Dosing and uses of Complera (emtricitabine/rilpivirine/tenofovir DF)
Adult dosage forms and strengths
emtricitabine/rilpivirine/tenofovir DF (ie, tenofovir disoproxil fumarate)
tablet
- 200mg/25mg/300mg
HIV Infection
Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults with HIV-1 RNA <100,000 copies/mL, and in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) patients on a stable ART regimen at start of therapy in order to replace their current ART regimen
Combination consists of 2 NRTIs (ie, emtricitabine and tenofovir) and 1 NNRTI (ie, rilpivirine)
Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults
1 tablet (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir 300 mg) PO qDay with a meaL
Initiation considerations
- More patients treated with rilpivirine who had >100,000 copies/mL HIV-1 RNA at the start of therapy experienced virologic failure compared with those with <100,000 copies/mL
- Observed virologic failure rate in rilpivirine-treated patients conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
- More patients treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz
Dosage modifications
Renal impairment
- CrCl ≥50 mL/min: Dose adjustment not necessary
- CrCl <50 mL/min: Do not use
Dosing Considerations
Initiating in ART-naive patients
- More patients treated with rilpivirine who had >100,000 copies/mL HIV-1 RNA at the start of therapy experienced virologic failure compared with those with <100,000 copies/mL
- Observed virologic failure rate in rilpivirine-treated patients conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
- More patients treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz
Replacing current ART regimen in virologically-suppressed adults
- Patients should:
- Have no history of virologic failure
- Have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months before switching therapy
- Currently be on their 1st or 2nd ART regimen before switching therapy
- Have no current or past history of resistance to emtricitabine/rilpivirine/tenofovir
Pediatric dosage forms and strengths
emtricitabine/rilpivirine/tenofovir DF (ie, tenofovir disoproxil fumarate)
tablet
- 200mg/25mg/300mg
HIV Infection
Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults with HIV-1 RNA ≤100,000 copies/mL, and in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) patients on a stable ART regimen at start of therapy in order to replace their current ART regimen
Combination consists of 2 NRTIs (ie, emtricitabine and tenofovir) and 1 NNRTI (ie, rilpivirine)
Indicated as complete regimen for treatment of HIV-1 infection in treatment-naïve adults and adolescents aged ≥12 yr
≥12 years and weight ≥35 kg: 1 tablet (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir 300 mg) PO qDay with a meaL
Initiation considerations
- More patients treated with rilpivirine who had >100,000 copies/mL HIV-1 RNA at the start of therapy experienced virologic failure compared with those with <100,000 copies/mL
- Observed virologic failure rate in rilpivirine-treated patients conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
- More patients treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz
Dosage modifications
Renal impairment
- CrCl ≥50 mL/min: Dose adjustment not necessary
- CrCl <50 mL/min: Do not use
Dosing Considerations
Initiating in ART-naive patients
- More patients treated with rilpivirine who had >100,000 copies/mL HIV-1 RNA at the start of therapy experienced virologic failure compared with those with <100,000 copies/mL
- Observed virologic failure rate in rilpivirine-treated patients conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
- More patients treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz
Replacing current ART regimen in virologically-suppressed adults
- Patients should:
- Have no history of virologic failure
- Have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months before switching therapy
- Currently be on their 1st or 2nd ART regimen before switching therapy
- Have no current or past history of resistance to emtricitabine/rilpivirine/tenofovir
Complera (emtricitabine/rilpivirine/tenofovir DF) adverse (side) effects
>10% (rilpivirine)
Increased ALT (Grade 1: 16%)
Increased AST (Grade 1: 13%)
Increased total cholesterol (Grade 1: 13%)
Increased LDL cholesterol (Grade 1: 11%)
>10% (emtricitabine and tenofovir)
Diarrhea
Nausea
Fatigue
Headache
Dizziness
Depression
Insomnia
Abnormal dreams
Rash
1-10% (rilpivirine)
Increased creatinine (5%)
Increased total bilirubin (Grade 1: 5%)
Headache (2%)
Insomnia (2%)
Dizziness (1%)
Nausea (1%)
Depressive disorder (1%)
Abnormal dreams (1%)
Rash (1%)
1-10% (emtricitabine or tenofovir)
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
Rhinitis
Skin discoloration (hyperpigmentation of palms/soles)
Postmarketing Reports
Rilpivirine
- Renal and urinary disorders: Nephrotic syndrome
- Skin and subcutaneous tissue disorders: Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
Tenofovir
- Immune system disorders: Allergic reaction, including angioedema
- Metabolism and nutrition disorders: Lactic acidosis, hypokalemia, hypophosphatemia
- Respiratory, thoracic, and mediastinal disorders: Dyspnea
- Gastrointestinal disorders: Pancreatitis, increased amylase, abdominal pain
- Hepatobiliary disorders: Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
- Skin and subcutaneous tissue disorders: Rash
- Musculoskeletal and connective tissue disorders: Rhabdomyolysis, osteomalacia
Warnings
Black box warnings
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, in combination with other antiretrovirals
Not approved for chronic hepatitis B virus (HBV) infection
Safety and efficacy is not established with coinfection of HBV and HIV-1
Severe acute exacerbations of hepatitis B have been reported with coinfection of HBV and HIV-1 and have discontinued emtricitabine or tenofovir, which are components of Complera
Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months after discontinuing Complera in patients who are coinfected with HIV-1 and HBV; if appropriate, initiation of antihepatitis B therapy may be warranted
Contraindications
Hypersensitivity
Coadministration with proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) may decrease rilpivirine absorption by increasing gastric pH, resulting in decreased plasma concentration; may result in loss of virologic response and possibly cause resistance to NNRTIs
CYP3A enzyme inducers
- May result in loss of virologic response and possible resistance to NNRTIs
- Anticonvulsants (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
- Antimycobacterials (eg, rifabutin, rifampin, rifapentine)
- Glucocorticoid systemic dexamethasone (more than a single dose)
- St. John’s wort
Cautions
Lactic acidosis/severe hepatomegaly with steatosis (see Black box warnings)
Coinfection with HIV-1 and HBV (see Black box warnings)
Severe skin and hypersensitivity reactions reported, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with rilpivirine-containing regimens; discontinue therapy 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
Assess CrCl before initiating treatment; monitor CrCl and serum phosphorus in patients at risk
Avoid concurrent or recent use of nephrotoxic drugs
Avoid drugs that may reduce the exposure of rilpivirine (see Contraindications)
Coadministration with drugs known to increase QT interval and increase risk of Torsade de Pointes
Severe depressive disorders reported; immediate medical evaluation recommended
Do not use with drugs containing emtricitabine, rilpivirine or tenofovir disoproxil fumarate including Atripla, Edurant, Emtriva, Truvada, Viread, or with drugs containing lamivudine
Do not administer in combination with adefovir (Hepsera)
Redistribution/accumulation of body fat observed in patients receiving antiretroviral therapy
May increase risk for immune reconstitution syndrome
Bone effects of tenofovir DF
- Bone mineral density may decrease
- Osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported
Pregnancy and lactation
Pregnancy category: B; Antiretroviral Pregnancy Registry 1-800-258-4263
Lactation: Unknown whether distributed in breast milk; the CDC recommends that mothers should not breastfeed their infants because of risk of postnatal HIV transmission
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Complera (emtricitabine/rilpivirine/tenofovir DF)
Mechanism of action
Emtricitabine: Nucleoside reverse transcriptase inhibitor (NRTI); following phosphorylation, interferes with HIV viral DNA polymerase and inhibits viral replication; cytosine analogue
Rilpivirine: Antiviral agent; diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1; inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase
Tenofovir: Nucleoside reverse transcriptase inhibitor (NRTI); following hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with AMP as substrate
Absorption
Bioavailability
- Emtricitabine: 93%
- Rilpivirine: Exposure 25% higher with combined tablet compared with administration of separate agents; absolute bioavailability unknown
- Tenofovir: <25% (fasting)
Peak Plasma Time
- Emtricitabine: 1-2 hr
- Rilpivirine: 4-5 hr
- Tenofovir: 1 hr
Peak Plasma Concentration
- Emtricitabine: 1.8 mcg/mL
- Rilpivirine: 80 ng/mL
- Tenofovir: 0.3 mcg/mL
AUC
- Emtricitabine: 10 mcg•hr/mL
- Rilpivirine: 2.397 mcg•hr/mL
- Tenofovir: 2.29 mcg•hr/mL
Distribution
Protein Bound
- Emtricitabine: <4%
- Rilpivirine: 99.7%
- Tenofovir: <0.7%
Metabolism
Metabolized by
- Rilpivirine: CYP3A
Metabolites
- Emtricitabine: 3′-sulfoxide diastereomers (approximately 9% of the dose) and the glucuronic acid conjugate (approximately 4% of the dose)
Elimination
Half-life
- Emtricitabine: 10 hr
- Rilpivirine: 50 hr
- Tenofovir: 17 hr
Renal clearance
- Emtricitabine: 213 mL/min
- Tenofovir: 243.5 mL/min
Excretion
- Emtricitabine: Urine 86%; feces 14%
- Rilpivirine: Urine 6.1%; feces 85%
- Tenofovir: Urine 70-80%
Administration
Oral Administration
Take with food
