Data from FDA - Curated by EPG Health - Last updated 08 June 2018

Indication(s)

1 INDICATIONS AND USAGE 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. 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). 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, 14) 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)].

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Advisory information

contraindications
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)
Adverse reactions
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) 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 IntensityIntensities 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 disordersIncludes 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 BaselineExcludes 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 ChangeThe 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. 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 (14.2)]. The median duration of exposure was 63.5 weeks. There were no patients who discontinued treatment due to ADRs. No new ADRs were identified compared to those seen in adults. ADRs were reported in nineteen pediatric subjects (52.8%). Most ADRs were Grade 1 or 2. The most common ADRs reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3), vomiting (5.6%) and rash (5.6%). Observed laboratory abnormalities were comparable to those in adults. Adrenal Function In trial TMC278 C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL. Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level < 18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known. 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)

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION One tablet taken once daily with a meal. (2.1) 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 (2.2) 2.1 Recommended Dosage 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 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)].
Use in special populations
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 evidence of adverse developmental outcomes was observed following oral administration of rilpivirine (see Data). During organogenesis, systemic exposures (AUC) to rilpivirine were up to 15 (rats) and 70 (rabbits) times the exposure in humans at the recommended daily dose of rilpivirine. In the rat pre- and post-natal developmental study, maternal systemic exposure (AUC) was approximately 63 times the exposure at the recommended daily dose of rilpivirine. 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 390 exposures to rilpivirine during pregnancy resulting in live births, (including over 247 exposed during first trimester), 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 1.2% (95% CI: 0.3% to 3.5%) and 1.4% (95% CI: 0.2% to 5.0%) 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 (C0h 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/postnatal development study with rilpivirine, where rats were administered up to 400 mg per kg per day through lactation, no significant adverse effects directly related to drug were noted in the offspring. 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 In animals, no studies have been conducted to assess the excretion of rilpivirine into milk directly; however, rilpivirine was present in plasma of rat pups exposed through the milk of lactating rats (dosed up to 400 mg per kg per day). 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 (6.2), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. 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)].

Interactions

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: rifabutinThe 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: clarithromycin erythromycin telithromycin ↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. 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, 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.

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Category Value
Authorisation number NDA202022
Agency product number 212WAX8KDD
Orphan designation No
Product NDC 59676-278
Date Last Revised 02-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1102277
Storage and handling 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].
Marketing authorisation holder Janssen Products, LP