INDINAVIR (Crixivan).

Indinavir 400 mg capsules are semitranslucent white capsules coded "CRIXIVAN[TM] 400 mg" in green. Other dose formulations of indinavir are available. Dosing may vary.

"Merck & Co. is the second major drug company to announce an expanded access program for the drug indinavir sulfate, a member of the family of protease inhibitor drugs. Through a free lottery, Merck plans to distribute this drug known as Crixivan to 1,400 AIDS patients in the United States."

Washington Post, A7, July 17, 1995

"The lottery, an impersonal mechanism based on chance alone, may be used to distribute benefits and burdens in a social organization. It takes no account of an individual's birth, education, training, achievements, social connections, and the like. It is a random selection system that also takes no account of merit, experience, effort, contributions, or need. Such a system is thought to be unfair by most societies because there have been valid principles of justice worked out for allocating social burdens and benefits."

Journal of the International Association of Physicians in AIDS Care, 3:11, 1997

Also known as: indinavir sulfate, IDV, MK639, L-735,524

Background and description. Indinavir is a protease inhibitor manufactured by Merck & Co., Inc. It was granted accelerated approval for use in combination with nucleoside reverse transcriptase inhibitors (NRTIs) by the US Food & Drug Administration (FDA) in March 1996.

Guidelines classification. The Panel on Clinical Practices for the Treatment of HIV Infection classifies indinavir as a "strongly recommended" protease inhibitor.

Dose. The recommended dose of indinavir is 800 mg (two 400 mg capsules) every 8 hours.

Food restrictions. Indinavir must be taken without food, but with water, 1 hour before or 2 hours after a meal. It may also be administered with other liquids such as skim milk, juice, coffee or tea or with a light meal, such as dry toast with jelly, juice and coffee with skim milk and sugar; or corn flakes, skim milk and sugar. Patients taking indinavir should drink approximately 48 ounces of liquids every 24 hours.

Storage. Indinavir should be stored in a tightly closed container at room temperature (59 [degrees] to 86 [degrees] F)

Side effects and toxicity. The major side effect of indinavir is the formation of kidney stones (nephrolithiasis), pain on urination (dysuria) and back and flank pain. Proper hydration may prevent the symptoms. Additionally, sustained creatinine elevations have been reported with long-term use of indinavir. Metabolic (lipid and glucose) and morphologic (fat accumulation and fat atrophy) abnormalities have been associated with protease inhibitors in general.

Drug interactions. Indinavir should not be taken with the following: cisapride (Propulsid), triazolam (Halcion), midazolam (Versed), ergot derivatives (Wigraine and Cafergot) and the lipid-lowering drugs simvastatin (Zocor) and lovastatin (Mevacor). Lipid-lowering drugs such as atorvastatin (Lipitor), pravastatin (Pravachol) or fluvastatin (Lescol) should be used with caution. Ketaconazole (Nizoral) inhibits the metabolism of indinavir and a dose reduction of indinavir to 600 mg every 8 hours is recommended when combining the 2 drugs. Similarly the dose of rifabutin (Mycobutin) should be reduced by 50% when used with indinavir. Indinavir increases the levels of sildenafil (Viagra) and dose reductions to 25 mg within a 48-hour period are recommended.

Consideration should be given to increasing the indinavir dose to 1000 mg every 8 hours when combined with efavirenz (Sustiva) or nevirapine (Viramune). Delavirdine (Rescriptor) increases the levels of indinavir; some studies have used 600 mg of indinavir with 400 mg of delavirdine 3 times a day to compensate for this increase. In addition, the buffering agent in didanosine (Videx) interferes with the absorption of indinavir and thus the drugs should be taken at least 1 hour apart. Finally, combining indinavir with nelfinavir (Viracept) results in an increase in indinavir levels. Studies have used 1250 mg of nelfinavir with 1200 mg of indinavir twice a day with a low-fat snack.

Resistance and cross-resistance. Mutations at positions 82 and 90 are most associated with treatment failure. Other mutations can occur at positions 20, 24, 48, 54 and 84. Resistance to indinavir can lead to cross-resistance to other protease inhibitors.

Clinical data. The approval of indinavir was based on 3 studies. The Merck 035 study showed durable longterm efficacy of the combination indinavir/zidovudine (Retrovir)/lamivudine (Epivir) for the management of HIV. Up to 2 years after beginning triple-combination therapy, 78% of subjects had viral loads below 500 copies/mL, while 66% of subjects had viral loads below 50 copies/mL.

ACTG 320 compared indinavir/zidovudine/lamivudine versus zidovudine/lamivudine. The study enrolled 1156 patients. It was terminated after an interim analysis, resulting in a median follow-up of 38 weeks. The percentages of patients with AIDS-defining illnesses or death were as follows: 35% progressed to an illness and 10% died in the indinavir/zidovudine/lamivudine arm; and 63% progressed to an illness and 19% died in the zidovudine/lamivudine arm.

Study 028 was conducted in Brazil and enrolled 996 antiretroviral naive patients who were randomized to 1 of 3 arms: indinavir/zidovudine, indinavir alone, or zidovudine alone. Treatment regimens containing zidovudine were modified in blinded manner with the optional addition of lamivudine. The study was terminated after an interim analysis, resulting in a median follow-up of 56 weeks. The percentages of patients with AIDS-defining illnesses or death were as follows: 21% progressed to an illness and 8% died in the indinavir/zidovudine arm; 27% progressed to an illness and 5% died in the indinavir-alone arm; 62% progressed to an illness and 11% died in the zidovudinealone arm.

Patient assistance. Merck offers a patient assistance program for those who qualify. For more information call 800.850.3430.