EDURANT

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 drug reactions to EDURANT (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 ADRs occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs 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 (0.1%) subject in the EDURANT arm and 10 (1.5%) subjects in the efavirenz arm. Common Adverse Drug Reactions ADRs of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are presented in Table 2. Selected laboratory abnormalities are included in Table 3. Table 2: Selected Adverse Drug 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 drug 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 ADR 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 Drug Reactions ADRs of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving EDURANT are listed 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 3. Table 3: 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 (7.3%) 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. 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 4. The clinical benefit of these findings has not been demonstrated. Table 4: 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 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 (14.3) ] . 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. Trial 208580 [MOCHA] Based on data from the Week 16 analysis of the MOCHA study in 15 adolescents (aged 12 to younger than 18 years and weighing ≥35 kg) receiving EDURANT (25 mg once daily) in addition to continuing background antiretroviral therapy, the safety profile during the oral-lead in period in adolescents was consistent with the safety profile established with EDURANT 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. 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)

4 CONTRAINDICATIONS EDURANT is contraindicated for coadministration with the drugs in Table 1 for which significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to EDURANT or to the class of NNRTIs [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Table 1: Drugs That are Contraindicated with EDURANT Drug Class Contraindicated Drugs in Class Clinical Comment Anticonvulsants Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. Antimycobacterials Rifampin Rifapentine Glucocorticoid (systemic) Dexamethasone (more than a single-dose treatment) Herbal Products St John's wort ( Hypericum perforatum ) Proton Pump Inhibitors e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. Coadministration of EDURANT is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. ( 4 )

11 DESCRIPTION EDURANT ® (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C 22 H 18 N 6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin. Chemical Structure

2 DOSAGE AND ADMINISTRATION One tablet taken once daily with a meal. ( 2.1 , 2.2 ) See full prescribing information for dosing information when used in combination with cabotegravir (2.2) 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 is one 25 mg tablet once daily taken orally with a meal. ( 2.1 , 12.3 ) Rifabutin coadministration: Take two 25 mg tablets of rilpivirine once daily with a meal for the duration of the rifabutin coadministration. ( 2.3 ) 2.1 Recommended Dosage in Treatment-Naïve Patients The recommended dosage of EDURANT in patients 12 years of age and older and weighing at least 35 kg is one 25 mg tablet taken orally once daily with a meal [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] . 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 is one 25 mg tablet once daily taken orally with a meal. 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) ] . 2.2 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. 2.3 Recommended Dosage with Rifabutin Coadministration If EDURANT is coadministered with rifabutin, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) 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.

1 INDICATIONS AND USAGE EDURANT is 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 12 years of age and older and weighing at least 35 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-Naïve Patients EDURANT, 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 12 years of age and older and weighing at least 35 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 (2.2) ] : 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).

10 OVERDOSAGE There is no specific antidote for overdose with EDURANT. Human experience of overdose with EDURANT is limited. Treatment of overdose with EDURANT consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

7 DRUG INTERACTIONS [see Dosage and Administration (2) , Contraindications (4) and Clinical Pharmacology (12.3) ]. Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. Table 5 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with EDURANT are also included in Table 5. Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3) ] Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment ↑=increase, ↓=decrease, ↔=no change Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) The combination of EDURANT and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT. ↓ rilpivirine (concomitant intake) Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4) ] . Antimycobacterials: rifampin rifapentine ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4) ] . Antimycobacterials: rifabutin The interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. ↓ rilpivirine Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout coadministration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily. Azole Antifungal Agents: fluconazole itraconazole ketoconazole This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily. posaconazole voriconazole ↑ rilpivirine ↓ ketoconazole Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with EDURANT. Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4) ] . H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) The combination of EDURANT and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT. ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) Herbal Products: St John's wort ( Hypericum perforatum ) ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4) ] . HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTI (delavirdine) ↑ rilpivirine ↔ delavirdine It is not recommended to coadminister EDURANT with delavirdine and other NNRTIs. Other NNRTIs (efavirenz, etravirine, nevirapine) ↓ rilpivirine ↔ other NNRTIs HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine ↔ rilpivirine ↔ didanosine No dose adjustment is required when EDURANT is coadministered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal). HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir) darunavir/ritonavir ↑ rilpivirine ↔ boosted darunavir Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is coadministered with darunavir/ritonavir. lopinavir/ritonavir ↑ rilpivirine ↔ boosted lopinavir Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is coadministered with lopinavir/ritonavir. other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) ↑ rilpivirine ↔ boosted PI Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of coadministered PIs. unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) ↑ rilpivirine ↔ unboosted PI Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of coadministered PIs. Macrolide or ketolide antibiotics: azithromycin clarithromycin erythromycin ↑ rilpivirine ↔ azithromycin ↔ clarithromycin ↔ erythromycin Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [ Warnings and Precautions (5.4) ]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. Narcotic Analgesics: methadone ↓ R(-) methadone ↓ S(+) methadone No dose adjustments are required when initiating coadministration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. Proton Pump Inhibitors: e.g., esomeprazole lansoprazole omeprazole pantoprazole rabeprazole ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4) ] . In addition to the drugs included in Table 5, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3) ] : acetaminophen, atorvastatin, chlorzoxazone, cabotegravir, ethinylestradiol, norethindrone, raltegravir, sildenafil, simeprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when EDURANT is coadministered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine. Consider alternatives to EDURANT when coadministered with drugs with a known risk of torsade de pointes. ( 5.4 ) EDURANT should not be used in combination with NNRTIs. ( 4 , 7 ) Coadministration of EDURANT with drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine. ( 4 , 7 ) Coadministration of EDURANT with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine. ( 4 , 7 ) Refer to the Full Prescribing Information for other drugs that should not be coadministered with EDURANT and for other drugs that may require a change in dose or regimen. ( 7 ) QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of 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 [see Clinical Pharmacology (12.2) ] . Consider alternatives to EDURANT when coadministered with a drug with a known risk of torsade de pointes.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rilpivirine is an antiviral drug [see Microbiology (12.4) ] . 12.2 Pharmacodynamics Effects on Electrocardiogram The effect of EDURANT at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern). When doses of 75 mg once daily and 300 mg once daily of EDURANT (3 times and 12 times the dose in EDURANT) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state C max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean C max observed with the recommended 25 mg once daily dose of EDURANT [see Warnings and Precautions (5.4) ] . 12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects. Table 6: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96) Parameter Rilpivirine 25 mg once daily N=679 AUC 24h (ng∙h/mL) Mean±Standard Deviation 2235±851 Median (Range) 2096 (198 – 7307) C 0h (ng/mL) Mean±Standard Deviation 79±35 Median (Range) 73 (2 – 288) Absorption and Bioavailability After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT is unknown. Effects of Food on Oral Absorption The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. Distribution Rilpivirine is approximately 99.7% bound to plasma proteins in vitro , primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. Metabolism In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. Elimination The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14 C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine. Special Populations Pregnancy and Postpartum The exposure (C 0h and AUC 24h ) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 7 ). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum. Table 7: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy and Postpartum Pharmacokinetics of total rilpivirine (mean ± SD, t max : median [range]) Postpartum (6–12 Weeks) (n=11) 2 nd Trimester of pregnancy (n=15) 3 rd Trimester of pregnancy (n=13) C 0h , ng/mL 111±69.2 65.0±23.9 63.5±26.2 C min , ng/mL 84.0±58.8 54.3±25.8 52.9±24.4 C max , ng/mL 167±101 121±45.9 123±47.5 t max , h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93) AUC 24h , ng.h/mL 2714±1535 1792±711 1762±662 Pediatric Patients The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age receiving EDURANT 25 mg once daily were comparable to those in treatment-naïve HIV-1 infected adults receiving EDURANT 25 mg once daily. There was no clinically significant impact of body weight on rilpivirine pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg). Table 8: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48) Parameter Rilpivirine 25 mg once daily N=34 AUC 24h (ng∙h/mL) Mean±Standard Deviation 2424±1024 Median (Range) 2269 (417 – 5166) C 0h (ng/mL) Mean±Standard Deviation 85±40 Median (Range) 79 (7 – 202) The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients who are less than 12 years of age and less than 35 kg have not been established [see Use in Specific Populations (8.4) ] . Renal Impairment Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.6) ] . Hepatic Impairment Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7) ] . Gender, Race, Hepatitis B and/or Hepatitis C Virus Co-infection No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between gender, race and patients with hepatitis B and/or C-virus co-infection. Drug Interactions [see Contraindications (4) and Drug Interactions (7) ]. Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Coadministration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs. EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the C max , AUC, and C min values of rilpivirine are summarized in Table 9 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the C max , AUC, and C min values of other drugs are summarized in Table 10 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7) ]. Table 9: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs Coadministered Drug Dose/Schedule N Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Coadministered Drug (90% CI); No Effect=1.00 Coadministered Drug Rilpivirine C max AUC C min CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 14 1.79 (1.56–2.06) 2.30 (1.98–2.67) 2.78 (2.39–3.24) Lopinavir/ritonavir (soft gel capsule) 400/100 mg b.i.d. 150 mg q.d. 15 1.29 (1.18–1.40) 1.52 (1.36–1.70) 1.74 (1.46–2.08) Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d. 21 1.00 (0.90–1.10) 1.00 (0.95–1.06) 1.00 (0.92–1.09) Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 0.96 (0.81–1.13) 1.01 (0.87–1.18) 0.99 (0.83–1.16) Coadministration With HIV Integrase Strand Transfer Inhibitors Cabotegravir 30 mg q.d. 25 mg q.d. 11 0.96 (0.85–1.09) 0.99 (0.89–1.09) 0.92 (0.79–1.07) Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12 (1.04–1.20) 1.12 (1.05–1.19) 1.03 (0.96–1.12) Coadministration With other Antivirals Simeprevir 150 mg q.d. 25 mg q.d. 23 1.04 (0.95–1.13) 1.12 (1.05–1.19) 1.25 (1.16–1.35) Coadministration With Drugs other than Antiretrovirals Acetaminophen 500 mg single dose 150 mg q.d. 16 1.09 (1.01–1.18) 1.16 (1.10–1.22) 1.26 (1.16–1.38) Atorvastatin 40 mg q.d. 150 mg q.d. 16 0.91 (0.79–1.06) 0.90 (0.81–0.99) 0.90 (0.84–0.96) Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 1.17 (1.08–1.27) 1.25 (1.16–1.35) 1.18 (1.09–1.28) Ethinylestradiol/Norethindrone 0.035 mg q.d./ 1 mg q.d. 25 mg q.d. 15 ↔ comparison based on historic controls ↔ ↔ Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose 24 0.99 (0.84–1.16) 0.91 (0.78–1.07) N.A. Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose 23 0.15 (0.12–0.19) 0.24 (0.20–0.28) N.A. Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose 24 1.21 (1.06–1.39) 1.13 (1.01–1.27) N.A. Ketoconazole 400 mg q.d. 150 mg q.d. 15 1.30 (1.13–1.48) 1.49 (1.31–1.70) 1.76 (1.57–1.97) Methadone 60–100 mg q.d., individualized dose 25 mg q.d. 12 ↔ ↔ ↔ Omeprazole 20 mg q.d. 150 mg q.d. 16 0.60 (0.48–0.73) 0.60 (0.51–0.71) 0.67 (0.58–0.78) Rifabutin 300 mg q.d. 25 mg q.d. 18 0.69 (0.62–0.76) 0.58 (0.52–0.65) 0.52 (0.46–0.59) Rifabutin 300 mg q.d. 50 mg q.d. 18 1.43 (1.30–1.56) 1.16 (1.06–1.26) 0.93 (0.85–1.01) (reference arm for comparison was 25 mg q.d. rilpivirine administered alone) Rifampin 600 mg q.d. 150 mg q.d. 16 0.31 (0.27–0.36) 0.20 (0.18–0.23) 0.11 (0.10–0.13) Sildenafil 50 mg single dose 75 mg q.d. 16 0.92 (0.85–0.99) 0.98 (0.92–1.05) 1.04 (0.98–1.09) Table 10: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT Coadministered Drug Dose/Schedule N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters With/Without EDURANT (90% CI); No Effect=1.00 Coadministered Drug Rilpivirine C max AUC C min CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 15 0.90 (0.81–1.00) 0.89 (0.81–0.99) 0.89 (0.68–1.16) Lopinavir/ritonavir (soft gel capsule) 400/100 mg b.i.d. 150 mg q.d. 15 0.96 (0.88–1.05) 0.99 (0.89–1.10) 0.89 (0.73–1.08) Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d. 13 0.96 (0.80–1.14) 1.12 (0.99–1.27) N.A. Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 1.19 (1.06–1.34) 1.23 (1.16–1.31) 1.24 (1.10–1.38) Coadministration With HIV Integrase Strand Transfer Inhibitors Cabotegravir 30 mg q.d. 25 mg q.d. 11 1.05 (0.96–1.15) 1.12 (1.05–1.19) 1.14 (1.04–1.24) Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10 (0.77–1.58) 1.09 (0.81–1.47) 1.27 (1.01–1.60) Coadministration With other Antivirals Simeprevir 150 mg q.d. 25 mg q.d. 21 1.10 (0.97–1.26) 1.06 (0.94–1.19) 0.96 (0.83–1.11) Coadministration With Drugs other than Antiretrovirals Acetaminophen 500 mg single dose 150 mg q.d. 16 0.97 (0.86–1.10) 0.91 (0.86–0.97) N.A. Atorvastatin 40 mg q.d. 150 mg q.d. 16 1.35 (1.08–1.68) 1.04 (0.97–1.12) 0.85 (0.69–1.03) 2-hydroxy-atorvastatin 16 1.58 (1.33–1.87) 1.39 (1.29–1.50) 1.32 (1.10–1.58) 4-hydroxy-atorvastatin 16 1.28 (1.15–1.43) 1.23 (1.13–1.33) N.A. Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 0.98 (0.85–1.13) 1.03 (0.95–1.13) N.A. Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06 (0.97–1.17) 0.98 (0.93–1.04) AUC (0–last) N.A. Ethinylestradiol 0.035 mg q.d. 25 mg q.d. 17 1.17 (1.06–1.30) 1.14 (1.10–1.19) 1.09 (1.03–1.16) Norethindrone 1 mg q.d. 17 0.94 (0.83–1.06) 0.89 (0.84–0.94) 0.99 (0.90–1.08) Ketoconazole 400 mg q.d. 150 mg q.d. 14 0.85 (0.80–0.90) 0.76 (0.70–0.82) 0.34 (0.25–0.46) R(-) methadone 60–100 mg q.d., individualized dose 25 mg q.d. 13 0.86 (0.78–0.95) 0.84 (0.74–0.95) 0.78 (0.67–0.91) S(+) methadone 13 0.87 (0.78–0.97) 0.84 (0.74–0.96) 0.79 (0.67–0.92) Metformin 850 mg single dose 25 mg q.d. 20 1.02 (0.95–1.10) 0.97 (0.90–1.06) N (maximum number of subjects with data) for AUC (0–∞) =15 N.A. Omeprazole 20 mg q.d. 150 mg q.d. 15 0.86 (0.68–1.09) 0.86 (0.76–0.97) N.A. Rifampin 600 mg q.d. 150 mg q.d. 16 1.02 (0.93–1.12) 0.99 (0.92–1.07) N.A. 25-desacetylrifampin 16 1.00 (0.87–1.15) 0.91 (0.77–1.07) N.A. Sildenafil 50 mg single dose 75 mg q.d. 16 0.93 (0.80–1.08) 0.97 (0.87–1.08) N.A. N -desmethyl-sildenafil 16 0.90 (0.80–1.02) 0.92 (0.85–0.99) N.A. 12.4 Microbiology Mechanism of Action Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ. Antiviral Activity in Cell Culture Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC 50 value for HIV-1 IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC 50 value of 5220 nM (range 2510 to 10830 nM) (920 to 3970 ng/mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC 50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC 50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL). The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L. In Treatment-Naïve Adult Subjects In the Week 96 pooled resistance analysis of the Phase 3 trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the EDURANT arm compared to the efavirenz arm, and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis subjects in the rilpivirine arm compared to 23% (13/56) in the efavirenz arm. Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 – 621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, T215S/T, or K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz resistance analysis subjects (see Table 11 ). NNRTI- and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤100,000 copies/mL compared to viruses from subjects with baseline viral load of >100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm 3 compared to viruses from subjects with baseline CD4+ cell counts <200 cells/mm 3 : 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions. Table 11: Proportion of Resistance Analysis Subjects Subjects who qualified for resistance analysis. with Frequently Emerging Reverse Transcriptase Substitutions from the Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis C209 and C215 N=1368 EDURANT + BR N=686 Efavirenz + BR N=682 BR=background regimen Subjects who Qualified for Resistance Analysis 15% (98/652) 9% (56/604) Subjects with Evaluable Post-Baseline Resistance Data 87 43 Emerging NNRTI Substitutions V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227 or M230 Any 62% (54/87) 53% (23/43) V90I 13% (11/87) 2% (1/43) K101E/P/T/Q 20% (17/87) 9% (4/43) K103N 1% (1/87) 40% (17/43) E138K/A/Q/G 40% (35/87) 2% (1/43) E138K+ M184I This combination of NNRTI and NRTI substitutions is a subset of those with the E138K. 25% (22/87) 0 V179I/L/D 6% (5/87) 7% (3/43) Y181C/I/S 10% (9/87) 2% (1/43) V189I 8% (7/87) 2% (1/43) H221Y 9% (8/87) 0 Emerging NRTI Substitutions A62V, K65R/N, D67N/G, K70E, L74I, V75I, Y115F, M184I/V, L210F, T215S/T, K219E/R Any 57% (50/87) 30% (13/43) M184I/V 54% (47/87) 26% (11/43) K65R/N 9% (8/87) 5% (2/43) A62V, D67N/G, K70E, Y115F, T215S/T or K219E/R These substitutions emerged in addition to the primary substitutions M184V/I or K65R/N; A62V (n=3), D67N/G (n=3), K70E (n=4), Y115F (n=2), T215S/T (n=1), K219E/R (n=8) in rilpivirine resistance analysis subjects. 21% (18/87) 2% (1/43) Cross-Resistance Site-Directed NNRTI Mutant Virus Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had decreased susceptibility to rilpivirine (fold change range of 3.7 – 554) in 38% and 66% of mutants analyzed, respectively. Treatment-Naïve HIV-1-Infected Adult Subjects Considering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L. Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209 and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine (≥2.5-fold change). Of these, 86% (n=43/50) were resistant to efavirenz (≥3.3-fold change), 90% (n= 45/50) were resistant to etravirine (≥3.2-fold change) and 62% (n=31/50) were resistant to nevirapine (≥6-fold change). In the efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects' viruses were resistant to etravirine and rilpivirine, and 95% (n=20/21) were resistant to nevirapine. Virus from subjects experiencing virologic failure on EDURANT developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class compared to virus from subjects who failed on efavirenz.

12.1 Mechanism of Action Rilpivirine is an antiviral drug [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Effects on Electrocardiogram The effect of EDURANT at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern). When doses of 75 mg once daily and 300 mg once daily of EDURANT (3 times and 12 times the dose in EDURANT) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state C max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean C max observed with the recommended 25 mg once daily dose of EDURANT [see Warnings and Precautions (5.4) ] .

12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects. Table 6: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96) Parameter Rilpivirine 25 mg once daily N=679 AUC 24h (ng∙h/mL) Mean±Standard Deviation 2235±851 Median (Range) 2096 (198 – 7307) C 0h (ng/mL) Mean±Standard Deviation 79±35 Median (Range) 73 (2 – 288) Absorption and Bioavailability After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT is unknown. Effects of Food on Oral Absorption The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. Distribution Rilpivirine is approximately 99.7% bound to plasma proteins in vitro , primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. Metabolism In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. Elimination The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14 C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine. Special Populations Pregnancy and Postpartum The exposure (C 0h and AUC 24h ) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 7 ). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum. Table 7: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy and Postpartum Pharmacokinetics of total rilpivirine (mean ± SD, t max : median [range]) Postpartum (6–12 Weeks) (n=11) 2 nd Trimester of pregnancy (n=15) 3 rd Trimester of pregnancy (n=13) C 0h , ng/mL 111±69.2 65.0±23.9 63.5±26.2 C min , ng/mL 84.0±58.8 54.3±25.8 52.9±24.4 C max , ng/mL 167±101 121±45.9 123±47.5 t max , h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93) AUC 24h , ng.h/mL 2714±1535 1792±711 1762±662 Pediatric Patients The pharmacokinetics of rilpivirine in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age receiving EDURANT 25 mg once daily were comparable to those in treatment-naïve HIV-1 infected adults receiving EDURANT 25 mg once daily. There was no clinically significant impact of body weight on rilpivirine pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg). Table 8: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48) Parameter Rilpivirine 25 mg once daily N=34 AUC 24h (ng∙h/mL) Mean±Standard Deviation 2424±1024 Median (Range) 2269 (417 – 5166) C 0h (ng/mL) Mean±Standard Deviation 85±40 Median (Range) 79 (7 – 202) The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients who are less than 12 years of age and less than 35 kg have not been established [see Use in Specific Populations (8.4) ] . Renal Impairment Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.6) ] . Hepatic Impairment Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7) ] . Gender, Race, Hepatitis B and/or Hepatitis C Virus Co-infection No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between gender, race and patients with hepatitis B and/or C-virus co-infection. Drug Interactions [see Contraindications (4) and Drug Interactions (7) ]. Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Coadministration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs. EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the C max , AUC, and C min values of rilpivirine are summarized in Table 9 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the C max , AUC, and C min values of other drugs are summarized in Table 10 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7) ]. Table 9: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs Coadministered Drug Dose/Schedule N Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Coadministered Drug (90% CI); No Effect=1.00 Coadministered Drug Rilpivirine C max AUC C min CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 14 1.79 (1.56–2.06) 2.30 (1.98–2.67) 2.78 (2.39–3.24) Lopinavir/ritonavir (soft gel capsule) 400/100 mg b.i.d. 150 mg q.d. 15 1.29 (1.18–1.40) 1.52 (1.36–1.70) 1.74 (1.46–2.08) Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d. 21 1.00 (0.90–1.10) 1.00 (0.95–1.06) 1.00 (0.92–1.09) Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 0.96 (0.81–1.13) 1.01 (0.87–1.18) 0.99 (0.83–1.16) Coadministration With HIV Integrase Strand Transfer Inhibitors Cabotegravir 30 mg q.d. 25 mg q.d. 11 0.96 (0.85–1.09) 0.99 (0.89–1.09) 0.92 (0.79–1.07) Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12 (1.04–1.20) 1.12 (1.05–1.19) 1.03 (0.96–1.12) Coadministration With other Antivirals Simeprevir 150 mg q.d. 25 mg q.d. 23 1.04 (0.95–1.13) 1.12 (1.05–1.19) 1.25 (1.16–1.35) Coadministration With Drugs other than Antiretrovirals Acetaminophen 500 mg single dose 150 mg q.d. 16 1.09 (1.01–1.18) 1.16 (1.10–1.22) 1.26 (1.16–1.38) Atorvastatin 40 mg q.d. 150 mg q.d. 16 0.91 (0.79–1.06) 0.90 (0.81–0.99) 0.90 (0.84–0.96) Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 1.17 (1.08–1.27) 1.25 (1.16–1.35) 1.18 (1.09–1.28) Ethinylestradiol/Norethindrone 0.035 mg q.d./ 1 mg q.d. 25 mg q.d. 15 ↔ comparison based on historic controls ↔ ↔ Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose 24 0.99 (0.84–1.16) 0.91 (0.78–1.07) N.A. Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose 23 0.15 (0.12–0.19) 0.24 (0.20–0.28) N.A. Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose 24 1.21 (1.06–1.39) 1.13 (1.01–1.27) N.A. Ketoconazole 400 mg q.d. 150 mg q.d. 15 1.30 (1.13–1.48) 1.49 (1.31–1.70) 1.76 (1.57–1.97) Methadone 60–100 mg q.d., individualized dose 25 mg q.d. 12 ↔ ↔ ↔ Omeprazole 20 mg q.d. 150 mg q.d. 16 0.60 (0.48–0.73) 0.60 (0.51–0.71) 0.67 (0.58–0.78) Rifabutin 300 mg q.d. 25 mg q.d. 18 0.69 (0.62–0.76) 0.58 (0.52–0.65) 0.52 (0.46–0.59) Rifabutin 300 mg q.d. 50 mg q.d. 18 1.43 (1.30–1.56) 1.16 (1.06–1.26) 0.93 (0.85–1.01) (reference arm for comparison was 25 mg q.d. rilpivirine administered alone) Rifampin 600 mg q.d. 150 mg q.d. 16 0.31 (0.27–0.36) 0.20 (0.18–0.23) 0.11 (0.10–0.13) Sildenafil 50 mg single dose 75 mg q.d. 16 0.92 (0.85–0.99) 0.98 (0.92–1.05) 1.04 (0.98–1.09) Table 10: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT Coadministered Drug Dose/Schedule N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters With/Without EDURANT (90% CI); No Effect=1.00 Coadministered Drug Rilpivirine C max AUC C min CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 15 0.90 (0.81–1.00) 0.89 (0.81–0.99) 0.89 (0.68–1.16) Lopinavir/ritonavir (soft gel capsule) 400/100 mg b.i.d. 150 mg q.d. 15 0.96 (0.88–1.05) 0.99 (0.89–1.10) 0.89 (0.73–1.08) Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) Didanosine 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine 150 mg q.d. 13 0.96 (0.80–1.14) 1.12 (0.99–1.27) N.A. Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 1.19 (1.06–1.34) 1.23 (1.16–1.31) 1.24 (1.10–1.38) Coadministration With HIV Integrase Strand Transfer Inhibitors Cabotegravir 30 mg q.d. 25 mg q.d. 11 1.05 (0.96–1.15) 1.12 (1.05–1.19) 1.14 (1.04–1.24) Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10 (0.77–1.58) 1.09 (0.81–1.47) 1.27 (1.01–1.60) Coadministration With other Antivirals Simeprevir 150 mg q.d. 25 mg q.d. 21 1.10 (0.97–1.26) 1.06 (0.94–1.19) 0.96 (0.83–1.11) Coadministration With Drugs other than Antiretrovirals Acetaminophen 500 mg single dose 150 mg q.d. 16 0.97 (0.86–1.10) 0.91 (0.86–0.97) N.A. Atorvastatin 40 mg q.d. 150 mg q.d. 16 1.35 (1.08–1.68) 1.04 (0.97–1.12) 0.85 (0.69–1.03) 2-hydroxy-atorvastatin 16 1.58 (1.33–1.87) 1.39 (1.29–1.50) 1.32 (1.10–1.58) 4-hydroxy-atorvastatin 16 1.28 (1.15–1.43) 1.23 (1.13–1.33) N.A. Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 0.98 (0.85–1.13) 1.03 (0.95–1.13) N.A. Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06 (0.97–1.17) 0.98 (0.93–1.04) AUC (0–last) N.A. Ethinylestradiol 0.035 mg q.d. 25 mg q.d. 17 1.17 (1.06–1.30) 1.14 (1.10–1.19) 1.09 (1.03–1.16) Norethindrone 1 mg q.d. 17 0.94 (0.83–1.06) 0.89 (0.84–0.94) 0.99 (0.90–1.08) Ketoconazole 400 mg q.d. 150 mg q.d. 14 0.85 (0.80–0.90) 0.76 (0.70–0.82) 0.34 (0.25–0.46) R(-) methadone 60–100 mg q.d., individualized dose 25 mg q.d. 13 0.86 (0.78–0.95) 0.84 (0.74–0.95) 0.78 (0.67–0.91) S(+) methadone 13 0.87 (0.78–0.97) 0.84 (0.74–0.96) 0.79 (0.67–0.92) Metformin 850 mg single dose 25 mg q.d. 20 1.02 (0.95–1.10) 0.97 (0.90–1.06) N (maximum number of subjects with data) for AUC (0–∞) =15 N.A. Omeprazole 20 mg q.d. 150 mg q.d. 15 0.86 (0.68–1.09) 0.86 (0.76–0.97) N.A. Rifampin 600 mg q.d. 150 mg q.d. 16 1.02 (0.93–1.12) 0.99 (0.92–1.07) N.A. 25-desacetylrifampin 16 1.00 (0.87–1.15) 0.91 (0.77–1.07) N.A. Sildenafil 50 mg single dose 75 mg q.d. 16 0.93 (0.80–1.08) 0.97 (0.87–1.08) N.A. N -desmethyl-sildenafil 16 0.90 (0.80–1.02) 0.92 (0.85–0.99) N.A.

20221102

21

3 DOSAGE FORMS AND STRENGTHS 25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with "TMC" on one side and "25" on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. 25 mg tablets ( 3 )

EDURANT rilpivirine hydrochloride rilpivirine hydrochloride rilpivirine CROSCARMELLOSE SODIUM MAGNESIUM STEARATE LACTOSE MONOHYDRATE POVIDONE K30 POLYSORBATE 20 SILICON DIOXIDE MICROCRYSTALLINE CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) POLYETHYLENE GLYCOL 3000 TITANIUM DIOXIDE TRIACETIN white to off white biconvex TMC;25

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine. In rats, there were no drug related neoplasms at exposures 3 times those observed in humans at the recommended daily dose of 25 mg. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans at the recommended daily dose of 25 mg. Rilpivirine was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. Impairment of Fertility In rat fertility and early embryonic development studies with rilpivirine, no effects on fertility were observed at rilpivirine exposures (AUC) greater than 36 times (male) and 40 times (female) the exposure in humans at the recommended daily dose of 25 mg.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine. In rats, there were no drug related neoplasms at exposures 3 times those observed in humans at the recommended daily dose of 25 mg. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans at the recommended daily dose of 25 mg. Rilpivirine was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. Impairment of Fertility In rat fertility and early embryonic development studies with rilpivirine, no effects on fertility were observed at rilpivirine exposures (AUC) greater than 36 times (male) and 40 times (female) the exposure in humans at the recommended daily dose of 25 mg.

NDA202022

EDURANT

rilpivirine hydrochloride

59676-278

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Mechanism of Action Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ. Antiviral Activity in Cell Culture Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC 50 value for HIV-1 IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC 50 value of 5220 nM (range 2510 to 10830 nM) (920 to 3970 ng/mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC 50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC 50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL). The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc, or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L. In Treatment-Naïve Adult Subjects In the Week 96 pooled resistance analysis of the Phase 3 trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the EDURANT arm compared to the efavirenz arm, and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis subjects in the rilpivirine arm compared to 23% (13/56) in the efavirenz arm. Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 – 621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, T215S/T, or K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz resistance analysis subjects (see Table 11 ). NNRTI- and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤100,000 copies/mL compared to viruses from subjects with baseline viral load of >100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm 3 compared to viruses from subjects with baseline CD4+ cell counts <200 cells/mm 3 : 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions. Table 11: Proportion of Resistance Analysis Subjects Subjects who qualified for resistance analysis. with Frequently Emerging Reverse Transcriptase Substitutions from the Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis C209 and C215 N=1368 EDURANT + BR N=686 Efavirenz + BR N=682 BR=background regimen Subjects who Qualified for Resistance Analysis 15% (98/652) 9% (56/604) Subjects with Evaluable Post-Baseline Resistance Data 87 43 Emerging NNRTI Substitutions V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227 or M230 Any 62% (54/87) 53% (23/43) V90I 13% (11/87) 2% (1/43) K101E/P/T/Q 20% (17/87) 9% (4/43) K103N 1% (1/87) 40% (17/43) E138K/A/Q/G 40% (35/87) 2% (1/43) E138K+ M184I This combination of NNRTI and NRTI substitutions is a subset of those with the E138K. 25% (22/87) 0 V179I/L/D 6% (5/87) 7% (3/43) Y181C/I/S 10% (9/87) 2% (1/43) V189I 8% (7/87) 2% (1/43) H221Y 9% (8/87) 0 Emerging NRTI Substitutions A62V, K65R/N, D67N/G, K70E, L74I, V75I, Y115F, M184I/V, L210F, T215S/T, K219E/R Any 57% (50/87) 30% (13/43) M184I/V 54% (47/87) 26% (11/43) K65R/N 9% (8/87) 5% (2/43) A62V, D67N/G, K70E, Y115F, T215S/T or K219E/R These substitutions emerged in addition to the primary substitutions M184V/I or K65R/N; A62V (n=3), D67N/G (n=3), K70E (n=4), Y115F (n=2), T215S/T (n=1), K219E/R (n=8) in rilpivirine resistance analysis subjects. 21% (18/87) 2% (1/43) Cross-Resistance Site-Directed NNRTI Mutant Virus Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had decreased susceptibility to rilpivirine (fold change range of 3.7 – 554) in 38% and 66% of mutants analyzed, respectively. Treatment-Naïve HIV-1-Infected Adult Subjects Considering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L. Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209 and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine (≥2.5-fold change). Of these, 86% (n=43/50) were resistant to efavirenz (≥3.3-fold change), 90% (n= 45/50) were resistant to etravirine (≥3.2-fold change) and 62% (n=31/50) were resistant to nevirapine (≥6-fold change). In the efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects' viruses were resistant to etravirine and rilpivirine, and 95% (n=20/21) were resistant to nevirapine. Virus from subjects experiencing virologic failure on EDURANT developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class compared to virus from subjects who failed on efavirenz.

PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label 30 Tablets NDC 59676-278-01 EDURANT ® (rilpivirine) tablets 25 mg Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. ALERT: Find out about medicines that should NOT be taken with EDURANT ® from your healthcare provider. Rx only PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label

Indications and Usage ( 1.2 ) 3/2022 Dosage and Administration ( 2.2 ) 3/2022 Warnings and Precautions Fat Redistribution (5.5) Removed 10/22

EDURANT ® is a registered trademark of Johnson & Johnson © 2011 Janssen Products, LP

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Severe Skin and Hypersensitivity Reactions Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking EDURANT and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of more serious reactions such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing a swelling of the face, eyes, lips, mouth, tongue or throat, which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems as it may be a sign of a more serious reaction. Advise patients that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.1) ] . Hepatotoxicity Inform patients that hepatotoxicity has been reported with EDURANT. Inform patients that laboratory monitoring for hepatotoxicity during therapy with EDURANT is recommended, especially for patients with underlying liver disease such as hepatitis B or C virus infection [see Warnings and Precautions (5.2)] . Depressive Disorders Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with EDURANT. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.3) ] . Drug Interactions EDURANT may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4) , Warnings and Precautions (5.4) , and Drug Interactions (7) ] . For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg 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 Dosage and Administration (2.3) ] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when EDURANT is started [see Warnings and Precautions (5.5) ]. Administration Instruction Advise patients to take EDURANT with a meal once a day as prescribed. A protein drink alone does not replace a meal. EDURANT must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose of EDURANT or discontinue therapy with EDURANT without consulting their physician. If the patient misses a dose of EDURANT within 12 hours of the time it is usually taken, advise the patient to take EDURANT with a meal as soon as possible and then take the next dose of EDURANT at the regularly scheduled time. If a patient misses a dose of EDURANT by more than 12 hours, advise the patient to not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of EDURANT at any one time. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2) ] .

14 CLINICAL STUDIES 14.1 Treatment-Naïve Adult Subjects The evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated substitutions (RASs). The Phase 3 trials were identical in design, apart from the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR. In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 12 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms. Table 12: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis) Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials EDURANT + BR N=686 Efavirenz + BR N=682 BR=background regimen Demographic Characteristics Median Age, years (range) 36 (18–78) 36 (19–69) Sex Male 76% 76% Female 24% 24% Race White 61% 60% Black/African American 24% 23% Asian 11% 14% Other 2% 2% Not allowed to ask per local regulations 1% 1% Baseline Disease Characteristics Median Baseline Plasma HIV-1 RNA (range), log 10 copies/mL 5.0 (2–7) 5.0 (3–7) Percentage of Patients with Baseline Plasma Viral Load: ≤100,000 54% 48% >100,000 to ≤500,000 36% 40% >500,000 10% 12% Median Baseline CD4+ Cell Count (range), cells/mm 3 249 (1–888) 260 (1–1137) Percentage of Subjects with: Hepatitis B/C Virus Co-infection 7% 10% Percentage of Patients with the Following Background Regimens: tenofovir disoproxil fumarate plus emtricitabine 80% 80% zidovudine plus lamivudine 15% 15% abacavir plus lamivudine 5% 5% Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 13. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment. Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm 3 experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm 3 . Table 13: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96 EDURANT + BR N=686 Efavirenz + BR N=682 N=total number of subjects per treatment group; BR=background regimen. Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively. HIV-1 RNA <50 copies/mL CI=Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96. 76% 77% HIV-1 RNA ≥50 copies/mL Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. 16% 10% No virologic data at Week 96 window Reasons Discontinued study due to adverse event or death Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. 4% 8% Discontinued study for other reasons and last available HIV-1 RNA <50 copies/mL (or missing) Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 4% 5% Missing data during window but on study <1% <1% HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤100,000 82% 78% >100,000 70% 75% HIV-1 RNA ≥50 copies/mL by Baseline HIV-1 RNA (copies/mL) ≤100,000 9% 8% >100,000 24% 11% HIV-1 RNA <50 copies/mL by CD4+ cell count (cells/mm 3 ) <200 68% 74% ≥200 81% 77% HIV-1 RNA ≥50 copies/mL by CD4+ cell count (cells/mm 3 ) <200 27% 10% ≥200 10% 9% At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm 3 for EDURANT-treated subjects and 219 cells/mm 3 for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials. Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine. Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received ≤2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RASs. At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving EDURANT 25 mg (N=93) compared to subjects receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm 3 in subjects receiving EDURANT 25 mg and 160 cells/mm 3 in subjects receiving efavirenz. At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA <50 copies/mL compared to 57% (51/89) of subjects in the control group. 14.2 Virologically-Suppressed Adults Treated in Combination with Cabotegravir The use of EDURANT in combination with VOCABRIA (cabotegravir) as an oral lead-in and in patients who miss planned injections with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) was evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR [NCT02938520], Trial 201585: ATLAS [NCT2951052]), and one Phase 3b randomized, multicenter, parallel-group, open-label, non-inferiority trial (Trial 207966: ATLAS-2M [NCT03299049]) in subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL). See full prescribing information for VOCABRIA and CABENUVA for additional information. 14.3 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/mm 3 (range: 123 to 983 cells/mm 3 ). 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/mm 3 .

8.5 Geriatric Use Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy.

8.4 Pediatric Use The safety, efficacy and pharmacokinetics of EDURANT were evaluated in a single arm, open-label, Phase 2 trial that enrolled 36 antiretroviral treatment-naïve, HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ] . MOCHA Trial (NCT03497676) in Adolescents The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non comparative study, MOCHA (IMPAACT 2017) [see Adverse Reactions (6.1) ] . Refer to the VOCABRIA and CABENUVA prescribing information for additional information when EDURANT is used in combination with cabotegravir. Safety and effectiveness in pediatric patients less than 12 years of age or weighing less than 35 kg have not been established.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data ) . In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans at the recommended dose of 25 mg once daily (see Data ) . Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required 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 is one 25 mg tablet once daily taken orally with a meal. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Clinical Pharmacology (12.3) ] . Data Human Data Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens. Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum. Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C 0h and AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV–1-infected adults. Animal Data Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the recommended dose of 25 mg daily.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period. ( 2.1 , 8.1 , 12.3 ) Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data ) . In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans at the recommended dose of 25 mg once daily (see Data ) . Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required 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 is one 25 mg tablet once daily taken orally with a meal. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Clinical Pharmacology (12.3) ] . Data Human Data Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens. Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum. Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C 0h and AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV–1-infected adults. Animal Data Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the recommended dose of 25 mg daily. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of rilpivirine in human milk, the effects on a breastfed infant, or the effects on milk production. Rilpivirine is present in rat milk (see Data ) . Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in nursing infants, mothers should not breastfeed if they are receiving EDURANT. Data Animal Data Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on lactation day 7 in the rat pre- and postnatal development study. 8.4 Pediatric Use The safety, efficacy and pharmacokinetics of EDURANT were evaluated in a single arm, open-label, Phase 2 trial that enrolled 36 antiretroviral treatment-naïve, HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.3) ] . MOCHA Trial (NCT03497676) in Adolescents The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non comparative study, MOCHA (IMPAACT 2017) [see Adverse Reactions (6.1) ] . Refer to the VOCABRIA and CABENUVA prescribing information for additional information when EDURANT is used in combination with cabotegravir. Safety and effectiveness in pediatric patients less than 12 years of age or weighing less than 35 kg have not been established. 8.5 Geriatric Use Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment or end-stage renal disease, rilpivirine should be used with caution and with increased monitoring for adverse effects, as rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment No dosage adjustment of EDURANT is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. EDURANT has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING EDURANT ® (rilpivirine) tablets are supplied as white to off-white, film-coated, round, biconvex, 6.4 mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each tablet is debossed with "TMC" on one side and "25" on the other side. EDURANT tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01). Store EDURANT tablets in the original bottle in order to protect from light. Store EDURANT tablets at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP controlled room temperature].

Store EDURANT tablets in the original bottle in order to protect from light. Store EDURANT tablets at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP controlled room temperature].