Tybost + darunavir: Pediatric label updates

FDA approved changes to the TYBOST (cobicistat) tablet labeling to expand the patient population for TYBOST® coadministered with darunaivr to include pediatric patients with HIV-1 infection weighing at least 40 kg. This change is supported by safety and efficacy data in virologically suppressed pediatric patients with HIV-1 from Clinical Trial GS-US-216-0128 (Trial 128). The label was updated as follows: Section 1: INDICATIONS AND USAGE TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients: weighing at least 35 kg coadministered with atazanavir or weighing at least 40 kg coadministered with darunavir. Section 2: DOSAGE AND ADMINISTRATION, subsection 2.2 Recommended Dosage in Pediatric Patients Administer TYBOST in conjunction with darunavir and other antiretroviral agents in the treatment of pediatric patients weighing at least 40 kg with HIV-1 infection. The recommended dosages are TYBOST  150 mg orally once daily and darunavir 800 mg orally once daily given with food. TYBOST must be coadministered at the same time as atazanavir or darunavir. Section 6: ADVERSE REACTIONS Adverse Reactions from Clinical Trials Experience in Pediatric Subjects The safety of TYBOST was evaluated in HIV-1 infected virologically suppressed pediatric subjects between the ages of 12 to less than 18 years through Week 48 in an open-label clinical trial (Trial 128) of TYBOST coadministered with darunavir (N=7 plus two nucleoside reverse transcriptase inhibitors. In this trial, the safety profile of TYBOST was similar to that in adults. Section 8 USE IN SPECIFIC POPULATIONS, subsection: 8.4 Pediatric Use The safety and effectiveness of TYBOST coadministered with darunavir and two nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection have been established in virologically suppressed pediatric patients weighing at least 40 kg. Safety and effectiveness of TYBOST in combination with darunavir in pediatric patients weighing less than 40 kg have not been established. Section 12 CLINICAL PHARMACOLOGY subsection 12.3 Pharmacokinetics Pediatric Patients In pediatric subjects aged 12 to less than 18 years who received TYBOST 150 mg coadministered with darunavir 800 mg (N=7), geometric mean darunavir Cmax and AUCtau values were similar between adults and adolescents. Geometric mean darunavir AUCtau and Ctau 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 adolescent subjects relative to adults, respectively. This difference was not considered clinically significant based on exposure-response relationships. Geometric mean cobicistat AUCtau, Cmax, and Ctau values were comparable in adolescents and adults. Please refer to product labeling for more details. Section 12.4 Microbiology In an as-treated analysis of pediatric subjects between the ages of 12 to less than 18 years who received TYBOST coadministered with atazanavir or darunavir plus two NRTIs in Trial 128, 3 of 20 subjects qualified for resistance analysis through Week 48; all 3 subjects were receiving TYBOST coadministered with atazanavir and 1 had evaluable data and no significant resistance-associated substitutions in protease or reverse transcriptase. Section 14 Clinical Studies 14.2       Clinical Trial Results in HIV-1 Infected Virologically Suppressed Pediatric Subjects – Trial 128 Trial 128 was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of TYBOST coadministered with atazanavir or darunavir in HIV-1 infected virologically suppressed pediatric subjects ages 12 years and older with 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 or darunavir, both administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to TYBOST 150 mg once daily and continued atazanavir (N=14) or darunavir once daily (N=7) and 2 NRTIs. The mean age of subjects was 14 years (range 12–17 years); median weight was 55 kg; 62% were male, 38% were Asian, 33% were White, 19% were Black, and 67% were not Hispanic or Latino. At baseline, 20/21 subjects had plasma HIV-1 RNA <50 1="" 50="" and="" copies="" div="" had="" hiv-1="" ml.="" ml="" of="" plasma="" rna="" subject=""> In subjects who switched to TYBOST coadministered with darunavir, 86% (6/7) of subjects remained suppressed (HIV-1 RNA <50 -12="" -1389="" 1117="" 1="" 219="" 2416="" 28="" 45="" 48.="" 48="" 56="" 5="" 658="" 6="" 800="" a="" above="" all="" and="" at="" available="" baseline="" cd4="" cell="" cells="" change="" copies="" count="" counts="" data="" div="" from="" had="" in="" median="" missing="" ml="" mm3="" of="" range="" respectively.="" respectively="" subject="" subjects="" the="" to="" was="" week="" with="">

The updated label will soon be available at Drugs@FDA or DailyMed Kimberly Struble Division of Antiviral Products Food and Drug Administration Elizabeth Thompson Division of Antiviral Products Food and Drug Administration Michael Stanfield Jr. Division of Antiviral Products Food and Drug Administration