obligations [1%:<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 3. The clinical benefit of these findings has not been demonstrated. Table 3: Lipid Values, Mean Change from Baseline * 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 † (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change † (mg/dL) N = number of subjects per treatment group; BR = background regimen * Excludes subjects who received lipid lowering agents during the treatment period † The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values 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: 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. 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) 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. Co-administration 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. Co-administration of Edurant and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration 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 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Edurant and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Edurant are also included in Table 4. Table 4: 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 * The interaction between Edurant and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. † This interaction study has been performed with a dose higher than the recommended dose for Edurant assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of Edurant 25 mg once daily. HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) didanosine * † ↔ rilpivirine ↔ didanosine No dose adjustment is required when Edurant is co-administered 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: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTI (delavirdine) rilpivirine ↔ delavirdine It is not recommended to co-administer Edurant with delavirdine and other NNRTIs. Other NNRTIs (efavirenz, etravirine, nevirapine) ↓ rilpivirine ↔ other NNRTIs HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration 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 co-administered 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 co-administered 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 co-administered 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 co-administered PIs. Other Agents 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 co-administration 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) Antimycobacterials: rifabutin * ↓ rilpivirine Concomitant use of Edurant with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of Edurant with rifabutin, the Edurant dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the Edurant dose should be decreased to 25 mg once daily. Azole Antifungal Agents : fluconazole itraconazole ketoconazole * † 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 co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with Edurant. H 2 -Receptor Antagonists : cimetidine famotidine * † nizatidine ranitidine ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) The combination of Edurant and H 2 -receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H 2 -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) 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 co-administration of methadone with Edurant. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. In addition to the drugs included in Table 4, 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 co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine. 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, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology (12.2) ] . Edurant should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B No adequate and well-controlled or pharmacokinetic studies of Edurant use in pregnant women have been conducted. Studies in animals have shown no evidence of relevant embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Edurant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to Edurant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Edurant . 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 Adverse Reactions (6.2) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] . Please see Dosage and Administration (2) for dosing recommendations for pediatric patients 12 years of age and older. Safety and effectiveness in pediatric patients less than 12 years of age have not been established. 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. Hepatic Impairment No dose 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) ] . 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) ] . 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. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance. Edurant 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. Edurant - Clinical Pharmacology Mechanism of Action Rilpivirine is an antiviral drug [see Microbiology (12.4) ] . 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 supratherapeutic doses of 75 mg once daily and 300 mg once daily of 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 (5.1) ] . 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 5: 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 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. No dose adjustment is required in patients with mild or moderate hepatic impairment. Edurant has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.6) ] . Hepatitis B and/or Hepatitis C Virus Co-infection Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine. 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 (8.7) ] . Gender No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women. Race Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine. 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 6: 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 less than 12 years of age have not been established [see Use in Specific Populations (8.4) ] . 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. Co-administration of Edurant and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of Edurant and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration 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 q.d. 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 co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the C max , AUC, and C min values of rilpivirine are summarized in Table 7 (effect of other drugs on Edurant). The effect of co-administration of Edurant on the C max , AUC, and C min values of other drugs are summarized in Table 8 (effect of Edurant on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7) .] Table 7: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Co-administered Drugs Co-administered Drug Dose/Schedule N Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Co-administered Drug (90% CI); No Effect = 1.00 Co-administered 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 * 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 co-administered drug. † comparison based on historic controls Co-Administration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. * 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) Co-Administration 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) Co-Administration With HIV Integrase Strand Transfer Inhibitors 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) Co-Administration 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) Co-Administration 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 ↔ † ↔ † ↔ † 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., individualised 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 8: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Edurant Co-administered Drug Dose/Schedule N Mean Ratio of Co-administered Drug Pharmacokinetic Parameters With/Without Edurant (90% CI); No Effect = 1.00 Co-administered 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 * 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 co-administered drug. † AUC (0 last) ‡ N (maximum number of subjects with data) for AUC (0 ) = 15 Co-Administration With HIV Protease Inhibitors (PIs) Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d. * 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) Co-Administration 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) Co-Administration With HIV Integrase Strand Transfer Inhibitors 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) Co-Administration 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) Co-Administration With Drugs other than Antiretrovirals Acetami liable to
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