COMPLERA

COMPLERA- emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate tablet, film coated
Gilead Sciences, Inc.

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA.

Closely monitor hepatic function 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 [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

COMPLERA® is 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 COMPLERA [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)].

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation and During Treatment with COMPLERA

Prior to or when initiating COMPLERA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation of COMPLERA, and during treatment with COMPLERA, 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 [see Warnings and Precautions (5.5)].

2.2 Recommended Dosage

COMPLERA is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of COMPLERA in adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with food [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

2.3 Recommended Dosage During Pregnancy

For pregnant patients who are already on COMPLERA prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of COMPLERA taken once daily may be continued. Lower exposures of rilpivirine, a component of COMPLERA, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

2.4 Not Recommended in Patients with Moderate or Severe Renal Impairment

COMPLERA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].

2.5 Recommended Dosage with Rifabutin Coadministration

If COMPLERA is coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant®) with COMPLERA once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Each COMPLERA tablet contains 200 mg of emtricitabine (FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine [RPV]), and 300 mg of tenofovir disoproxil fumarate (TDF, equivalent to 245 mg of tenofovir disoproxil).

The tablets are purplish pink, capsule shaped, film coated, debossed with “GSI” on one side, and plain faced on the other side.

4 CONTRAINDICATIONS

COMPLERA is contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [see Warnings and Precautions (5.7), Drug Interactions (7), and Clinical Pharmacology (12.3)]:

  • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
  • Antimycobacterials: rifampin, rifapentine
  • 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

5 WARNINGS AND PRECAUTIONS

5.1 Severe 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 COMPLERA. Patients coinfected with HIV-1 and HBV who discontinue COMPLERA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with COMPLERA. 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.

5.2 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 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 COMPLERA 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.

5.3 Hepatotoxicity

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 COMPLERA. 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 COMPLERA is 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.

5.4 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 RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

During the Phase 3 trials in adults (N=1368) 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.

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