EDURANT PED (rilpivirine hydrochloride 25 mg) Dailymed

Recent Major Changes Section

Indications and Usage ( 1.1)	03/2024
Dosage and Administration ( 2.1, 2.3, 2.4, 2.5)	03/2024
Warnings and Precautions ( 5.6)	03/2024

1 Indications And Usage

EDURANT and EDURANT PED are a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve patients 2 years of age and older and weighing at least 14 kg with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1.1).

Limitations of Use:

• More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1.1, 14)

EDURANT is indicated in combination with VOCABRIA (cabotegravir), for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. ( 1.2)

1.1 Treatment of HIV-1 in Treatment-Nave Patients

EDURANT and EDURANT PED, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 2 years of age and older and weighing at least 14 kg with plasma HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.

Limitations of Use

• More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14.1)] .

1.2 Treatment of HIV-1 in Combination with Cabotegravir

EDURANT is indicated in combination with VOCABRIA (cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as [see Dosage and Administration (2.6)] :

• oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).
• oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).

• One 25 mg EDURANT tablet taken once daily with a meal for patients weighing at least 25 kg. ( 2.2)
• Pediatric patients 2 years of age and older and weighing at least 14 kg to less than 25 kg: Dosage of EDURANT PED is based on body weight. ( 2.3)
• EDURANT PED must be dispersed in drinking water and taken with a meal. ( 2.4)
• Do not substitute EDURANT tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. ( 2.1, 5.6)
• See full prescribing information for dosing information when used in combination with cabotegravir. ( 2.6)
• For pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) the recommended dosage in adults and pediatric patients weighing more than 25 kg is one 25 mg tablet once daily taken orally with a meal. ( 2.5, 12.3)
• Rifabutin coadministration: Take two 25 mg tablets of EDURANT once daily with a meal for the duration of the rifabutin coadministration. ( 2.7)

2.1 Overview of Different Dosage Forms

EDURANT is available in two dosage forms:

• EDURANT 25 mg film-coated tablets for adults and pediatric patients weighing at least 25 kg.
• EDURANT PED 2.5 mg tablets for oral suspension should only be given to pediatric patients weighing at least 14 kg to less than 25 kg [see Dosage and Administration (2.3)] .

Do not substitute EDURANT tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. A difference in bioavailability between 1 × 25 mg film-coated tablet and 10 × 2.5 mg tablets for oral suspension was observed; therefore, they are NOT substitutable [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Take EDURANT and EDURANT PED once daily with a meal in combination with other antiretrovirals [see Clinical Pharmacology (12.3)].

2.2 Recommended Dosage in Treatment-Nave Adult Patients

The recommended dosage of EDURANT in adult patients is one 25 mg tablet taken orally once daily with a meal [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] .

2.3 Recommended Dosage in Treatment-Nave Pediatric Patients 2 Years of Age and Older and Weighing at least 14 kg

The recommended dosage of EDURANT and EDURANT PED in pediatric patients 2 years of age and older and weighing at least 14 kg is based on body weight (see Table 1). Both EDURANT and EDURANT PED should be taken orally once daily with a meal [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)] .

Table 1: Recommended Dosage of EDURANT and EDURANT PED for Pediatric Patients

Body Weight (kg)	EDURANT 25 mg Tablets	EDURANT PED 2.5 mg Tablets for Oral Suspension	Total Daily Dose
14 kg to less than 20 kg	Not recommended	5 tablets once daily	12.5 mg EDURANT PED once daily
20 kg to less than 25 kg	Not recommended	6 tablets once daily	15 mg EDURANT PED once daily
Greater than or equal to 25 kg	1 tablet once daily	Not recommended	25 mg EDURANT once daily

2.4 Preparation and Administration Instructions for EDURANT PED Only

Advise patients or caregivers of patients taking EDURANT PED to refer to the Instructions for Use to properly prepare and take the medication.

EDURANT PED must be dispersed in drinking water and taken immediately with a meal. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared. The patient should not chew or swallow EDURANT PED whole. The following instructions should be followed:

• Place the tablets for oral suspension in a cup, add 5 mL (1 teaspoon) of drinking water at room temperature. Do not crush the tablets.
• Swirl the cup carefully for 1–2 minutes to disperse the tablets. The oral suspension will start to look cloudy.
• Take all the prepared oral suspension immediately or to aid in administration, the oral suspension can be further diluted with 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce. Swirl and take all the medicine immediately. A spoon can be used if needed.
• Make sure the entire dose is taken and no medicine is left in the cup. If required, add another 5 mL (1 teaspoon) of drinking water (or alternative beverage or soft food), swirl and drink immediately.

2.5 Recommended Dosage During Pregnancy

For pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) the recommended dosage in adults and pediatric patients weighing at least 25 kg is one 25 mg tablet once daily taken orally with a meal. Refer to Table 1 for dosing recommendations for pediatric patients [see Dosage and Administration (2.2, 2.3)]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] .

2.6 Recommended Dosage in Combination with Cabotegravir in Adults and Adolescents 12 Years of Age and Older and Weighing at least 35 kg

Consult the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) before initiating EDURANT to ensure therapy with CABENUVA is appropriate.

Oral Lead-In Dosing to Assess Tolerability of Rilpivirine

Oral lead-in should be used for approximately 1 month (at least 28 days) to assess the tolerability of rilpivirine prior to the initiation of CABENUVA. The recommended oral daily dose is one 25 mg tablet of EDURANT (rilpivirine) in combination with one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) orally once daily at approximately the same time each day with a meal [see Clinical Pharmacology (12.3)].

Because EDURANT is indicated in combination with VOCABRIA (cabotegravir), the prescribing information for VOCABRIA (cabotegravir) tablets should also be consulted.

The last oral dose should be taken on the same day injections with CABENUVA are started.

Oral Dosing to Replace Planned Missed Injections of CABENUVA

Planned Missed Injections for Patients on Monthly Dosing Schedule

If a patient plans to miss a scheduled monthly injection of CABENUVA by more than 7 days, take daily oral therapy for up to 2 months to replace missed injection visits. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume monthly injection dosing.

Planned Missed Injections for Patients on Every-2-Month Dosing Schedule

If a patient plans to miss a scheduled every-2-month injection of CABENUVA by more than 7 days, take daily oral therapy for a duration of up to 2 months to replace 1 missed scheduled every-2-month injection. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume every-2-month injection dosing.

2.7 Recommended Dosage with Rifabutin Coadministration

If EDURANT is coadministered with rifabutin, the EDURANT dose should be increased to 50 mg (two 25 mg tablets) once daily, taken with a meal. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Refer to CABENUVA labeling for additional detail.

• Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develop and closely monitor clinical status, including hepatic serum biochemistries. ( 5.1)
• Hepatotoxicity: Hepatic adverse events have been reported in patients with underlying liver disease, including hepatitis B or C virus co-infection, or in patients with elevated baseline transaminases. A few cases of hepatotoxicity have occurred in patients with no pre-existing hepatic disease. Monitor liver function tests before and during treatment with EDURANT or EDURANT PED in patients with underlying hepatic disease, such as hepatitis B or C virus co-infection, or marked elevations in transaminase. Also consider monitoring liver functions tests in patients without pre-existing hepatic dysfunction or other risk factors. ( 5.2)
• Depressive Disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.3)
• Patients may develop immune reconstitution syndrome. ( 5.5)

5.1 Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT. No Grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2)] . Discontinue EDURANT or EDURANT PED immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, bulers, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.

5.2 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT or EDURANT PED. A few cases of hepatic toxicity have been reported in adult patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with EDURANT or EDURANT PED is recommended in patients with underlying hepatic disease such as hepatitis B or C virus infection, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.

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 or EDURANT PED, 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.

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of EDURANT or EDURANT PED and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)] :

• Loss of therapeutic effect of EDURANT or EDURANT PED and possible development of resistance.

In healthy subjects, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to EDURANT or EDURANT PED when coadministered with a drug that is known to have a risk of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.2)] .

See Table 6for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during EDURANT or EDURANT PED therapy and review concomitant medications during therapy.

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EDURANT. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium aviuminfection, cytomegalovirus, Pneumocystis jiroveciipneumonia or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6 Different Formulations Are Not Substitutable

EDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. A difference in bioavailability between 1 × 25 mg film-coated tablet and 10 × 2.5 mg tablets for oral suspension was observed; therefore, they are not substitutable [see Clinical Pharmacology (12.3)]. When a pediatric patient weighs 25 kg or greater, they must switch from EDURANT PED tablets for oral suspension to one 25 mg EDURANT tablet daily [see Dosage and Administration (2.3)]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to rilpivirine.

6 Adverse Reactions

The following adverse reactions are discussed below and in other sections of the labeling:

• Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Depressive Disorders [see Warnings and Precautions (5.3)]

The most common adverse reactions to EDURANT or EDURANT PED (incidence >2%) of at least moderate to severe intensity (≥ Grade 2) were depressive disorders, headache, insomnia and rash. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience in Adults

The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) [see Clinical Studies (14.1)] . The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most adverse reactions occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to adverse reaction, regardless of severity, was 2% and 4%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the EDURANT arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (<1%) subject in the EDURANT arm and 10 (2%) subjects in the efavirenz arm.

Common Adverse Reactions

Adverse reactions of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are presented in Table 3. Selected laboratory abnormalities are included in Table 4.

Table 3: Selected Adverse Reactions of at Least Moderate Intensity Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).(Grades 2–4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects (Week 96 Analysis)

System Organ Class, Preferred Term, %	Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials
	EDURANT + BR N=686	Efavirenz + BR N=682
N=total number of subjects per treatment group; BR=background regimen
Gastrointestinal Disorders
  Abdominal pain	2%	2%
  Nausea	1%	3%
  Vomiting	1%	2%
General Disorders and Administration Site Conditions
  Fatigue	2%	2%
Nervous System Disorders
  Headache	3%	4%
  Dizziness	1%	7%
Psychiatric Disorders
  Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.	5%	4%
  Insomnia	3%	4%
  Abnormal dreams	2%	4%
Skin and Subcutaneous Tissue Disorders
  Rash	3%	11%

No new adverse reaction terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks.

Less Common Adverse Reactions

Adverse reactions of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving EDURANT are uled below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with EDURANT.

Gastrointestinal Disorders: diarrhea, abdominal discomfort

Hepatobiliary Disorders: cholecystitis, cholelithiasis

Metabolism and Nutrition Disorders: decreased appetite

Nervous System Disorders: somnolence

Psychiatric Disorders: sleep disorders, anxiety

Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis

Laboratory Abnormalities in Treatment-Naïve Subjects

The percentage of subjects treated with EDURANT or efavirenz in the Phase 3 trials with selected laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 4.

Table 4: Selected Changes in Laboratory Parameters (Grades 1 to 4) Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Week 96 Analysis)

Laboratory Parameter Abnormality, (%)	DAIDS Toxicity Range	Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials
		EDURANT + BR N=686	Efavirenz + BR N=682
BIOCHEMISTRY
BR=background regimen; ULN=upper limit of normal
N=number of subjects per treatment group
Note: Percentages were calculated versus the number of subjects in ITT.
Increased Creatinine
  Grade 1	≥1.1–≤1.3 × ULN	6%	1%
  Grade 2	>1.3–≤1.8 × ULN	1%	1%
  Grade 3	>1.8–≤3.4 × ULN	<1%	0
  Grade 4	>3.4 × ULN	0	<1%
Increased AST
  Grade 1	≥1.25–≤2.5 × ULN	16%	19%
  Grade 2	>2.5–≤5.0 × ULN	4%	7%
  Grade 3	>5.0–≤10.0 × ULN	2%	2%
  Grade 4	>10.0 × ULN	1%	1%
Increased ALT
  Grade 1	≥1.25–≤2.5 × ULN	18%	20%
  Grade 2	>2.5–≤5.0 × ULN	5%	7%
  Grade 3	>5.0–≤10.0 × ULN	1%	2%
  Grade 4	>10.0 × ULN	1%	1%
Increased Total Bilirubin
  Grade 1	≥1.1–≤1.5 × ULN	5%	<1%
  Grade 2	>1.5–≤2.5 × ULN	3%	1%
  Grade 3	>2.5–≤5.0 × ULN	1%	<1%
  Grade 4	>5.0 × ULN	0	0
Increased Total Cholesterol (fasted)
  Grade 1	5.18–6.19 mmol/L 200–239 mg/dL	17%	31%
  Grade 2	6.20–7.77 mmol/L 240–300 mg/dL	7%	19%
  Grade 3	>7.77 mmol/L >300 mg/dL	<1%	3%
Increased LDL Cholesterol (fasted)
  Grade 1	3.37–4.12 mmol/L 130–159 mg/dL	14%	26%
  Grade 2	4.13–4.90 mmol/L 160–190 mg/dL	5%	13%
  Grade 3	≥4.91 mmol/L ≥191 mg/dL	1%	5%
Increased Triglycerides (fasted)
  Grade 2	5.65–8.48 mmol/L 500–750 mg/dL	2%	2%
  Grade 3	8.49–13.56 mmol/L 751–1,200 mg/dL	1%	3%
  Grade 4	>13.56 mmol/L >1,200 mg/dL	0	1%

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%) 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%) 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.

Serum Creatinine

In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with EDURANT. Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Serum creatinine increases occurred regardless of the background N(t)RTI regimen.

Serum Lipids

Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 5. The clinical benefit of these findings has not been demonstrated.

Table 5: Lipid Values, Mean Change from Baseline Excludes subjects who received lipid lowering agents during the treatment period

	Pooled Data from the Week 96 Analysis of the Phase 3 TMC278-C209 and TMC278-C215 Trials
	EDURANT + BR				Efavirenz + BR
	N	Baseline	Week 96		N	Baseline	Week 96
Mean (95% CI)		Mean (mg/dL)	Mean (mg/dL)	Mean Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values (mg/dL)		Mean (mg/dL)	Mean (mg/dL)	Mean Change (mg/dL)
N=number of subjects per treatment group; BR=background regimen
Total Cholesterol (fasted)	546	161	166	5	507	160	187	28
HDL-cholesterol (fasted)	545	41	46	4	505	40	51	11
LDL-cholesterol (fasted)	543	96	98	1	503	95	109	14
Triglycerides (fasted)	546	122	116	-6	507	130	141	11

Subjects Co-infected with Hepatitis B and/or Hepatitis C Virus

In subjects co-infected with hepatitis B or C virus receiving EDURANT, the incidence of hepatic enzyme elevation was higher than in subjects receiving EDURANT who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.

Use in Combination with Cabotegravir

Safety findings from Phase 3/3b trials in adults were similar when EDURANT was administered in combination with VOCABRIA (cabotegravir) or other antiretrovirals. See full prescribing information for VOCABRIA and CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for additional information.

Clinical Trials Experience in Pediatric Patients

Pediatric Population (≥12 to less than 18 years of age)

Pediatric Population (≥2 to less than 12 years of age)

Two clinical trials were conducted in pediatric subjects weighing at least 16 kg (5 to less than 12 years of age). A total of 18 and 26 pediatric subjects were enrolled in Trial TMC278-C213 and Trial TMC278HTX2002, respectively. Overall, the safety data in these pediatric studies were similar to those observed in adults. Safety results from the two trials are summarized below.

Trial TMC278-C213 Cohort 2

Cohort 2 of the single-arm, open-label Phase 2 trial, TMC278-C213 evaluated the safety of the EDURANT and EDURANT PED weight adjusted doses 25, 15 and 12.5 mg once daily in antiretroviral treatment-naïve HIV-1 infected patients (≥6 to <12 years of age and weighing at least 17 kg) [see Clinical Studies (14.4)] . The median duration of exposure for patients in the Week 48 analysis (including post-Week 48 extension) was 69.5 (range 35 to 218) weeks.

All adverse reactions were Grade 1 or 2. Adverse reactions reported in at least 2 subjects, regardless of grading, in Trial TMC278-C213 Cohort 2 were: decreased appetite (3/18, 17%), vomiting (2/18, 11%), ALT increased (2/18, 11%), AST increased (2/18, 11%), and rash (2/18, 11%). No adverse reactions led to discontinuation.

Trial TMC278HTX2002

The single arm, open-label Phase 2 trial, TMC278HTX2002, evaluated the safety of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg once daily in virologically suppressed HIV-1 infected patients (≥2 to <12 years of age and weighing at least 16 kg). The median duration of exposure for patients in the Week 48 analysis was 48.4 (range 47 to 52) weeks.

All adverse reactions were Grade 1 or 2. Adverse reactions reported in at least 2 subjects, regardless of grading, in Trial TMC278HTX2002 were: vomiting (4/26, 15%), abdominal pain (3/26, 12%), nausea (2/26, 8%), ALT increased (3/26, 12%), AST increased (2/26, 8%), and decreased appetite (2/26, 8%). No adverse reactions led to discontinuation.

6.2 Postmarketing Experience

Adverse reactions have been identified during postmarketing experience in patients receiving a rilpivirine containing regimen. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal and Genitourinary Disorders:nephrotic syndrome

Skin and Subcutaneous Tissue Disorders:Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)