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The COMPLERA (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) label was recently updated to expand the patient population for use to include pediatric patients from 12 to less than 18 years of age. Other revisions were made for consistency with the Edurant (rilpivirine) label and the major changes are summarized below.
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Information about FDA HIV product approvals, safety warnings, medical product labeling changes, notices of upcoming public meetings, and notices about proposed regulatory guidances.
The COMPLERA (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) label was recently updated to expand the patient population for use to include pediatric patients from 12 to less than 18 years of age. Other revisions were made for consistency with the Edurant (rilpivirine) label and the major changes are summarized below.
The recommended dose of COMPLERA in patients 12 years of age and older and weighing at least 35 kg is one tablet taken orally once daily with food.
WARNINGS AND PRECAUTIONS section 5.6 Depressive Disorders was updated to include the following:
During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving rilpivirine through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
Section 6 ADVERSE REACTIONS subsection on adrenal function in adults patients was updated as follows:
Adrenal Function: In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group, and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group.
In the rilpivirine group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the efavirenz group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the rilpivirine group and 9 subjects in the efavirenz group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known.
Section 6.3 Clinical Trial Experience in Pediatric Subjects was added
Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information.
Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase 2 trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received rilpivirine (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.
Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%).
Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information.
Adrenal Function
In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.
Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.
Tenofovir Disoproxil Fumarate: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See Warnings and Precautions (5.8)]. For additional information, including information on bone mineral density changes, please consult the VIREAD prescribing information.
The post-marketing experience section was updated to include weight increased.
Section 12.3 Pharmacokinetics was updated to include data on pediatric subjects as follows:
Pediatric Patients
Pediatric trials have not been conducted using the emtricitabine, rilpivirine, tenofovir disoproxil fumarate fixed-dose combination tablets. Pediatric information is based on trials conducted with the individual entities. In pediatric subjects, emtricitabine has been studied from 0 months to 17 years of age and tenofovir DF has been studied in 2 years of age and older. Information on the pharmacokinetics of rilpivirine is currently available only for pediatric subjects from 12 to less than 18 years of age [See Use in Specific Populations (8.4)].
Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg emtricitabine capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μghr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.
Rilpivirine: The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving rilpivirine 25 mg once daily were comparable to those in treatment-naïve HIV-1-infected adults receiving rilpivirine 25 mg once daily [See Table 6]. There was no clinically significant impact of body weight on rilpivirine pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).
Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μghr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
Section 14.2 Clinical Studies: Pediatric Subjects was added.
14.2 Pediatric Subjects
The pharmacokinetics, safety, and efficacy of rilpivirine in combination with other antiretroviral agents was evaluated in a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg (TMC-C213). Thirty-six (36) subjects were enrolled with a median age of 14.5 years (range 12 to 17 years), and were 55.6% female, 88.9% Black, and 11.1% Asian. The majority of subjects (24/36) received rilpivirine in combination with emtricitabine and tenofovir DF. Of these 24 subjects, 20 had baseline HIV RNA ≤100,000 copies/mL. The baseline characteristics and efficacy outcomes at Week 48 are further described below for the 20 subjects.
The median baseline plasma HIV-1 RNA and CD4+ cell count were 49,550 (range 2060 to 92,600 copies/mL) and 437.5 cells/mm3 (range 123 to 983 cells/mm3), respectively. At Week 48, 80% (16/20) of the subjects had HIV RNA <50 copies/mL, 15% (3/20) had HIV RNA ≥50 copies/mL, and one subject discontinued therapy prior to Week 48 and before reaching virologic suppression (HIV RNA <50 copies/mL). At Week 48, the mean increase in CD4+ cell count from baseline was 225 cells/mm3.
You will be able to view the complete label at drugs@fda or dailymed.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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