FDA approved changes to the product labeling for PREZCOBIX (darunavir/cobicistat) for use in pediatric patients weighing at least 40 kg and changes to the product labeling for EVOTAZ (atazanavir/cobicistat) for pediatric subjects weighing at least 35 kg. A summary of the changes are as follows:
DOSAGE AND ADMINISTRATION
PREZCOBIX
In treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily orally with food.
EVOTAZ
In treatment-naïve and treatment-experienced pediatric patients weighing at least 35 kg the recommend dosage of EVTOAZ is one tablet taken once daily orally with food.
ADVERSE REACTIONS
PREZCOBIX
Clinical Trials in Pediatric Patients
No clinical trials with PREZCOBIX were performed in pediatric patients. However, the safety of the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside reverse transcriptase inhibitors was evaluated in pediatric subjects of 12 to less than 18 years of age with HIV-1 infection through clinical trial GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) through Week 48. Safety analyses of this trial in these pediatric subjects did not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult subjects.
EVOTAZ
Adverse Reactions from Clinical Trial Experience in Pediatric Subjects
Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed subjects with HIV-1 infection between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128). Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.
USE IN SPECIFIC POPULATIONS
PREZCOBIX
The safety and effectiveness of PREZCOBIX for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through a trial with components of PREZCOBIX. Use of PREZCOBIX in this group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and virologic data from a study of components of PREZCOBIX (Trial GS US-216-0128) in pediatric subjects with HIV 1 infection aged 12 to less than 18 years.
The safety and effectiveness of PREZCOBIX have not been established in pediatric patients weighing less than 40 kg. Darunavir, a component of PREZCOBIX is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.
EVOTAZ
The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults.
Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.
CLINICAL PHARMACOLOGY
PREZCOBIX
Pediatric Patients Weighing at Least 40 kg
Available pharmacokinetic data for the different components of PREZCOBIX indicate that there were no clinically relevant differences in exposure between adults and pediatric subjects weighing at least 40 kg.
Darunavir and cobicistat: In pediatric subjects aged 12 to less than 18 years, weighing at least 40 kg who received darunavir 800 mg co administered with cobicistat 150 mg (N=7), geometric mean darunavir Cmax values were similar between adults and pediatric subjects. Geometric mean darunavir AUC24h and C24h values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in pediatric subjects relative to adults, respectively. These differences were not considered clinically significant. Geometric mean cobicistat AUC24h, Cmax, and C24h values were comparable in pediatric subjects and adults.
EVOTAZ
In pediatric subjects aged 12 to less than 18 years who received atazanavir 300 mg coadministered with cobicistat 150 mg (N=12), atazanavir exposures (AUCtau, Cmax, and Ctau) were 20 60% higher than in adults; the increases were not considered clinically significant.
CLINICAL STUDIES
PREZCOBIX
Clinical Trial Results in Pediatric Subjects with HIV-1 Infection
Trial GS‑US‑216‑0128 was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of darunavir co‑administered with cobicistat in adolescents aged 12 years and older with HIV-1 infection who were virolgically suppressed and had a baseline estimated creatinine clearance ≥90 mL/min/1.73 m². Subjects were on a stable antiretroviral regimen (for at least 3 months), consisting of darunavir administered with ritonavir, combined with 2 NRTIs. These subjects (N=7) were switched from ritonavir to cobicistat 150 mg once daily and continued darunavir and 2 NRTIs.
The median age of subjects was 14 years (range 12-16 years), median weight was 60 kg (range 45-78 kg), and 43% were male. At baseline, all subjects had plasma HIV-1 RNA <50 -12="" -342="" -6="" 1="" 219="" 28="" 2="" 45="" 48.="" 48="" 56="" 5="" 658="" 6="" 800="" 86="" a="" above="" all="" and="" at="" available="" baseline="" cd4="" cell="" cells="" change="" copies="" count="" counts="" data.="" data="" div="" from="" had="" in="" median="" missing="" ml.="" ml="" mm3="" mm="" nbsp="" of="" range="" remained="" respectively.="" respectively="" rna="" subject="" subjects="" suppressed="" the="" to="" was="" week="" with="">
EVOTAZ
Clinical Trial Results in Virologically Suppressed Pediatric Subjects with HIV-1 Infection – Study GS-US-216-0128
Study GS-US-216-0128 (NCT02016924) was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of atazanavir coadministered with cobicistat in pediatric subjects ages 12 years and older with HIV-1 infection who were virologically suppressed and had a baseline estimated creatinine clearance ≥90 mL/min/1.73 m2. Subjects were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to cobicistat 150 mg once daily and continued atazanavir (N=14) and 2 NRTIs.
The mean age of subjects was 14 years (range 12–17 years); median weight was 53 kg; 71% were male, 57% were Asian, 29% were White, 14% were Black, and 71% were not Hispanic or Latino. At baseline, 13/14 subjects had plasma HIV-1 RNA <50 1="" 50="" and="" copies="" div="" had="" hiv="" ml.="" ml="" of="" plasma="" rna="" subject="">
In subjects who switched to atazanavir coadministered with cobicistat, 93% (13/14) of subjects remained suppressed (HIV-1 RNA <50 1765="" 1="" 23="" 33="" 45="" 48.="" 486="" 48="" 705="" 770="" 8="" a="" and="" at="" baseline="" cd4="" cell="" cells="" change="" copies="" count="" div="" experienced="" failure="" from="" in="" median="" ml="" mm3="" of="" range="" respectively.="" respectively="" subject="" the="" to="" virologic="" was="" week="">
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