Edurant (rilpivirine) labeling updated

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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 <100 123="" 28="" 2="" 445.5="" 44="" 983="" and="" baseline="" cd4="" cell="" cells="" copies="" count="" for="" hiv-1="" median="" ml.="" ml="" mm3="" nbsp="" p="" plasma="" range:="" rna="" subjects="" the="" these="" to="" was="">

Among the subjects who had baseline HIV RNA ≤ 100,000, the proportion with HIV 1 RNA <50 48="" 50.0="" 79="" at="" copies="" in="" ml="" those="" versus="" was="" week="" 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.

You can view the complete label at drugs@fda or dailymed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administrationn

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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