General Information

Prezista (darunavir) is an HIV-1 protease inhibitor (PI). It is designed to disrupt formation of HIV viral particles in infected patients.

Prezista is specifically indicated for the treatment of HIV-1 infections in combination with ritonavir and other antiviral agents in treatment-experienced patients, including patients who have failed prior courses of treatment with other PIs.

Mechanism of Action

Prezista is an inhibitor of HIV-1 protease, designed to selectively inhibit the cleavage of HIV-encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Side Effects

Adverse events associated with the use of Prezista may include, but are not limited to, the following:

• Diarrhea
• Nausea
• Headache
• Nasopharyngitis
• Rash

Administration of Prezista has been associated with incidence of rare, severe, potentially life-threatening skin reactions, including erythema multiforme and Stevens-Johnson syndrome. Patients are advised to monitor their skin for signs of rash while taking Prezista, and treatment should be discontinued if severe rash develops.

In addition, certain laboratory abnormalities were associated with the use of Prezista (laboratory abnormalities are a common concern with PI administration). These included, but were not limited to, elevations of levels of triglycerides, pancreatic amylase, aspartate aminotransferase, total cholesterol, gamma glutamyl transferase, pancreatic lipase, partial thromboplastin, alanine aminotransferase and decreases in white blood cell counts. The magnitude of these abnormalities was generally lower for Prezista than for comparator PI regimens, though not for all measures. Careful monitoring of laboratory values is recommended while on Prezista therapy.

Pharmacokinetic changes have been noted when Prezista is co-administered with other medications, including changes in absorption, total exposure and elimination of one or both drugs. Some of these interactions may necessitate adjustment of dose schedule and careful monitoring of tolerability. Affected medications include but are not limited to: the NNRTI HIV medication efavirenz; the PI HIV medications lopinavir and saquinavir; the anticoagulant warfarin; certain antidepressants, including SSRIs; certain antifungal agents; certain statin cholesterol medications and the narcotic analgesic methadone. It is recommended that patients consult their physicians to discuss any potential drug interactions or dosing adjustments.

Risks of adverse reactions, some of which are potentially serious or life-threatening, have been identified when co-administering Prezista with a number of medications. These include, but are not limited to: the antihistamines astemizole and terfenadine; ergot derivatives including dihydroergotamine, ergonovine, ergotamine and methylergonovine; the gastrointestinal motility agent cisapride; the neuroleptic pimozide and the hypnotic sedatives midazolam and triazolam. The risks associated with these interactions should be thoroughly discussed with a medical professional, and use of alternative therapies should be considered, as appropriate.

Dosing/Administration

Prezista is supplied as an orange, oval-shaped, film-coated tablet for oral administration. The recommended initial dosing regimen is 600 mg twice daily, in combination with 100-mg ritonavir twice daily, with food.

Clinical Trial Results

FDA Approval
Trials TMC114-C213 and -C202
The accelerated approval of Prezista for the treatment of HIV-1 infections was based on 24-week data from a pair of ongoing, randomized phase 2b trials, dubbed TMC114-C213 and TMC114-C202, which were ongoing at the time of approval. Both trials investigated the efficacy of the drug in antiretroviral treatment-experienced HIV-1 infected adult subjects. In both studies, all subjects demonstrated at least one primary PI resistance mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at patient screening. Subjects in both studies received 600 mg Prezista plus 100 mg ritonavir twice daily, plus an optimized background regimen (OBR), including at least two nucleoside reverse transcriptase inhibitors (NRTI) with or without enfurvirtide, or a control regimen consisting of an investigator-selected PI regimen plus OBR. The 24-week data set included 318 subjects in TMC114-C213 and 319 subjects in TMC114-C202 who had completed 24 weeks of treatment or discontinued earlier. Pooled data from the two studies indicated that 69.5 percent of subjects receiving the Prezista regimen achieved virologic response, as measured by a reduction of HIV-1 RNA of at least 1log10 from baseline at week 24, compared to a 21.0 percent reduction for the control regimen. Mean change from baseline was -1.89 log10 copies/mL for Prezista vs. -0.48 log10 copies/mL for control. In addition, 63 percent of subjects achieved HIV-1 RNA levels <400 copies/mL, and 45.0 percent achieved levels < 50 copies/mL at week 24, vs. 19 percent and 12.1 percent for control, respectively. Twenty-six percent of subjects failed to sufficiently respond to treatment on the Prezista regimen, vs. 71 percent for control. Increase from baseline in mean CD4+ cell counts was greater for Prezista (92 cells/mm3) than control (17 cells/mm3).

Trials TMC114-C215 and -C208
Additional data supporting the approval of Prezista were obtained from a pair of non-randomized clinical trials, dubbed TMC114-C215 and TMC114-C208. These data included 24-week results from 246 subjects receiving the 600 mg Prezista/100 mg ritonavir twice daily regimen. These data indicated that 65 percent of subjects achieved a reduction in HIV-1 RNA of at least 1log10, 57 percent achieved levels <400 copies/mL and 40 percent achieved levels <50 copies/mL, compared to baseline; mean reduction was 1.65log10 copies/mL. Mean CD4+ counts increased by 80 cells/mm3 from baseline at week 20.

Ongoing Study Commitments

• Tibotec commits to submit the final study reports and datasets of the 96-week data for the ongoing Phase 2b studies TMC114-C202, TMC114-C213, TMC 114-C208 and TMC114-C215.
  Final study report: by December 31, 2007
• Tibotec commits to submit the final study reports and datasets of the 48-week data for the ongoing phase 3 studies TMC114-C211 and TMC114-C214.
  Final study report: by December 31, 2007
• Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric patients ages 6 to 17 years. Designed to assess the pharmacokinetics, safety, tolerability and antiviral activity of two alternative doses of a suitable pediatric formulation in combination with ritonavir, in treatment-experienced pediatric children and adolescents between 6 and 17 years of age.
  Protocol submission: completed
  Final report submission: 24-week data by June 30, 2008
• Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric patients younger than 6 years of age. Designed to evaluate dose requirements and safety in pediatric patients less than 6 years of age with HIV-1 infection after preliminary review of data from the 6- to 17-year-olds in trial TMC114-C212 with the Division of Antiviral Products (DAVP).
  Protocol submission: by December 31, 2008
  Final report submission: by June 30, 2011
• Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and rifabutin.
  Protocol submission: by July 31, 2006
  Final report submission: by June 30, 2007
• Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and buprenorphine/naloxone.
  Protocol submission: by December 31, 2006
  Final report submission: by January 31, 2008
• Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and carbamazepine.
  Protocol submission: by December 31, 2006
  Final report submission: by January 31, 2008
• Tibotec commits to complete the ongoing carcinogenicity study in mice and submit the final report.
  Protocol submission: completed
  Final report submission: by December 31, 2007
• Tibotec commits to complete the ongoing carcinogenicity study in rats and submit the final report.
  Protocol submission: completed
  Final report submission: by December 31, 2007
• Tibotec commits to conduct a cocktail study to determine the effects of steady state darunavir/rtv 600/100 mg b.i.d. on the metabolism of CYP450 probe substrates for the following enzymes: CYP2C9, CYP2C19 and CYP2D6.
  Protocol submission: by December 31, 2006
  Final report submission: by January 31, 2008
• Tibotec commits to evaluate the pharmacokinetics of darunavir/rtv in HIV-negative subjects with Child-Pugh A and Child-Pugh B liver disease to determine dosing recommendations.
  Protocol submission: by July 31, 2006
  Final report submission: by March 31, 2007
• Tibotec commits to conduct a study of darunavir in treatment-experienced female patients to elucidate any potential gender differences in efficacy and safety.
  Protocol submission: by December 31, 2006
  Final report submission: 24-week data by December 31, 2008
• Tibotec is asked to submit the results from their planned study TMC114-C127, a drug-drug interaction study between darunavir/rtv b.i.d. and methadone.
  Final report submission: not specified
• In addition to the required periodic adverse drug experience reports [21 CFR 314.80(c)(2)], Tibotec is asked to submit a separate periodic adverse drug experience report for rash.
  Final report submission: not specified
• Tibotec is asked to determine response rates based upon presence of specific cleavage site mutations at baseline and submit this analysis with the Prezista traditional approval application.
  Final report submission: not specified
• Tibotec is asked to determine the protease cleavage site mutations that occur most frequently (>10 percent) in virologic failure isolates and submit this analysis with the Prezista traditional approval application.
  Final report submission: not specified
• Tibotec is asked to determine whether the most frequently occurring protease cleavage site mutations contributed to decreases in darunavir susceptibility through site-directed mutagenesis and submit this analysis with the Prezista traditional approval application.
  Final report submission: not specified