FDA
TALK PAPER

Food and Drug Administration
U.S. Department of Health and Human Services
Public Health Service 5600 Fishers Lane Rockville, MD 20857
FDA Talk Papers are prepared by the Press Office to guide FDA personnel in responding with consistency and accuracy to questions from the public on subjects of current interest. Talk Papers are subject to change as more information becomes available.
Correction: The 12/18/97 version of this statement could be read to say that Posicor should not be taken with any statin or with any immunosuppressant. That is inaccurate. Two of the statins, fluvastatin and pravastatin, are not significantly metabolized in the same way as the other statins. Mibefradil therefore would NOT be expected to have significant effects on fluvastatin and pravastatin blood levels or increase the risk of muscle injury. On the other hand, neither of the immunosuppressants tacrolimus and cyclosporine should be used together with Posicor and any statin. The statement concerning the 3-way combination should therefore read: The new label warns against the simultaneous use of Posicor, any statin and either of the immunosuppressants tacrolimus or cyclosporine. Also, the list of statins on page 3 should have included fluvastatin.

                     
T97-65                        Susan M. Cruzan:     301-827-6242
Dec. 19, 1997                 
                              Consumer Inquiries:  800-532-4440

WARNING LABELING CHANGES FOR NEW HEART DRUG POSICOR

FDA is advising doctors about new warnings in the labeling of the drug Posicor (mibefradil), a treatment for hypertension and chronic angina. The new warnings provide additional information about two risks associated with the drug: extremely low heart rates, and, when Posicor is taken with certain cholesterol lowering drugs, a risk of muscle injury that can be life-threatening. The following may be used to respond to questions.

The new warning regarding low heart rates advises physicians against prescribing Posicor to patients at high risk of developing dangerously low heart rates. Such patients, especially older people, include those whose heart rates are already relatively low and those taking another drug that slows heart rate.

Posicor's risk of inducing excessively slow heart rates is similar to that of several other commonly used drugs, and was described in the labeling when the drug was first approved in June l997. The new, strengthened warning was developed after FDA and the manufacturer, Roche Laboratories, of Nutley, NJ, received reports of dangerously lowered heart rates in about 20 patients who had taken Posicor. Many of the patients described in the reports had relatively low heart rates before starting Posicor, or had certain types of pre-existing heart disease that put them at high risk of such low rates. More than half of them were also taking another heart-rate-lowering drug, usually a beta-blocker. No deaths have been reported, but many patients became weak and lightheaded.

The second new warning states that Posicor should not be given to patients who are also receiving lovastatin or simvastatin. These drugs used to lower cholesterol are known as statins. In addition, pending availability of further information, coadministration of Posicor with atorvastin or cerivastatin is strongly discouraged. Two of the "statins", fluvastatin and pravastatin, are not significantly metabolized in the same way as the other drugs. Mibefradil therefore would NOT be expected to have significant effects on fluvastatin or pravastatin blood levels or to increase the risk of muscle injury.

The new label also warns against the simultaneous use of Posicor, any statin, and either of the immunosuppressants tacrolimus or cyclosporine.

This new warning was added after the agency received 7 reports of drug-associated muscle injury among patients who had taken Posicor and simvastatin.

Drug-induced muscle injury is a known rare side effect of all of the statin cholesterol-lowering drugs including atorvastatin, cervistatin, fluvastatin, lovastatin, pravastatin, and simvastatin, and it seems to increase in frequency with increasing dose. Patients with drug-induced muscle injury usually experience nonspecific muscular symptoms (weakness, tenderness, and pain), but the most important consequences of injury are not muscular. The breakdown products of muscle can cause temporary or permanent damage to kidneys; and in severe cases, the heart can also be affected. Either of these complications can lead to death.

Although Posicor does not itself cause muscle injury, administration of Posicor interferes with the body's metabolism of lovastatin and simvastatin and may interfere with the metabolism of atorvastatin and cerivastatin. The observed incidence of muscle injury with coadministration of Posicor and simvastatin appears to be much higher than the incidence seen during treatment with simvastatin alone. The immunosuppressants tacrolimus and cyclosporine interfere with the elimination of all of the statins, and Posicor increases blood levels of cyclosporine and tacrolimus, so the three-way combination of Posicor, a statin, tacrolimus, or cyclosporine should also be avoided. Health care providers should report any adverse events related to Posicor to Roche Laboratories (800-526-6367) or to FDA. Reports may be submitted to FDA by telephone 800-332-1088), by fax (800-332-0178), or by mail using a postage paid MedWatch form from the back of the Physicians Desk Reference. The Medwatch report should be mailed to:

BACKGROUND: POSICOR LABELING CHANGES

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