Tybost: recent changes to labeling
On August 22, 2019, FDA approved changes to the TYBOST (cobicistat) tablet labeling to expand the patient population for TYBOST® coadministered with atazanavir to include pediatric patients with HIV-1 infection weighing at least 35 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 in combination with other antiretroviral agents in the treatment of HIV-1 infection in pediatric patients weighing at least 35 kg.
Section 2: DOSAGE AND ADMINISTRATION, subsection 2.2 Recommended Dosage in Pediatric Patients
Atazanavir:
Administer TYBOST in conjunction with atazanavir and other antiretroviral agents in the treatment of pediatric patients weighing at least 35 kg with HIV-1 infection. The recommended dosages are TYBOST 150 mg orally once daily and atazanavir 300 mg orally once daily given with food. TYBOST must be coadministered at the same time as atazanavir.
Darunavir:
TYBOST is not recommended in combination with darunavir in pediatric patients.
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 atazanavir (N=14) 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 atazanavir and two nucleoside reverse transcriptase inhibitors for the treatment of HIV-1 infection have been established in virologically suppressed pediatric patients weighing at least 35 kg.
Use of TYBOST 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 (Trial 128) in virologically suppressed, HIV-1 infected pediatric subjects aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naïve adults.
Safety and effectiveness of TYBOST in combination with atazanavir in pediatric patients weighing less than 35 kg have not been established. Safety and effectiveness of TYBOST in combination with darunavir in pediatric patients 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 atazanavir 300 mg (N=12), geometric mean atazanavir Cmax and AUCtau and cobicistat AUCtau values were approximately 20-30% higher than in adults and geometric mean atazanavir and cobicistat Ctau values were approximately 60% to 160% higher than in adults; the increases were not considered clinically significant. Please refer to product labeling for more details.
Subsection 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 plus two NRTIs in Trial 128, 3 of 14 subjects qualified for resistance analysis through Week 48; 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 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 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) 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-1="" ml.="" ml="" of="" plasma="" rna="" subject="">
In subjects who switched to TYBOST coadministered with atazanavir, 93% (13/14) of subjects remained suppressed (HIV-1 RNA <50 -0.3="" -500="" -60="" -6="" 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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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
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