Drug: Edurant

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]-2,6dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 • 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.

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The following adverse drug reactions (ADRs) are discussed in greater detail in other sections of the package insert:
  • Skin and Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Depressive Disorders [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
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. 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]. 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 1. Selected treatment-emergent laboratory abnormalities are included in Table 2. Table 1: Selected Treatment-Emergent Adverse Drug Reactions of at least Moderate Intensity* (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 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† 5% 4%   Insomnia 3% 4%   Abnormal dreams 2% 4% Skin and Subcutaneous Tissue Disorders   Rash 3% 11% N = total number of subjects per treatment group; BR = background regimen
* Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
† Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 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 Treatment-emergent 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 treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2. Table 2: Selected Treatment-Emergent 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 Increased Creatinine   Grade 1 ≥ 1.1- ≤ 1.3 x ULN 6% 1%   Grade 2 > 1.3- ≤ 1.8 x ULN 1% 1%   Grade 3 > 1.8- ≤ 3.4 x ULN < 1% 0   Grade 4 > 3.4 x ULN 0 < 1% Increased AST   Grade 1 > 1.25- ≤ 2.5 x ULN 16% 19%   Grade 2 > 2.5- ≤ 5.0 x ULN 4% 7%   Grade 3 > 5.0- ≤ 10.0 x ULN 2% 2%   Grade 4 > 10.0 x ULN 1% 1% Increased ALT   Grade 1 > 1.25- ≤ 2.5 x ULN 18% 20%   Grade 2 > 2.5- ≤ 5.0 x ULN 5% 7%   Grade 3 > 5.0- ≤ 10.0 x ULN 1% 2%   Grade 4 > 10.0 x ULN 1% 1% Increased Total Bilirubin   Grade 1 > 1.1- ≤ 1.5 x ULN 5% < 1%   Grade 2 > 1.5- ≤ 2.5 x ULN 3% 1%   Grade 3 > 2.5- ≤ 5.0 x ULN 1% < 1%   Grade 4 > 5.0 x 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% 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. Adrenal Function In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the EDURANT group and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the EDURANT group (+18.4 ± 8.36 nmol/L) than in the efavirenz group (+54.1 ± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. 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*
Mean (95% CI) 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 (mg/dL) Mean (mg/dL) Mean Change† (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change† (mg/dL) 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 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 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. 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) Read the Edurant (rilpivirine tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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The recommended dose of EDURANT is one 25 mg tablet once daily taken orally with a meal [see CLINICAL PHARMACOLOGY]. Rifabutin Co-administration For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) once daily, taken with a meal. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

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[See DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and CLINICAL PHARMACOLOGY] 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]
Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment 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) Other NNRTIs (efavirenz, etravirine, nevirapine) ↑ rilpivirine
↔ delavirdine
↓ rilpivirine
↔ other NNRTIs It is not recommended to co-administer EDURANT with delavirdine and 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) unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) ↑ rilpivirine
↔ boosted PI
↑ rilpivirine
↔ unboosted 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.
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)
↓ rilpivirine (concomitant intake) 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. 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. H2 -Receptor Antagonists:
cimetidine
famotidine*†
nizatidine
ranitidine ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
↓ rilpivirine (famotidine taken 2 hours before 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. 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. ↑ = 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. 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]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir 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]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. Read the Edurant Drug Interactions Center for a complete guide to possible interactions Learn More »

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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 adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. This indication is based on safety and efficacy analyses through 96 weeks from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects [see Clinical Studies]. The following points should be considered when initiating therapy with EDURANT:
  • 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].
  • Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm³experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm³ [see Clinical Studies].
  • The observed virologic failure rate in EDURANT treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [see Microbiology].
  • More subjects treated with EDURANT developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz [see Microbiology].
EDURANT is not recommended for patients less than 18 years of age [see Use In Specific Populations].

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EDURANT should not be co-administered with the following drugs, as 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 and CLINICAL PHARMACOLOGY]:
  • the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
  • the antimycobacterials rifampin, rifapentine
  • proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
  • the glucocorticoid systemic dexamethasone (more than a single dose)
  • St John's wort (Hypericum perforatum)
Last reviewed on RxList: 5/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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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.

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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. 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]. Manufactured by: Janssen-Cilag SpA, Latina, Italy. Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560. Issued May 2015Last reviewed on RxList: 5/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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Drug Interactions Caution should be given to prescribing EDURANT with drugs that may reduce the exposure of rilpivirine [see CONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]. In 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 DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. Skin And Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT. No grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see ADVERSE REACTIONS]. Discontinue EDURANT immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated. Depressive Disorders The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with EDURANT. During the Phase 3 trials (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among EDURANT (n = 686) or efavirenz (n = 682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both EDURANT and efavirenz. The incidence of discontinuation due to depressive disorders among EDURANT or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the EDURANT arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to EDURANT, and if so, to determine whether the risks of continued therapy outweigh the benefits. Hepatotoxicity Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with EDURANT is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EDURANT. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with EDURANT from your healthcare provider. A Patient Package Insert for EDURANT is available for patient information. Patients should be informed that EDURANT is not a cure for HIV infection. Patients must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using EDURANT. Female patients should be advised not to breastfeed because it is unknown if EDURANT can be passed to the baby in the breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Patients should be advised 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. Patients should not 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, the patient should 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, the patient should 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. EDURANT may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort. EDURANT should not be co-administered with the following drugs, as 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: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the antimycobacterials rifampin, rifapentine; proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; the glucocorticoid systemic dexamethasone (more than a single dose); or St. John's wort (Hypericum perforatum). For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg once daily, taken with a meal. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal. Patients should be informed that skin reactions ranging from mild to severe, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported with rilpivirine-containing regimens. Instruct patients to immediately stop taking EDURANT tablets and seek medical attention if they develop a rash associated with any of the following symptoms: 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. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated. Patients should be informed that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with EDURANT. If they experience depressive symptoms, they should seek immediate medical evaluation. Patients should be informed that hepatotoxicity has been reported with EDURANT. Patients should also be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including EDURANT, and that the cause and long-term health effects of these conditions are not known at this time. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis and Mutagenesis Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60 and 160 mg/kg/day were administered to mice and doses of 40, 200, 500 and 1500 mg/kg/day were administered to rats. In rats, there were no drug related neoplasms. 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 doses in the carcinogenicity studies, the systemic exposures (based on AUC) to rilpivirine were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg q.d.). Rilpivirine has tested negative in the absence and presence of a metabolic activation system in the in vitro Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay. Rilpivirine did not induce chromosomal damage in the in vivo micronucleus test in mice. Impairment of Fertility No human data on the effect of rilpivirine on fertility are available. In a study conducted in rats, there were no effects on mating or fertility with rilpivirine up to 400 mg/kg/day, a dose of rilpivirine that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily. 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 Safety and effectiveness in pediatric patients 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]. 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]. Last reviewed on RxList: 5/19/2015
This monograph has been modified to include the generic and brand name in many instances.

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