Emtricitabine, Rilpivirine Hydrochloride And Tenofovir Disoproxil Fumarate

FDA Drug Information • Also known as: Complera

Brand Names: Complera
Dosage Form: TABLET, FILM COATED
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

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) ] . WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients coinfected with HIV-1 and HBV who 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. ( 5.1 )

Description

11 DESCRIPTION COMPLERA is a fixed-dose combination tablet containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. COMPLERA tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, pregelatinized starch. The tablets are film coated with a coating material containing FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin. Emtricitabine: The chemical name of FTC is 5-fluoro-1-[(2 R ,5 S )-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: FTC is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C. Chemical Structure Rilpivirine: RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C 22 H 18 N 6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is a white to almost...

What Is Emtricitabine, Rilpivirine Hydrochloride And Tenofovir Disoproxil Fumarate Used For?

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) ] . COMPLERA, 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 COMPLERA. ( 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 ) 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) ] .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating COMPLERA, test for hepatitis B virus infection. Prior to initiation 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. ( 2.1 ) Recommended dosage in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. ( 2.2 ) For pregnant patients who are already on COMPLERA prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. ( 2.3 ) Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. ( 2.4 ) Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration. ( 2.5 , 7.6 , 12.3 ) 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...

Side Effects (Adverse Reactions)

6 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 2–4) 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 Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 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 1368 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 Frequencies of adverse reactions are based on all Grades 2–4 treatment-emergent adverse events assessed to be related to study drug. (Grades 2–4) Reported in ≥2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) Preferred Term RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2% 2% Headache...

Drug Interactions

7 DRUG INTERACTIONS COMPLERA is 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 ) 7.1 Not Recommended with Other Antiretroviral Medications Because COMPLERA is 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 COMPLERA. Drug interaction studies were conducted with the components of COMPLERA (FTC, RPV, and TDF as single agents) or with COMPLERA as a combination product [see Dosage and Administration (2) , Contraindications (4) , and Clinical Pharmacology (12.3) ] . 7.2 Drugs 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. 7.3 Drugs 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) ] . 7.4 Drugs 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 COMPLERA 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) ] . 7.5 QT 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...

Contraindications

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 COMPLERA is contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to COMPLERA. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to COMPLERA 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 15–20%. 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 COMPLERA 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 COMPLERA and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data ) ....

Overdosage

10 OVERDOSAGE If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with COMPLERA 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. Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis. Rilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV. Tenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING COMPLERA tablets are purplish pink, capsule shaped, film coated, debossed with "GSI" on one side, and plain faced on the other side. Each bottle contains 30 tablets (NDC 61958-1101-1), a silica gel desiccant, and a polyester fiber coil, and is closed with a child-resistant closure. Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) [See USP Controlled Room Temperature]. Keep container tightly closed. Dispense only in original container.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.