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On August 26, 2015 the Edurant (rilpivirine) product labeling was updated to
include the use of rilpivirine in combination with other antiretroviral agents
for the treatment of HIV-1 infection to include treatment-naïve pediatric
patients from 12 to less than 18 years of age with HIV-1 RNA less than or equal
to 100,00 copies/mL. The summary of the changes are provided below. In addition
to the addition of the adolescent data to the label, changes were made the
Warnings and Precautions with respect to Depressive Disorders and updates to
the adrenal function subsection in section 6 Adverse Reactions.
Section 2: DOSAGE AND ADMINISTRATION was updated as follows:
The recommended dosage of EDURANT in patients 12 years of
age and older and weighing at least 35 kg is one 25 mg tablet once daily taken
orally with a meal. EDURANT is not recommended for patients less than 12 years
of age.
Section 5 Warnings and Precautions was updated as follows:
5.3
Depressive Disorders
The adverse reaction depressive disorders (depressed mood,
depression, dysphoria, major depression, mood altered, negative thoughts,
suicide attempt, suicidal ideation) has been reported with EDURANT. Patients
with severe depressive symptoms should seek immediate medical evaluation to assess
the possibility that the symptoms are related to EDURANT, and if so, to
determine whether the risks of continued therapy outweigh the benefits.
During the Phase 3 trials in adults (N = 1368) through 96
weeks, the incidence of depressive disorders (regardless of causality,
severity) reported among EDURANT (n = 686) or efavirenz (n = 682) was 9% and
8%, respectively. Most events were mild or moderate in severity. The incidence
of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both
EDURANT and efavirenz. The incidence of discontinuation due to depressive
disorders among EDURANT or efavirenz was 1% in each arm. Suicidal ideation was
reported in 4 subjects in each arm while suicide attempt was reported in 2
subjects in the EDURANT arm.
During the Phase 2 trial in pediatric subjects 12 to less
than 18 years of age (N = 36) receiving EDURANT 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 – Adults was revised as follows
Adrenal Function
In the pooled Phase 3 trials, 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 EDURANT group and of -0.02 (-0.48, 0.44) micrograms/dL in
the efavirenz group.
In the EDURANT 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, fourteen subjects in the EDURANT group and nine 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 EDURANT group is not known.
Section 6.2: Clinical Trials Experience: Pediatric Patients
was added as follows.
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 patients 12 to less than 18 years
of age and weighing at least 32 kg received EDURANT (25 mg once daily) in
combination with other antiretroviral agents [see Clinical Studies (14.2)]. The
median duration of exposure was 63.5 weeks. There were no patients who
discontinued treatment due to ADRs. No new ADRs were identified compared to
those seen in adults.
ADRs were reported in nineteen pediatric subjects (52.8%).
Most ADRs were Grade 1 or 2. The most common ADRs 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.
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.
Section 12 Clinical Pharmacology was updated to include the
adolescent pharmacokinetic data
Section 14 Clinical Studies section was added as follows:
14.2 Treatment-Naïve
Pediatric Subjects (12 to less than 18 years of age)
The pharmacokinetics, safety, tolerability and efficacy of
EDURANT 25 mg once daily, in combination with an investigator-selected
background regimen (BR) containing two NRTIs, was evaluated in trial
TMC278-C213, 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. Thirty six (36) subjects were enrolled in the
trial to complete at least 48 weeks of treatment. The 36 subjects had a median
age of 14.5 years (range: 12 to 17 years), and were 55.6% female, 88.9% Black
and 11.1% Asian.
In the efficacy analysis, most subjects (75%; 28/36) had
baseline HIV RNA <100,000 copies/mL. For these 28 subjects the median
baseline plasma HIV-1 RNA was 44,250 (range: 2,060-92,600 copies/mL) and the
median baseline CD4+ cell count was 445.5 cells/mm3 (range: 123 to 983 cells/mm3).
Among the subjects who had baseline HIV RNA ≤ 100,000, the
proportion with HIV 1 RNA <50 copies/mL at Week 48 was 79% (22/28), versus
50.0% (4/8) in those with >100,000 copies/mL. The proportion of virologic
failures among subjects with a baseline viral load ≤100,000 copies/mL was 21.4%
(6/28), versus 37.5% (3/8) in those with >100,000 copies/mL. At Week 48, the
mean increase in CD4+ cell count from baseline was 201.2 cells/mm3.
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