Norvir (ritonavir)

General Information

Norvir (ritonavir) is an antiretroviral drug. 

Norvir tablets and oral solution are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

Norvir oral powder is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients.

Dosing/Administration:

Adults

• Norvir must be used in combination with other antiretroviral agents.
• Norvir tablets should be swallowed whole, and not chewed, broken or crushed. Take Norvir with meals.
• The recommended dose of Norvir in adults is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Norvir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration. 

Pediatrics

• Norvir must be used in combination with other antiretroviral agents. The recommended dosage of Norvir in pediatric patients older than 1 month is 350 to 400 mg per m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Norvir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered.
• Oral Solution: Norvir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained. Norvir oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v). Special attention should be given to accurate calculation of the dose of Norvir, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. Dosing is based on body surface area. See drug prescription label for guidelines.
• Oral Powder: Norvir oral powder should be used only for dosing increments of 100 mg. Norvir powder should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. Norvir oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals.

Mechanism of Action

Norvir (ritonavir) is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the Gag-Pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

Side Effects

Adverse effects associated with the use of Norvir alone or in combination with other antiretroviral drugs may include, but are not limited to, the following:

• gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)
• neurological disturbances (including paresthesia and oral paresthesia)
• rash
• fatigue/asthenia

The Norvir drug label comes with the following Black Box Warning: Co-administration of Norvir with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of Norvir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing Norvir or when prescribing other medications to patients already taking Norvir.

Clinical Trial Results

A randomized, double-blind, placebo-controlled study involving 1,090 subjects with advanced AIDS and previous antiretroviral therapy was conducted at 67 investigational sites in the United States., Canada, Europe, and Australia. Norvir or placebo was added to baseline therapy, if any. A six-month analysis of this population showed that the cumulative mortality rate among Norvir subjects was 5.8%--approximately half of the 10.1% rate among subjects receiving placebo. This six-month study depicts the first survival benefit demonstrated by a protease inhibitor. The clinical benefit of Norvir treatment for periods longer than six months is unknown.

In a subset of 211 subjects, statistically significant increases in the average CD4 count from baseline were observed with Norvir over the first 16 weeks of the study. The CD4 count was not significantly changed in the placebo group. In a subset of 159 subjects, Norvir produced statistically significant decreases in average HIV RNA levels compared to placebo. Measurement of viral RNA is an indicator of the amount of HIV in a subject's blood. The clinical significance of HIV RNA is unknown.

A second trial evaluated Norvir alone, AZT alone, and the two agents in combination in 356 subjects randomized to one of the three treatment groups. These subjects had not been treated with antiretroviral drugs. Norvir and the combination group produced statistically significant decreases in mean average viral RNA levels compared with AZT. Furthermore, statistically significant mean average increases in CD4 count were observed at 16 weeks with both arms compared to AZT.

Additionally, in an open-label, triple combination trial involving 32 subjects, combination therapy involving Norvir and the nucleoside analogues AZT and ddC nearly doubled the median CD4 cell count from baseline. The triple therapy also caused reductions in the number of HIV RNA particles in the blood by week 20.