FDA recently approved changes to the INTELENCE (etravrine) label to expand the population to pediatric patients 2 years to less than 6 years of age weighing at least 10 kg. The major changes include the following.
The dosage of INTELENCE for patients greater than or equal to 10 kg to less than 20 kg is 100 mg twice daily. The method of administration section was updated to state:
Patients should be instructed to swallow the INTELENCE tablet(s) whole with a liquid such as water. Patients who are unable to swallow the INTELENCE tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:
In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.
USE IN SPECIFIC POPULATIONS
Pediatric Use
The safety and effectiveness of INTELENCE have been established for the treatment of HIV-infected pediatric patients from 2 years of age to less than 18 years. Use of INTELENCE in pediatric patients 2 years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of INTELENCE in adults with additional data from two Phase 2 trials in treatment-experienced pediatric subjects, TMC125-C213, 6 years to less than 18 years of age (N=101) and TMC125-C234/IMPAACT P1090, 2 years to less than 6 years of age (N=20). Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.
Treatment with INTELENCE is not recommended in pediatric patients less than 2 years of age. Five HIV-infected subjects from 1 year to < 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC12h geometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from 1 year to < 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in 3 of 4 evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in 1 of the 3 subjects who experienced virologic failure.
CLINICAL PHARMACOLOGY
The pharmacokinetics of etravirine in 115 treatment‑experienced HIV‑1‑infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight‑based dosages resulted in etravirine exposure comparable to that in adults receiving INTELENCE 200 mg twice daily. The pharmacokinetic parameters for etravirine (AUC12h and C0h) are summarized in Table 6 below (see updated label).
The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established.
CLINICAL STUDIES
Pediatric Subjects (2 Years to Less Than 6 Years of Age [TMC125-C234/IMPAACT P1090])
TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age. The study enrolled subjects who had virologic failure on an antiretroviral treatment regimen after at least 8 weeks of treatment, or who had interrupted treatment for at least 4 weeks. Enrolled subjects had a history of virologic failure while on an antiretroviral regimen, with a confirmed HIV-1 RNA plasma viral load greater than 1,000 copies/mL and with no evidence of phenotypic resistance to etravirine at screening.
The median baseline plasma HIV-1 RNA was 4.4 log10 copies/mL, the median baseline CD4+ cell count was 817.5 x 106 cells/mm3, and the median baseline CD4+ percentage was 28%.
Virologic response, defined as achieving plasma viral load less than 400 HIV-1 RNA copies/mL, was evaluated.
Study treatment included etravirine plus an optimized background regimen of antiretroviral drugs. In addition to etravirine, all 20 subjects received a ritonavir-boosted protease inhibitor in combination with 1 or 2 NRTIs (n=14) and/or in combination with an integrase inhibitor (n=7).
At the time of the Week 24 analysis, seventeen subjects had completed at least 24 weeks of treatment or discontinued earlier. At Week 24, the proportion of subjects with less than 400 HIV-1 RNA copies/mL was 88% (15/17), and the proportion of subjects with less than 50 HIV-1 RNA copies/mL was 50% (7/14), for those with available data. The median change in plasma HIV-1 RNA from baseline to Week 24 was -2.14 log10 copies/mL. The median CD4+ cell count increase and the median CD4+ percentage increase from baseline was 298 x 106 cells/mm3 and 5%, respectively.
The dosage of INTELENCE for patients greater than or equal to 10 kg to less than 20 kg is 100 mg twice daily. The method of administration section was updated to state:
Patients should be instructed to swallow the INTELENCE tablet(s) whole with a liquid such as water. Patients who are unable to swallow the INTELENCE tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:
- place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication,
- stir well until the water looks milky,
- add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided.
- drink the mixture immediately,
- rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.
In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.
USE IN SPECIFIC POPULATIONS
Pediatric Use
The safety and effectiveness of INTELENCE have been established for the treatment of HIV-infected pediatric patients from 2 years of age to less than 18 years. Use of INTELENCE in pediatric patients 2 years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of INTELENCE in adults with additional data from two Phase 2 trials in treatment-experienced pediatric subjects, TMC125-C213, 6 years to less than 18 years of age (N=101) and TMC125-C234/IMPAACT P1090, 2 years to less than 6 years of age (N=20). Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.
Treatment with INTELENCE is not recommended in pediatric patients less than 2 years of age. Five HIV-infected subjects from 1 year to < 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC12h geometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from 1 year to < 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in 3 of 4 evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in 1 of the 3 subjects who experienced virologic failure.
CLINICAL PHARMACOLOGY
The pharmacokinetics of etravirine in 115 treatment‑experienced HIV‑1‑infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight‑based dosages resulted in etravirine exposure comparable to that in adults receiving INTELENCE 200 mg twice daily. The pharmacokinetic parameters for etravirine (AUC12h and C0h) are summarized in Table 6 below (see updated label).
The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established.
CLINICAL STUDIES
Pediatric Subjects (2 Years to Less Than 6 Years of Age [TMC125-C234/IMPAACT P1090])
TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE in 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age. The study enrolled subjects who had virologic failure on an antiretroviral treatment regimen after at least 8 weeks of treatment, or who had interrupted treatment for at least 4 weeks. Enrolled subjects had a history of virologic failure while on an antiretroviral regimen, with a confirmed HIV-1 RNA plasma viral load greater than 1,000 copies/mL and with no evidence of phenotypic resistance to etravirine at screening.
The median baseline plasma HIV-1 RNA was 4.4 log10 copies/mL, the median baseline CD4+ cell count was 817.5 x 106 cells/mm3, and the median baseline CD4+ percentage was 28%.
Virologic response, defined as achieving plasma viral load less than 400 HIV-1 RNA copies/mL, was evaluated.
Study treatment included etravirine plus an optimized background regimen of antiretroviral drugs. In addition to etravirine, all 20 subjects received a ritonavir-boosted protease inhibitor in combination with 1 or 2 NRTIs (n=14) and/or in combination with an integrase inhibitor (n=7).
At the time of the Week 24 analysis, seventeen subjects had completed at least 24 weeks of treatment or discontinued earlier. At Week 24, the proportion of subjects with less than 400 HIV-1 RNA copies/mL was 88% (15/17), and the proportion of subjects with less than 50 HIV-1 RNA copies/mL was 50% (7/14), for those with available data. The median change in plasma HIV-1 RNA from baseline to Week 24 was -2.14 log10 copies/mL. The median CD4+ cell count increase and the median CD4+ percentage increase from baseline was 298 x 106 cells/mm3 and 5%, respectively.
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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