July 17, 1996

Dear Healthcare Provider:

Subject: HIV Protease Inhibitors and Patients with Hemophilia

FDA has recently learned of approximately 15 case reports of spontaneous bleeding episodes in HIV positive patients with hemophilia who were being treated with HIV protease inhibitors at the time of the event. Of the cases of spontaneous bleeding preliminarily associated with these drugs, 11 have involved hematomas and 5 hemarthroses (one patient reporting both). None involved serious injury or death. The majority of patients have been able to continue taking their protease inhibitor therapy in spite of the bleeding event.

To date, there is no conclusive evidence to establish that the protease inhibitors are the cause of these spontaneous bleeding episodes. However, as these products were all approved under FDA's accelerated approval mechanisms for treatments for life-threatening illness, FDA believes it is important to investigate any question about safety that arises early in the marketing experience.

There are three HIV protease inhibitors currently approved for marketing in the Unites States for the treatment of HIV infection: saquinavir (Invirase) from Hoffman-La Roche, ritonavir (Norvir) from Abbott Laboratories, and indinavir (Crixivan) from Merck Research Laboratories. To date, all cases reported have involved European patients. There have been no reported cases in this country.

At this time, it is unknown whether there is a causal relationship between the use of protease inhibitors and bleeding episodes in patients with hemophilia. All of these reports involved patients with hemophilia and advanced HIV infection who were receiving multiple drug treatments. Clinical studies using these drugs have not reported an increased incidence of either bleeding or coagulation abnormalities in patients with or without hemophilia.

However, in light of these reports, the FDA and the drug manufacturers recommend that health care providers monitor hemophiliac patients for spontaneous bleeding episodes whenever any of the protease inhibitors is used as part of treatment for HIV. Patients with hemophilia and HIV infection who are currently using protease inhibitor therapy should not discontinue using their treatment, but should instead consult with their health care providers if they have any concerns. Health care providers and patients should not hesitate to initiate therapy with these drugs.

Questions about specific drugs should be referred to the manufacturer of that drug. Health care professionals are encouraged to report unexpected spontaneous bleeding events directly to the FDA MEDWATCH program: 1-800 FDA-1088/FAX 1-800-FDA-0178; or to the respective pharmaceutical manufacturers:

Invirase (saquinavir), Hoffman-La Roche, 1-800-526-6367;
Norvir (ritonavir), Abbott Laboratories, 1-800-633-9110;
Crixivan (indinavir), Merck Research Laboratories, 1-800-672-6372

Sincerely,

David W. Fiegal, Jr., M.D., M.P.H.
Office of Antimicrobial Drug Evaluation -- ODE-4
Food and Drug Administration
Rockville, MD 20857

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