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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.

CONTRAINDICATIONS

• 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

• 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 (ECG) in healthy subjects.
• Depressive disorders: The incidence of depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) reported in clinical trials (N=686) was 9% (most were mild or moderate in severity); and Grades 3 and 4 depressive disorders (regardless of causality) was 1%. Suicidal ideation was reported in 4 subjects and suicide attempt was reported in 2 subjects. Patients with severe depressive symptoms should seek immediate medical evaluation and the risks of continued therapy should be determined.
• Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity in patients 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 patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered.
• 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.

ADVERSE REACTIONS

• In adults with no ARV treatment history: Common adverse reactions reported in clinical studies (incidence ≥2%, Grades 2-4) were depressive disorders (2%), insomnia (2%) and headache (2%).
• In virologically suppressed adults: No new types of 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.

DRUG INTERACTIONS

• 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 benefits 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

Adults: One 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.

INDICATION

COMPLERA is indicated as a complete regimen for the treatment of HIV-1 infection in adults with no ARV treatment history and with HIV-1 RNA ≤100,000 copies/mL at the start of therapy; and in certain virologically suppressed (HIV-1 RNA <50 copies/mL) adults on a stable ARV regimen at the start of therapy to replace their current regimen, efficacy was established in patients who were virologically suppressed on a stable 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. COMPLERA is not recommended for patients <18 years of age.

• Prescribing considerations in adults 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.
• Prescribing considerations in virologically suppressed adults: Patients must have no history of virologic failure, be stably suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months prior to switching therapy, currently be on their first or second ARV regimen prior to switching therapy, and have no current or past history of resistance to any component of COMPLERA.

View full Prescribing Information, including BOXED WARNING