General Information

Norvir has been recommended as a treatment for HIV infection when used in combination with nucleoside analogues. A protease inhibitor, Norvir was recommended in combination with nucleoside analogues or as a monotherapy in subjects where therapy is warranted.

In March of 1997, Norvir was approved for the treatment of children with HIV and AIDS. The recommended dosage of Norvir in children, in combination with nucleoside analogues, is 400 mg/m2, twice daily, and should not exceed 600 mg, twice daily. The starting dose is 250 mg/m2 twice daily, which should be titrated to 400 mg/m2. The evaluation of the antiviral effect of Norvir in children is ongoing.

Clinical Results

In clearing Norvir for the treatment of HIV infection, the FDA reviewed efficacy and safety data from trials that showed the agent to have substantial antiviral activity and to reduce the risk of disease progression and mortality. This marks the fastest drug approval in the history of the FDA--72 days from the date of the filing of the new drug application.

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, ongoing trial is testing 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.

The dosing recommendation for Norvir in children (age 2-16) is based primarily on pharmacokinetic and safety data from an ongoing Phase I/II study being conducted by a team of scientists at the HIV and AIDS Malignancy Branch of the National Cancer Institute, in collaboration with Abbott Laboratories.

Currently, researchers have enrolled 51 HIV-infected children with either no prior therapy, progressive disease, or toxicity to another antiretroviral regimen. The use of Norvir was evaluated in the 44 children who had completed at least four weeks of treatment as of Sept. 30, 1996. Norvir was given alone for the first 12 weeks, then in combination with zidovudine and /or didanosine.

Side Effects

The most common adverse effects were nausea (23% to 26%), diarrhea (13% to 18%), vomiting (13% to 15%), muscular weakness (9% to 14%), taste disturbance (5% to 10%), anorexia (1% to 6%), abnormal functioning of tissue (3% to 6%), and abdominal pain (3% to 7%).

In HIV-infected subjects age two to 16 years, the adverse event profile was similar to that seen during clinical trials and post-marketing experience in adults. The most common adverse events in adults include nausea, diarrhea, vomiting, asthenia and taste disturbance. Safety of Norvir in children below age two has not been established. Norvir should not be used in combination with highly metabolized medications known to cause serious or life-threatening adverse events.

Mechanism of Action

Protease inhibitors are a new class of drug with a mechanism of action that is different from most of the previously available antiretroviral treatments for AIDS. Protease inhibitors, such as Norvir, block the action of protease, an enzyme involved in the final development of the virus. By blocking protease activity, protease inhibitors prevent production of infectious viral particles.