COMPLERA is indicated as a complete regimen for the treatment of HIV-1 infection:
- In patients 12 years and older who have no antiretroviral (ARV) treatment history with HIV-1 RNA ≤100,000 copies/mL
- To replace the current ARV regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months on their first or second ARV regimen with no history of treatment failure and no known resistance to any component of COMPLERA. Efficacy was established in patients who were stable on a ritonavir-boosted, protease inhibitor-containing regimen. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.
Prescribing considerations in patients with no ARV treatment history: Virologic failure (HIV-1 RNA ≥50 copies/mL) was higher in subjects with baseline HIV-1 RNA >100,000 copies/mL and in subjects with baseline CD4 cell count <200 cells/mm3 (regardless of baseline HIV-1 RNA levels). Compared to efavirenz, virologic failure in rilpivirine-treated subjects conferred a higher rate of overall resistance and cross-resistance to the NNRTI class and more subjects developed tenofovir- and lamivudine/emtricitabine-associated resistance.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of COMPLERA, in combination with other antiretrovirals.
- COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, which are components of COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
- Coadministration: COMPLERA should not be coadministered with drugs that induce CYP3A or increase gastric pH as this may lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class. Use of the following drugs with COMPLERA is contraindicated: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors (e.g., esomeprazole, lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole), systemic dexamethasone (>1 dose) and St. John's wort.
WARNINGS AND PRECAUTIONS
- Skin and hypersensitivity reactions: Severe skin and hypersensitivity reactions have been reported with the use of rilpivirine-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). In clinical trials of rilpivirine + FTC/TDF, most rashes were Grade 1 or 2 and occurred in the first 4-6 weeks of treatment; Grades 2-4 rash occurred in 1% of subjects. Discontinue COMPLERA immediately for severe skin or hypersensitivity reactions, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Monitor clinical status and laboratory parameters, and initiate appropriate therapy.
- New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, additionally monitor serum phosphorus, urine glucose, and urine protein. Do not administer COMPLERA in patients with CrCl <50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high-dose or multiple NSAIDs in patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function.
- New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF.
- In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy.
- In patients at risk for renal dysfunction, additionally monitor serum phosphorus, urine glucose, and urine protein.
- Do not administer COMPLERA in patients with CrCl <50 mL/min.
- Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients.
- Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function.
- Drug interactions: Use COMPLERA with caution when given with drugs that may reduce the exposure of rilpivirine or when coadministered with a drug with known risk of Torsades de Pointes. Supratherapeutic doses of rilpivirine have been shown to prolong the QTc interval of the electrocardiogram in healthy subjects.
- Depressive disorders: Evaluate patients with severe depressive symptoms to assess if symptoms are due to COMPLERA and if the risks of continued treatment outweigh the benefits. In adult clinical trials (N=686), the incidence of depressive disorders was 9%, Grades 3-4 depressive disorders was 1%, and discontinuation due to depressive disorders was 1%; and suicidal ideation and suicide attempt was reported in 4 and 2 subjects, respectively. In a pediatric (age 12 to <18 years) clinical trial (N=36), the incidence of depressive disorders was 19% and Grades 3-4 depressive disorders was 6%; suicidal ideation and suicide attempt were reported in 1 subject.
- Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity in adults without pre-existing hepatic disease or other identifiable risk factors. Patients with underlying hepatitis B or C, or those with marked elevations in liver-associated tests may be at increased risk. Appropriate laboratory testing and monitoring before and during therapy is recommended in patients with underlying hepatic disease or in patients with marked elevations in liver-associated tests prior to treatment initiation; consider testing and monitoring in patients without pre-existing hepatic dysfunction or other risk factors.
- Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in adult and pediatric patients treated with tenofovir DF. In clinical trials conducted in pediatric subjects, the total body BMD gain was less in tenofovir DF-treated subjects as compared to the control group. Consider monitoring BMD in adult and pediatric patients with a history of pathologic fracture or risk factors for bone loss.
- Antiviral products: COMPLERA is a complete regimen for the treatment of HIV-1 infection. Do not coadminister with other antiretrovirals including products containing any of the same active components (unless needed for dose adjustment); products containing lamivudine; or with adefovir dipivoxil.
- Fat redistribution and accumulation has been observed in patients receiving ARV therapy.
- Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable times to onset, has been reported.
- In adult clinical studies: Most common adverse reactions (incidence ≥2%, Grades 2-4) in adults with no ARV treatment history were depressive disorders (2%), insomnia (2%) and headache (2%). No new adverse reactions to COMPLERA were identified in stable, virologically suppressed patients switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% after switching to COMPLERA.
- In a pediatric clinical study: Most common adverse reactions (reported by ≥2 patients, all Grades) in patients 12 to <18 years with no ARV treatment history were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%), and rash (6%).
- CYP3A inducers: Drugs that induce CYP3A may decrease rilpivirine plasma concentrations, which may lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class.
- CYP3A inhibitors: Drugs that inhibit CYP3A may increase rilpivirine plasma concentrations.
- Drugs increasing gastric pH may significantly decrease rilpivirine plasma concentrations and lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class.
- Use of proton pump inhibitors with COMPLERA is contraindicated.
- Antacids should be administered ≥2 hours before or ≥4 hours after COMPLERA.
- H2-receptor antagonists should be administered ≥12 hours before or ≥4 hours after COMPLERA.
- Drugs affecting renal function: Coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir.
- Prescribing information: Consult the full Prescribing Information for COMPLERA for more information on potentially significant drug interactions, including clinical comments.
PREGNANCY AND BREASTFEEDING
- Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.
- Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed.
DOSAGE AND ADMINISTRATION
- Dosage: Patients 12 years and older (≥35 kg): 1 tablet taken orally once daily with food.
- Renal impairment: Do not use in patients requiring dose reduction, including patients with estimated CrCl <50 mL/min.
- Rifabutin coadministration: Additional rilpivirine 25 mg taken once daily with a meal is recommended.
View full Prescribing Information, including BOXED WARNING >
- COMPLERA [package insert]. Foster City, CA; Gilead Sciences, Inc; 2016.
- Molina J-M, Cahn P, Grinsztejn B, et al; for ECHO Study Group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246.
- Cohen CJ, Andrade-Villanueva J, Clotet B, et al; for THRIVE Study Group. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229-237.
- Palella F, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA suppressed participants. AIDS. 2014;28(3):335-344.
- Data on file, Gilead Sciences, Inc.
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©2016 Gilead Sciences, Inc. All rights reserved. CPAP0302 04/16