Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:
as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy or
to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets [see Microbiology (12.4) and Clinical Studies (14) ]. Limitations of Use:
More rilpivirine-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 rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14) ]. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, a combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV-1 infection in patients weighing at least 35 kg (1) as initial therapy in those with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, or (2) or to replace a stable antiretroviral regiment in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 1 , 14 ) Limitations of Use:
More rilpivirine-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 rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1 , 14 )
Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets or to the class of NNRTIs [see Warnings and Precautions (5.7) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]:
Glucocorticoid (systemic): dexamethasone (more than a single-dose)
Herbal Products: St John’s wort (Hypericum perforatum)
Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 4 )
Warnings and precautions
Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. ( 5.2 )
Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. ( 5.3 )
Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.4 )
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.5 )
Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.6 )
Concomitant use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. ( 5.7 )
Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.8 )
Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.9 )
5.1Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
Test all patients with HIV-1 for the presence of chronic hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1) ]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
5.2Skin 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 RPV-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 1% of subjects receiving RPV plus FTC/TDF.
Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2 )]. Discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets 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.
5.3Hepatotoxicity
Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
5.4Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits.
During the Phase 3 trials in adults (N=1,368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV (n=686) or efavirenz (EFV, n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1% for both RPV and EFV. The incidence of discontinuation due to depressive disorders among RPV or EFV 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 RPV arm. During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving RPV through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36).
None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
5.5New Onset or Worsening Renal Impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2) ] . Prior to initiation of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.
In patients with chronic kidney disease, also assess serum phosphorus. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.4) ]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in H
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. ( 7.1 )
Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.7 , 7 )
7.1Not Recommended with Other Antiretroviral Medications
Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided. This section describes clinically relevant drug interactions with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Drug interaction studies were conducted with the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (FTC, RPV, and TDF as single agents) or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product [see Dosage and Administration (2) , Contraindications (4) , and Clinical Pharmacology (12.3) ].
7.2Drugs Inducing or Inhibiting CYP3A Enzymes
Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4) , Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3) ]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs.
Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.
7.3Drugs Increasing
Gastric pH Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H 2 -receptor antagonists requires staggered administration [see Contraindications (4) and Clinical Pharmacology (12.3) ].
7.4Drugs Affecting Renal Function Because FTC
and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.5) ].
7.5QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between RPV 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 doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2) ].
Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes.
7.6Significant Drug Interactions
Important drug interaction information for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product, or are potential drug interactions [see Clinical Pharmacology (12.3) , Tables 9 to 14].
For list of contraindicated drugs, [see Contraindications (4) ]. Table 4 Significant a Drug Interactions a. This table is not all inclusive. b. Increase = ↑; Decrease = ↓; No Effect = ↔ c. The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. d. This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug.
The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. Concomitant Drug Class: Drug Name Effect on Concentration b Clinical Comment Antacids: antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate) ↔ RPV (antacids taken at least 2 hours before or at least 4 hours after RPV) ↓ RPV (concomitant intake) Administer antacids at least 2 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Antimycobacterials: rifampin rifapentine rifabutin ↓ RPV ↓ RPV c Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV c,d ↓ ketoconazole c,d No dose adjustment is required when emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ↑ tenofovir c Patients receiving emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF.
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data) .
In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3) ]. The rate of miscarriage for individual drugs 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%. Based on the experience of HIV-1-infected pregnant individuals who completed a clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on a stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL).
Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely [see Data and Clinical Pharmacology (12.3) ]. In animal studies, no adverse developmental effects were observed when the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data).
Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Data Human Data Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.
Rilpivirine: RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects on an RPV-based regimen during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6 to 12 weeks after delivery) and pregnancy outcomes are missing for six subjects.
The exposure (C 0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period [see Clinical Pharmacology (12.3) ]. One subject discontinued the trial following fetal death 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 to 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 available HIV test results, all were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum (all 10 infants received prophylactic treatment with zidovudine). RPV was well tolerated during pregnancy and postpartum.
There were no new safety findings compared with the known safety profile of RPV in HIV-1-infected adults. Based on prospective reports to the APR of exposures to RPV-containing regimens during pregnancy (including over 290 exposed during first trimester and over 160 exposed in the second/third trimester), there was no significant increase in overall risk of major birth defects with RPV compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
The prevalence of major birth defects in live births was 1.0% (95% CI: 0.2% to 2.9%) and 1.2% (95% CI: 0.2% to 4.4%) following first and second/third trimester exposure, respectively, to RPV-containing regimens. Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 3,500 exposed in the first trimester and over 1,500 exposed in the second/third trimester), there was no increase in overall risk of major birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF-containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens. Animal Data Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively).
No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the off spring exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.
Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/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
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Adverse reactions
The following adverse reactions are discussed in other sections of the labeling:
Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ].
Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2) ].
Hepatotoxicity [see Warnings and Precautions (5.3) ].
Depressive Disorders [see Warnings and Precautions (5.4) ].
New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5) ].
Bone Loss and Mineralization Defects [see Warnings and Precautions (5.6) ].
Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.8) ].
Immune Reconstitution Syndrome [see Warnings and Precautions (5.9) ].
Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2 to 4) are depressive disorders, insomnia, and headache. ( 6.1 )
Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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 practice. Adverse Reactions from Clinical Trials Experience in Adult Subjects In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History Studies C209 and C215 The safety assessment of RPV, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1,368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects.
A total of 686 subjects received RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen [see Clinical Studies (14) ]. The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse reactions observed at Week 96 in subjects who received RPV or EFV + FTC/TDF as background regimen are shown in Table 1.
No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant). The proportion of subjects who discontinued treatment with RPV or EFV + FTC/TDF due to adverse reactions, regardless of severity, was 2% and 5%, respectively.
The most common adverse reactions leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the RPV + FTC/TDF arm and 12 (2.2%) subjects in the EFV + FTC/TDF arm. Rash led to discontinuation in 1 (0.2%) subject in the RPV + FTC/TDF arm and 10 (1.8%) subjects in the EFV + FTC/TDF arm. Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are shown in Table 1.
Table 1 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) a. Frequencies of adverse reactions are based on all Grades 2 to 4 treatment-emergent adverse events assessed to be related to study drug. b. Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.
Preferred Term RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 Depressive disorders b Headache Insomnia Abnormal dreams Dizziness Nausea Rash 2% 2% 2% 1% 1% 1% 1% 2% 2% 2% 3% 7% 2% 5% Rilpivirine: Adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with RPV plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.
In Virologically Suppressed HIV-1-Infected Adult Subjects No new adverse reactions to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were identified in stable, virologically suppressed subjects switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of FTC and TDF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving FTC or TDF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with RPV + FTC/TDF or EFV + FTC/TDF in studies C209 and C215 with selected laboratory abnormalities (Grades 1 to 4), representing worst-grade toxicity, is presented in Table 2.
Table 2 Selected Laboratory Abnormalities (Grades 1 to 4) Reported in Adult Subjects Who Received RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) N=number of subjects per treatment group ULN=Upper limit of normal value. Note: Percentages were calculated versus the number of subjects in ITT population with FTC + TDF as background regimen. Laboratory Parameter Abnormality DAIDS Toxicity Range RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 BIOCHEMISTRY Increased Creatinine Grade 1 1.1 to 1.3 x ULN 6% 1% Grade 2 >1.3 to 1.8 x ULN 1% 1% Grade 3 >1.8 to 3.4 x ULN <1% 0 Grade 4 >3.4 x ULN 0 <1% Increased AST Grade 1 1.25 to 2.5 x ULN 16% 19% Grade 2 >2.5 to 5.0 x ULN 4% 7% Grade 3 >5.0 to 10.0 x ULN 2% 3% Grade 4 >10.0 x ULN 1% 1% Increased ALT Grade 1 1.25 to 2.5 x ULN 19% 22% Grade 2 >2.5 to 5.0 x ULN 5% 7% Grade 3 >5.0 to 10.0 x ULN 1% 2% Grade 4 >10.0 x ULN 1% 1% Increased Total Bilirubin Grade 1 1.1 to 1.5 x ULN 6% <1% Grade 2 >1.5 to 2.5 x ULN 3% 1% Grade 3 >2.5 to 5.0 x ULN 1% <1% Increased Total Cholesterol (fasted) Grade 1 200 to 239 mg/dL 14% 31% Grade 2 240 to 300 mg/dL 6% 18% Grade 3 >300 mg/dL <1% 2% Increased LDL Cholesterol (fasted) Grade 1 130 to 159 mg/dL 13% 28% Grade 2 160 to 190 mg/dL 5% 13% Grade 3 >190 mg/dL 1% 4% Increased Triglycerides (fasted) Grade 2 500 to 750 mg/dL 1% 2% Grade 3 751 to 1,200 mg/dL 1% 2% Grade 4 >1,200 mg/dL 0 1% Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with F
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate
Active substance
emtricitabine
Pharmacologic class
Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor
H 2 -Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ RPV c,d (famotidine taken 12 hours before RPV or 4 hours after RPV) ↓ RPV c,d (famotidine taken 2 hours before RPV) Administer H 2 -receptor antagonists at least 12 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Herbal Products: St John’s wort ( Hypericum perforatum ) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered. Narcotic Analgesics : methadone ↓ R(-) methadone c ↓ S(+) methadone c ↔ RPV c ↔ methadone c (when used with tenofovir) No dose adjustments are required when initiating coadministration of methadone with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.
However, clinical monitoring is recommended as methadone maintenance therapy may
