Indinavir (Crixivan«), Merck Protease Inhibitor, Approved

FDA approval of indinavir, Merck's protease inhibitor, was announced on March 14; the drug is expected to be available by March 25. For several months, indinavir will be made available under a temporary special distribution system, primarily through Stadtlanders Pharmacy. Merck's price to wholesalers will be $12 a day, or $4380 per year (retail prices are not known as this issue of AIDS TREATMENT NEWS goes to press). This price is significantly less than the prices of the other two protease inhibitors now approved (from Abbott Laboratories, and Hoffmann-La Roche).

Indinavir has been studied in more than 2,000 people. It was approved under the FDA's accelerated approval regulations, based on 24-week studies which showed improvements in markers of HIV disease progression -- large viral load decreases, and CD4 count improvements -- especially when indinavir was used in combination with other antiretrovirals. Long-term studies are now ongoing to test the effect of indinavir in preventing clinical progression of HIV disease.

The package insert includes extensive prescribing information, lists of possible side effects, and key clinical trial results. "Crixivan must be taken at intervals of 8 hours. For optimal absorption, Crixivan should be administered without food but with water one hour before or two hours after a meal. Alternatively, Crixivan may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g. dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar.... To insure adequate hydration, it is recommended that the patient drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours." Administration with grapefruit juice *decreased* blood levels of Crixivan in one test. The dose of Crixivan is the same whether it is used alone, or with other antiretrovirals -- but the package insert should be checked for instructions on combination use, e.g. with ddI. A number of warnings and
precautions, including int
eractions and incompatibilities with several other drugs, are also listed in the package insert.

It is important to take the full dose consistently as prescribed -- without reducing the dose, skipping doses, or taking "drug holidays." But if a dose is missed, do not double the next dose. In case of nephrolithiasis (kidney stones or related symptoms, which have occurred in about 4% of patients taking indinavir), a short drug interruption may be considered.

For information on obtaining Crixivan, and on Merck's reimbursement assistance program which is called SUPPORT(TM), patients and physicians can call 800/927-8888, beginning March 18.

Note: At this time, the impression among treatment advocates is that overall, Merck's indinavir seems to be the best choice of the three protease inhibitors now approved. Still, those who can wait to start protease inhibitors may want to wait until more is known about how to use them in the best combination regimens to minimize viral resistance (which seems to be more of a problem with the Merck and Abbott drugs than it is with saquinavir, the Roche protease inhibitor). But those who do want to start indinavir within the next six to 12 months should know that there will be a limited supply of this drug over the next several months (depending on U.S. and international demand) -- and that those who seek indinavir immediately may have the best chance to obtain it. Any supply problem should end around autumn of this year, when new manufacturing facilities are scheduled to begin production. (We do not expect any shortage of the Roche or Abbott protease inhibitors.)

Since it is medically inadvisable to start indinavir and then discontinue (as that would encourage the development of resistant viruses, reducing future usefulness of this and certain other protease inhibitors), Merck is setting up a system to track prescriptions in order to make sure that refills are available for all who start using the drug. Current plans are to accept new patients into this system on a first-come-first-served basis.

If you expect to need indinavir in the near future, check with your physician now about getting it. But if you can wait, the supply and distribution problems should be over within a year -- and the drug may be more useful then than it would be now, since physicians will know more about how best to use it.