction in NSAID use or analgesic consumption compared to those taking placebo (J Rheum 2000;27:205-211).

The link between hormone replacement therapy (HRT) and breast cancer has been one of the most contentious issues in medicine during the last 20 years. A recent study is sure to cloud the issue even more with the finding that HRT regimens containing estrogen and progesterone are more likely to increase breast cancer risk than estrogen alone. The data come from follow-up of the Breast Cancer Detection Demonstration Project that was conducted from 1973 to 1980. The relative risk of breast cancer increased by 0.01 with each year estrogen alone was used and by 0.08 with each year of progesterone use. The findings, however, are complicated by the fact that estrogen alone was associated with an increased risk for breast cancer in lean women but not in heavy women. The authors conclude that the risks and benefits of HRT should be discussed in the context of the type of hormone replacement regimen and the individual characteristics of the woman, such as body mass index (JAMA 2000;283:485-491).

Two separate case reports link the new hypoglycemic agent rosiglitazone (Avandia-SmithKline Beecham) to severe hepatotoxicity. The case reports, from two different hospitals in Pennsylvania, described diabetic men in their 60s who developed evidence of severe hepatocellular injury within 2-3 weeks of starting rosiglitazone. There was no other obvious cause of hepatotoxicity, and both patients recovered after the drug was discontinued (Ann Intern Med 2000;132:118-124). These case reports are important because rosiglitazone is structurally similar to troglitazone, a drug that has been associated with liver failure. In early clinical trials, rosiglitazone was not associated with liver toxicity.

The drug manufacturer, SmithKline Beecham, had independent experts review at least one of these cases, and concluded that the liver injury was due to ischemia and not drug-related injury. Their findings were presented in a letter to the editor in the same issue of the Annals of Internal Medicine (Ann Intern Med 2000;132:164).

Montelukast (Singulair-Merck), an oral leukotriene receptor antagonist, has better long-term efficacy than the long-acting inhaled beta-agonist salmeterol (Serevent-Glaxo) in preventing exercise-induced bronchoconstriction. One hundred ninety-one adults with exercise-induced asthma were randomized to treatment with montelukast, 10 mg once a day, or salmeterol 50 mcg inhaled twice daily.

The bronchoprotective effect of montelukast was maintained throughout the eight weeks of study. In contrast, significant loss of bronchoprotection at weeks 4 and 8 was seen with salmeterol. The authors conclude that long-term administration of montelukast provided consistent inhibition of exercise-induced bronchoconstriction without the development of tolerance (Ann Intern Med 2000;132:97-104).