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July 1998 Bruce H. Woolley, Pharm.D., Editor Vol. 5, No. 7


Mibefradil (Posicor®/Roche), a T-channel calcium channel blocker, wasvoluntarily removed from the market on June 8th.  In the company's three year trial,they found a significant increase in clinically significant interactions. Posicor is apotent inhibitor of CytP450-3A4 and a moderate inhibitor of 2D6. In a June 12th updatedletter Roche stated that feedback indicated that some patients had experienced druginteractions upon substituting certain alternate therapy for the withdrawn mibefradil(Posicor®).  They stated:

1. If you choose to substitute amlodipine or atenolol, they should preferably bestarted two to three days after mibefradil discontinuation.

2. If you choose to substitute other calcium channel blockers (except felodipine) orother beta blockers (except timolol), they should preferably be started seven days aftermibefradil discontinuation.

3.  If you choose to substitute felodipine or timolol, they should preferably bestarted fourteen days after mibefradil discontinuation.

4.  No special precaution regarding the timing for switching is necessary forother antihypertensive or anti-anginal medications (e.g., ACE inhibitors, angiotensin IIantagonists, diuretics, nitrates). Any drug metabolized by the cytochrome P450 3A4 or 2D6isoenzymes may interact with mibefradil.  Therefore, as a reminder, theco-administration of mibefradil with drugs metabolized by the 3A4 or 2D6 isoenzymes of thecytochrome P450 system may result in increased plasma levels of those drugs, so doseadjustments may be necessary as mibefradil is withdrawn.

Generic (and trade) names for drugs that may interact with mibefradil substitution mayinclude  amiodarone (Cordarone), astemizole (Hismanal), bepridil (Vascor), cisapride(Propulsid), cyclosporine Neoral, Sandimmune), cyclophosphamide (Cytoxan), desipramine(Norpramin), erythromycin, etoposide (VePesid), flecainide (Tambocor), flutamide(Eulexin), halofantrine (Halfan), ifosfamide (Ifex), imipramine (Tofranil), lovastatin(Mevacor), mexiletine (Mexitil), pimozide (Orap), propafenone (Rythmol), quinidine,simvastatin (Zocor), tacrolimus (Prograf), tamoxifen (Nolvadex), terfenadine (Seldane),thioridazine (Mellaril), vinblastine (Velban), vincristine (Oncovin).

Bromfenac sodium (Duract®/Wyeth-Ayerst), a nonsteroidalanti-inflammatory analgesic, was voluntarily withdrawn from the market on June 22nd. Theaction was in response to postmarketing reports of severe hepatic failure resulting infour deaths and eight liver transplants. Marketing approval was granted in July 1997 forshort-term (<10days) management of acute pain and was never approved for long-term use in chronic pain. All but one of the 12 cases noted had ingested the drug for longer than the ten days. The one exception involved a patient with significant pre-existing liver disease. Wyeth-Ayerst had issued a “Dear Health Professional” letter in February and had revised the product labeling to include a black box warning. Despite the warnings it was concluded by the company that additional steps to limit use to ten days were not feasible and the withdrawal decision was made. Patients should discontinue use of the medication immediately. Information concerning bromfenac can be obtained by calling 800-281-9260.


The FDA has granted marketing approval for cetirizine (Zyrtec®/Pfizer) for use in thetreatment of seasonal and perennial allergic rhinitis and for chronic idiopathic urticariain children 2 years and older. The carboxylated metabolic product of hydroxyzine hasproven effective in the late phase of the allergic response, partly due to its inhibitionof eosinophilic accumulation. Side effects in adults include: drowsiness, fatigue and drymouth. In children, the side effects include: headache, drowsiness, sore throat, andstomach pain.


Approval has been granted for candesartan cilexetil (Atacand®/Merck) for the treatmentof hypertension alone or in combination with other agents. The fifth drug in the classcalled angiotensin II receptor blockers is dosed once daily, without regard to food, withan adverse effect profile similar to placebo. As with other drugs in this therapeuticclass, it is contraindicated in pregnancy and in those patients allergic to any ingredientof the formulation.


Reuters recently reported that the FDA has proposed new rules that will allow off-labelpromotion of drugs to health care professionals. They wrote: “This information canonly be disseminated for ‘off-label-uses which have been, or will be studied andsubmitted for FDA approval...I must be reliable and balanced.” The article alsostated that any information disseminated must concern a drug or device that has beengranted marketing approval by the FDA and must be in the form of a study published in ascientific journal. The FDA must be notified at least 60 days prior to the disseminationof the information.


Warfarin sodium (Coumadin®/DuPont Merck) labeling will soon contain a precautionarystatement, “Patients should be informed that all warfarin sodium products representthe same medication, and should not be taken concomitantly, as overdosage mayresult.” The company stated that confusion has resulted, in part because the genericand trade formulations have different shapes and markings. By law, generic warfarin mustcarry the same precaution label.


The first new drug for the treatment of pulmonary tuberculosis in 25 years has beengranted marketing approval. Rifapentine (Priftin®/Hoechst Marion Roussel) is along-acting formulation of rifampin which can be taken twice weekly. The companyrecommends that the drug always be given in conjunction with at least one otheranti-tuberculosis medication. Side effects include: red to orange discoloration of theurine, perspiration, sputum and tears.


The FDA has sent a non-approvable letter for a novel antipsychotic called ziprasidone(Zeldox®/Pfizer). The governmental agency requested additional data concerningthe safety and efficacy of the product. John Niblack, executive vice president anddirector of research at Pfizer stated that: “We are obviously disappointed at thisdevelopment, but remain confident of the safety and efficacy of Zeldox...We believe thatthe additional studies and analyses suggested by the FDA can be undertaken in a relativelyshort period.”


TNGT:Fc (Enbrel®/Immunex) has been granted priority review by the FDA. Priority reviewrequires the FDA to make a decision on marketing within six months of the company filingfor approval. The requested approval is for the treatment of rheumatoid arthritis and ifapproved, with be co-marketed by Immunex and Wyeth-Ayerst.


A recent article (JAMA 1998; 279:1903-1907) reporting on 10 studies involving 16,614elderly patients showed that <33% of beta blocker patients experienced adequate control of their blood pressure compared with 66% of those taking diuretics as monotherapy. The beta blockers did not have an impact on mortality and risk of heart attack, and were found to produce more side effects (including fatigue and depression) than diuretics. Diuretics were effective in preventing cerebrovascular events, fatal strokes, coronary heart disease, cardiovascular mortality and all-cause mortality. Beta blockers reduced the risk of only cerebrovascular events. The authors concluded that beta blockers should not be considered first-line therapy for uncomplicated hypertension in otherwise healthy elderly patients. They also recommended that patients currently taking beta blockers should not interrupt or alter their therapy without consulting with their physician.


Marketing approval has been granted by the FDA for famciclovir (Famvir®/SmithKlineBeecham) as a treatment for recurrent herpes simplex virus infections in HIV-infectedpatients. This is the first oral drug to be approved for this indication. According to thecompany, significant healing occurred when clinical trial patients were treated within 48hours of lesion onset (genital herpes or cold sores) with a twice daily dose of 500 mg ora five times daily dose of 400 mg for a total of seven days. Side effects includedheadache and nausea..


In a paper presented on, June 14, at the annual meeting of the American DiabetesAssociation, Dr. Andrew Greenberg of the University of Texas reported that the geneticallyengineered human hormone leptin (manufactured by Amgen) may help seriously obese peoplelose weight. The results of his six month study involving 60 subjects with a body massindex (BMI) of 27.5 to 36 who were given leptin injections lost 16 pounds as compared to a4 pound loss with placebo. Participants of the study ingested diets providing 500 caloriesless than their basic energy needs and were advised to exercise. The synthetic hormonewill not replace a sound weight management program but may be an adjunct in reducing thepathophysiological risks of obesity. The study showed no significant adverse effects;however, additional studies are needed for determination of long-term safety and efficacy.


The 1989 epidemic outbreak of eosinophilia-myalgia syndrome (EMS) in the United Statesand its apparent association with dietary supplements containing L-tryptophan caused theFDA to limit the importation of L-tryptophan. Over 1500 cases of EMS, including 38 deaths,were reported to the Centers for Disease Control and Prevention (CDC). In epidemiologicalstudies, more than 95% of cases were traced to a supplier in Japan; however, not all whoingested this product developed EMS and cases had occurred prior to and after theepidemic. These and other findings lead to the FDA conclusion that the etiology could notbe related to a contaminant in a single source. Consequently, the FDA cannot determinethat oral dosage forms of L-tryptophan can be safely used. However, manufacturedL-tryptophan is a lawful and essential component of foods, such as infant formulas,enteral products and approved parenteral drug products. L-tryptophan may also be added asa nutrient to special dietary foods which are intended for use under medical supervision.

Now the FDA has received reports of EMS in patients taking 5-OH tryptophan, ametabolite of L-tryptophan. They have issued a warning about supplements containing thismetabolite, a popular supplement purported to be a serotonin enhancer thought to be apharmacologic means for weight loss and for the treatment of depression. The agency hasstated that they will continue to carefully monitor the results of basic and clinicalresearch studies and will take appropriate steps based on the results. Until the data fromthese studies are completed and evaluated health professionals should not recommendproducts containing this metabolite.

The information and opinions expressed in the Therapeutics Letter do notnecessarily reflect the official policy of the sponsoring organizations.