Ritonavir (NORVIR(TM)), Abbott Protease Inhibitor, Approved

With record speed, ritonavir (Norvir(TM)), Abbott Laboratories' protease inhibitor, was approved by the FDA on March 1, 1996 (one day after approval was recommended by the FDA's Antiviral Drugs Advisory Committee) -- and was for sale in some pharmacies within a week. For more information on the debates at the advisory meeting which recommended this approval, see "Protease Inhibitors at FDA Advisory Hearings," below.

Ritonavir is the only protease inhibitor which already has proven survival benefit (the others might work just as well, since they have comparable effects on viral load and CD4 counts, but they have not completed their clinical-endpoint trials yet, so no data on survival are available). But ritonavir has also raised more safety concerns than the others. It has strong interactions with many drugs used by persons with HIV; it should not be used concurrently with at least 22 of them, and requires dose reduction and/or monitoring with some others. Patients taking other medications must consult with their physicians before starting ritonavir. Abbott has prepared physician and patient instructions regarding potential drug interactions.

Other concerns are that ritonavir has little safety data beyond six months at this time. It strongly inhibits a specific liver enzyme, which presumably is in the body for a reason; blocking this enzyme for extended periods might cause problems. And we have heard more anecdotal reports of side effects with ritonavir than with the other protease inhibitors.

There is also the problem of resistance and cross resistance (especially cross resistance to Merck's Crixivan); this may be minimized by optimal use of the drug -- by combining it with two or more other antivirals, and by not missing doses or taking "drug holidays."

It is likely that many people who could afford to wait a few months or more before starting protease inhibitors may choose to do so. By that time, the Merck drug will also be available; and physicians will know more about which drugs to choose and how to make best use of them. Combinations may work best when a patient starts all the drugs in that combination at about the same time, without extensive prior use of any of them.

For those considering starting ritonavir now, we note some information from the package insert (the FDA-approved prescribing information for physicians). This document will be published in the PHYSICIAN'S DESK REFERENCE; meanwhile, patients may be able to get a copy from their pharmacist or physician.

Administration

Ritonavir is sold in two forms, capsules and oral solution. It should be taken with meals if possible.

"The recommended dosage of ritonavir is 600 mg twice daily by mouth. Some patients experience nausea upon initiation of 600 mg b.i.d. dosing; dose escalation may provide some relief: 300 mg b.i.d. for 1 day, 400 mg b.i.d. for 2 days, 500 mg b.i.d. for 1 day, and then 600 mg b.i.d. thereafter. In addition, patients initiating combination regimens with NORVIR and nucleosides may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding nucleosides before completing two weeks of NORVIR monotherapy."

"Patients should be informed to take ritonavir every day as prescribed. Patients should not alter the dose or discontinue ritonavir without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patients should not double the next dose."

There is no children's dose, as there have been no studies of safety or effectiveness in children.

Drug Interactions

The package insert begins with a warning box: "Co-administration of NORVIR with certain nonsedating antihistamines, sedative hypnotics, or anti-arrhythmics may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. See Contraindications and Precautions sections." Later text includes cautions and warnings about other kinds of drugs as well.

The warnings about drug interactions are too extensive to reproduce here. Patients and physicians should note that they appear in different sections of the package insert, including Special Populations -- drug-drug interactions; Contraindications; and Precautions -- drug interactions.

Tobacco use has been found to decrease ritonavir blood levels by 18 percent.

Adverse Events

After about three months of use of the drug in clinical trials, "the most frequently reported clinical adverse events, other than asthenia [lack of strength, fatigue], among patients receiving NORVIR were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia [loss of appetite], abdominal pain, taste perversion, and circumoral and peripheral paresthesias [abnormal sensation]." Tables showing percentages of patients with dozens of other clinical and laboratory abnormalities which might be drug related are included in the package insert.

Because ritonavir can cause changes in some laboratory tests, certain testing should be done to establish a baseline before the drug is started. The testing should be repeated periodically during therapy, or if symptoms occur, to monitor for possible problems.

"Ritonavir pharmacokinetics have not been studied in patients with hepatic insufficiency." However, some patients with hepatitis have been included in the clinical trials of the drug.

Cost and Reimbursement

Ritonavir is the most expensive antiretroviral; Abbott's charge to wholesalers is $6500 per year. We could not get the "average wholesale price" (the price which wholesalers charge pharmacies) by press time. We found some confusion about retail prices; patients should check several pharmacies, including mail-order or other large pharmacies serving many persons with HIV, before making major purchasing decisions.

"NORVIR is indicated in combination with nucleoside analogues or as monotherapy for the treatment of HIV infection when therapy is warranted." This official language from the package insert should help in getting reimbursement from insurance companies which use FDA approval as the basis for their reimbursement decisions, as there are no CD4 or other stated limits for use of ritonavir. But many managed-care systems use their own formularies which do not include all FDA-approved drugs, so the FDA's approval language may matter less with them.

Because interrupting therapy can make one more likely to develop virus resistant to this and some other protease inhibitors, persons should avoid starting either ritonavir or indinavir unless they expect to be able to continue without interruptions.

For assistance in getting reimbursement for ritonavir, call 800/659-9050.