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On December 13, 2010, FDA approved new labeling for Prezista (darunavir) to include a once daily dosing for treatment-experienced adult patients with no darunavir resistance associated substitutions. The major revisions to the package insert are summarized below. Other minor changes to the package insert and patient package insert were made for consistency.
Summary of Revisions:
A DOSAGE AND ADMINISTRATION Section 2.1 Treatment-Experienced Adult patient was revised as follows:
The recommended oral dose for treatment-experienced adult patients with no darunavir resistance associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) is 800 mg Prezista once daily with ritonavir 100 mg once daily and with food.
The recommended oral dose for treatment-experienced adult patients with at least one darunavir resistance associated substitution (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) is 600 mg Prezista twice daily taken with ritonavir 100 mg twice daily and with food.
For antiretroviral treatment experienced patients genotypic testing is recommended. However, when genotypic testing is not feasible, Prezista/ritonavir 600/100 mg twice daily dosing is recommended
The following statement was added to section 6: ADVERSE REACTIONS
The overall safety profile of PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily is based on clinical trials and post-marketing data, and is consistent with the data presented below.
Section 12.3 Pharmacokinetics Table 8 was updated to include the population pharmacokinetic estimates of darunavir from Trial TMC114-C229 Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily.
Overall, darunavir exposures following darunavir/ritonavir 800/100 mg once daily in treatment experienced subjects were consistent with those previously assessed in treatment-naïve subjects
Section 12.4 Microbiology was updated to include the results from Trial TMC114-C229 as follows:
In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving PREZISTA/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on PREZISTA/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on PREZISTA/ritonavir 600/100 mg twice dailyIsolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the PREZISTA/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the PREZISTA/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.
Section 14 CLINICAL STUDIES subsection 14.3 Treatment-Experiened Adult Subjects was updated to include the results from Trial TMC114-C229 as follows:
Study TMC114-C229
Study TMC114-C229 is a randomized, open label trial comparing PREZISTA/ritonavir 800/100 mg once daily to PREZISTA/ritonavir 600/100 mg twice daily in treatment experienced HIV 1 infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of > 1,000 HIV 1 RNA copies/ml. Both arms used an optimized background regimen consisting of 2
NRTIs selected by the investigator.
HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.
Table 16 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No imbalances between the 2 arms were noted.
Virologic success (defined as HIV-1 RNA < 50 copies/mL) at Week 48 was 69% for both Prezista/ritonavir 800/100 mg once daily and Prezista/ritonavir 600/100 mg twice daily.
The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the PREZISTA/ritonavir 800/100 mg once daily arm and the PREZISTA/ritonavir 600/100 mg twice daily arm, respectively).
The revised labeling will be posted soon at Drugs@FDA.
PREZISTA is a product of Tibotec Pharmaceuticals.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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