This is the retyped text of a letter from Abbott Laboratories. Contact the company for a copy of any referenced enclosures.

November, 1996

Dear Health Care Provider:

I am writing you with important new safety and prescribing information about Norvir® (ritonavir), Abbott's HIV protease inhibitor. The Norvir Product Information has been updated to reflect new information about drug interactions and adverse events based on postmarketing experience. New information on the interaction of Norvir in combination with Invirase® (saquinavir, Roche) has also been added. And finally, a review of the importance of dose titration upon the initiation of Norvir therapy is included.

NEW DRUG INTERACTIONS

• Ergot alkaloid preparations have been added as contraindications. Based on postmarketing experience, coadministration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities. Some of the patients received treatment with intravenous vasodilators.

• Pimozide (Orap®. Gate Pharmaceuticals) has also been added as a contraindication, based on a predicted interaction between Norvir and pimozide.

• Cardiac and neurologic events have been reported in postmarketing experience when ritonavir has been coadministered with disopyramide, mexiletine, nefazadone, or fluoxetine. The possibility of drug interaction in these cases cannot be excluded. The list of medications whose plasma levels may be potentially affected when used with Norvir (Table 3) has been updated.

• Two phase I interaction studies evaluated the single-dose and multiple-dose pharmacokinetic interactions between ritonavir and saquinavir in healthy non-HIV infected volunteers. Results were consistent with the fact that ritonavir is a potent CYP 3A4 inhibitor. Saquinavir plasma concentrations were increased significantly (greater than 20-fold increase in concentrations) when coadministration with ritonavir. The pharmacokinetics of ritonavir were not significantly affected with coadministered of saquinavir. This information has been added to the Drug Interaction section.

POSTMARKETING ADVERSE EVENTS

• TheWARNINGS section of the product information for Norvir has been revised to include the following information:

  To alert health care providers about the potential for hypersensitivity reactions with Norvir therapy. This section states that allergic reactions including urticaria, mild skin eruptions, bronchospasm, angioedema, and rarely, anaphylaxis and Stevens-Johnson syndrome have been reported.

  Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving Norvir alone or in combination with other antiretroviral drugs (see Table 5). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering Norvir to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

  There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS. A definitive causal relationship has not been established.

• The PRECAUTIONS section has been updated to include the following statement:

  As with other HIV protease inhibitors, there have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B receiving ritonavir. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.

• The ADVERSE REACTIONS section has been revised as follows:

  There have been postmarketing reports of seizure. Hyperglycemia has been reported in individuals with and without a known history of diabetes. Cause and effect relationship has not been established. Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

• The OVERDOSE section has been updated. Renal failure with eosinophilia has been reported with ritonavir overdose.

  DOSE TITRATION

  Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased by 100 mg twice daily increments up to 600 mg twice daily. Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued.

  There have been reports of difficulty distinguishing between the names ritonavir and Retrovir (zidovudine, Glaxo Wellcome Inc.) on prescriptions, resulting in patients receiving the wrong medication. It is recommended that physicians use the trademark name, Norvir, when prescribing ritonavir.

  Norvir is indicated in combination with nucleoside analogues or as monotherapy for the treatment of HIV-infection when therapy is warranted. For patients with advanced HIV disease, this indication is based on the results from a study that showed a reduction in both mortality and AIDS-defining clinical events for patients who received Norvir. Median duration of follow-up in this study was 6 months. The clinical benefit from Norvir therapy for longer periods of treatment is unknown. For patients with less advanced disease, this indicatin is based on changes in surrogate markers in studies evaluating patients who received Norvir alone or in combination with other antiretroviral agents.

  The most common adverse events seen in the clinical studies included nausea, vomiting, diarrhea, weakness, and taste perversion. Many other adverse evnets, some potentially serious, have been noted with the use of ritonavir. See the Norvir Product Information for a more complete list.

  Enclosed is a copy of the Norvir Product Information, and updated Health Care Professional Drug Interaction and Patient Dosing Interaction Cards. If you would like further medical information please contact Medical Services at 1-800-633-9110. If you would like additional copies of the Patient Dosing Interaction Card, ask your Abbott HIV Specialist or Medical Center Representative, or call 1-800-441-4987.

  Sincerely,

  David Pizzuti, M.D.
  Divisional Vice President
  Medical Affairs and Pharmaceutical Ventures

  Enclosures:
  Norvir® (ritonavir) Product Information, Abbott Laboratories
  Health Care Professional Drug Interaction Card
  Patient Drug Interaction Pocket Card

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  Abbott Laboratories
  Pharmaceutical Products Division
  200 Abbott Park Road
  Abbott Park, IL 60064-3537

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