Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 12 June 2018

Indication(s)

1 INDICATIONS AND USAGE ATRIPLA® is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. ATRIPLA, a combination of 2 nucleoside analog HIV-1 reverse transcriptase inhibitors and 1 non-nucleoside HIV-1 reverse transcriptase inhibitor, is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of ATRIPLA. (4.1) Coadministration with voriconazole due to a significant drug interaction with efavirenz, a component of ATRIPLA, that may decrease the therapeutic effectiveness of voriconazole and increase the risk of efavirenz-associated side effects. (4.2) 4.1 Hypersensitivity ATRIPLA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of ATRIPLA. 4.2 Contraindicated Drugs Coadminstration of ATRIPLA with voriconazole is contraindicated. Efavirenz, a component of ATRIPLA, significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because ATRIPLA is a fixed-dose combination product, the dose of efavirenz cannot be altered [See Clinical Pharmacology (12.3) Tables 4 and 5].
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6) 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 Efavirenz, Emtricitabine and Tenofovir DF: The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [See Boxed Warning, Warnings and Precautions (5.1)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions (5.3)]. QTc Prolongation [See Warnings and Precautions (5.5)]. Psychiatric Symptoms [See Warnings and Precautions (5.6)]. Nervous System Symptoms [See Warnings and Precautions (5.7)]. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.8)]. Rash [See Warnings and Precautions (5.10)]. Hepatotoxicity [See Warnings and Precautions (5.11)]. Bone Effects of Tenofovir DF [See Warnings and Precautions (5.12)]. Immune Reconstitution Syndrome [See Warnings and Precautions (5.14)]. Fat Redistribution [See Warnings and Precautions (5.15)]. Drug Interactions [See Contraindications (4.2), Warnings and Precautions (5.2) and Drug Interactions (7)]. For additional safety information about Sustiva (efavirenz), EMTRIVA (emtricitabine), or VIREAD (tenofovir DF) in combination with other antiretroviral agents, consult the prescribing information for these products. 6.1 Adverse Reactions from 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. Clinical Trials in Adult Subjects Study 934 Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1). Table 1 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Either Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. AZT/3TC+EFV N=257 N=254 Gastrointestinal Disorder Diarrhea 9% 5% Nausea 9% 7% Vomiting 2% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis 8% 4% Upper respiratory tract infections 8% 5% Nasopharyngitis 5% 3% Nervous System Disorders Headache 6% 5% Dizziness 8% 7% Psychiatric Disorders Anxiety 5% 4% Depression 9% 7% Insomnia 5% 7% Skin and Subcutaneous Tissue Disorders Rash EventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. 7% 9% Study 073 In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive ATRIPLA or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of ATRIPLA when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or Tenofovir DF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents. Efavirenz: The most significant adverse reactions observed in subjects treated with efavirenz were nervous system symptoms [See Warnings and Precautions (5.7)], psychiatric symptoms [See Warnings and Precautions (5.6)], and rash [See Warnings and Precautions (5.10)]. Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of efavirenz-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus. Pancreatitis has also been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with efavirenz 600 mg than in control subjects. Emtricitabine and Tenofovir DF: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials included arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis, and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction). Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Clinical Trials in Pediatric Subjects Efavirenz: Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects 3 months to 21 years of age who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults [See Warnings and Precautions (5.10)]. For additional information, please consult the Sustiva prescribing information. Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with emtricitabine in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information. Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with tenofovir DF were consistent with those observed in clinical trials of tenofovir DF in adults [See Warnings and Precautions (5.12)]. 6.2 Laboratory Abnormalities Efavirenz, Emtricitabine and Tenofovir DF: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2). Table 2 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFVFrom Weeks 96 to 144 of the trial, subjects received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. AZT/3TC+EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm3) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. In addition to the laboratory abnormalities described for Study 934 (Table 2), Grade 3/4 laboratory abnormalities of increased bilirubin (greater than 2.5 × upper limit of normal (ULN)), increased pancreatic amylase (greater than 2.0 × ULN), increased or decreased serum glucose (less than 40 or greater than 250 mg/dL), and increased serum lipase (greater than 2.0 × ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials. Hepatic Events: In Study 934, 19 subjects treated with efavirenz, emtricitabine, and tenofovir DF and 20 subjects treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (1/19) in the efavirenz, emtricitabine, and tenofovir DF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [See Warnings and Precautions (5.11)]. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of efavirenz, emtricitabine, or tenofovir DF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Efavirenz: Cardiac Disorders Palpitations Ear and Labyrinth Disorders Tinnitus, vertigo Endocrine Disorders Gynecomastia Eye Disorders Abnormal vision Gastrointestinal Disorders Constipation, malabsorption General Disorders and Administration Site Conditions Asthenia Hepatobiliary Disorders Hepatic enzyme increase, hepatic failure, hepatitis. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death. Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [See Warnings and Precautions (5.15)], hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor Psychiatric Disorders Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory, Thoracic and Mediastinal Disorders Dyspnea Skin and Subcutaneous Tissue Disorders Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section. Tenofovir DF: 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 (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions Asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dose in adults and pediatric patients (12 years of age and older and weighing at least 40 kg): One tablet once daily taken orally on an empty stomach, preferably at bedtime. (2) Dose in renal impairment: Should not be administered in patients with estimated creatinine clearance below 50 mL/min. (2) With rifampin coadministration, an additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. (2) Adults and pediatric patients 12 years of age and older with body weight at least 40 kg (at least 88 lbs): The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms. Renal impairment: Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment, such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min). Rifampin coadministration: When ATRIPLA is administered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended [See Drug Interactions (7.3) Table 3, and Clinical Pharmacology (12.3) Table 4].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Women should avoid pregnancy while receiving ATRIPLA and for 12 weeks after discontinuation. (5.9) Nursing mothers: Women infected with HIV should be instructed not to breastfeed. (8.3) Hepatic impairment: ATRIPLA is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (5.11, 8.6) Pediatrics: The incidence of rash was higher than in adults. (5.10, 6.1) 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.9)] Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263. Efavirenz: As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz. Animal Data Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation Days 7 to 18) or from gestation Day 7 through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation Day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose. 8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in humans have shown that efavirenz, tenofovir, and emtricitabine are excreted in human milk. Because the risks of low-level exposure to efavirenz, emtricitabine, and tenofovir to infants are unknown, and because of the potential for HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving ATRIPLA. Emtricitabine Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Tenofovir DF Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown. 8.4 Pediatric Use ATRIPLA should only be administered to pediatric patients 12 years of age and older with a body weight greater than or equal to 40 kg (greater than or equal to 88 lbs). Because ATRIPLA is a fixed-dose combination tablet, the dose adjustments recommended for pediatric patients younger than 12 years of age for each individual component cannot be made with ATRIPLA [See Warnings and Precautions (5.10, 5.12), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. 8.5 Geriatric Use Clinical trials of efavirenz, emtricitabine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment ATRIPLA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine an appropriate dose. Patients with mild hepatic impairment may be treated with ATRIPLA at the approved dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering ATRIPLA to these patients [See Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [See Warnings and Precautions (5.8)].
Pregnancy and lactation
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in humans have shown that efavirenz, tenofovir, and emtricitabine are excreted in human milk. Because the risks of low-level exposure to efavirenz, emtricitabine, and tenofovir to infants are unknown, and because of the potential for HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving ATRIPLA. Emtricitabine Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Tenofovir DF Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.

Interactions

7 DRUG INTERACTIONS This section describes clinically relevant drug interactions with ATRIPLA. Drug interaction trials are described elsewhere in the labeling [See Clinical Pharmacology (12.3)]. Efavirenz: Coadministration of efavirenz can alter the concentrations of other drugs, and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions must be considered before and during therapy. (4.2, 7.1, 12.3) Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. (7.2) HIV-1 protease inhibitors: Coadministration of ATRIPLA with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of ATRIPLA with either atazanavir or atazanavir and ritonavir is not recommended. (7.3) 7.1 Efavirenz Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations [See Dosage and Administration (2)]. There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [See Clinical Pharmacology (12.2)]. Consider alternatives to ATRIPLA when coadministered with a drug with a known risk of Torsade de Pointes. 7.2 Emtricitabine and Tenofovir DF Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of ATRIPLA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples 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 (5.8)]. Coadministration of tenofovir DF and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions (for didanosine dosing adjustment recommendations, see Table 3). Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily. Darunavir with ritonavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. Tenofovir DF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When tenofovir DF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving darunavir with ritonavir and ATRIPLA, or lopinavir/ritonavir with ATRIPLA, should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions (Table 3). Coadministration of atazanavir with ATRIPLA is not recommended, as coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA (Table 3). 7.3 Efavirenz, Emtricitabine and Tenofovir DF Other important drug interaction information for ATRIPLA is summarized in Table 3. The drug interactions described are based on trials conducted with either ATRIPLA, the components of ATRIPLA (efavirenz, emtricitabine, or tenofovir DF) as individual agents, or are potential drug interactions [for pharmacokinetic data see Clinical Pharmacology (12.3) , Tables 4−7. The tables include potentially significant interactions, but are not all inclusive]. Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: atazanavir ↓atazanavir ↑ tenofovir Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. Protease inhibitor: fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: indinavir ↓ indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. Protease inhibitor: lopinavir/ritonavir ↓ lopinavir ↑ tenofovir Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. Protease inhibitor: ritonavir ↑ ritonavir ↑ efavirenz When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. Protease inhibitor: saquinavir ↓ saquinavir Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. CCR5 co-receptor antagonist: maraviroc ↓ maraviroc Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. NRTI: didanosine ↑ didanosine Coadministration of ATRIPLA and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. Integrase strand transfer inhibitor: raltegravir ↓ raltegravir Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. Hepatitis C antiviral agents Protease inhibitor: boceprevir ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. Protease inhibitor: simeprevir ↓ simeprevir ↔ efavirenz Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir. NS5A inhibitors/NS5B polymerase inhibitors: ledipasvir/sofosbuvir ↑ tenofovir Patients receiving ATRIPLA and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF. sofosbuvir/velpatasvir ↑ tenofovir ↓ velpatasvir Coadministration of efavirenz-containing regimens and EPCLUSA® (sofosbuvir/velpatasvir) is not recommended. Other agents Anticoagulant: warfarin ↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by efavirenz. Anticonvulsants: carbamazepine ↓ carbamazepine ↓ efavirenz There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. phenytoin phenobarbital ↓ anticonvulsant ↓ efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressants: bupropion ↓ buproprion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. sertraline ↓ sertraline Increases in sertraline dose should be guided by clinical response. Antifungals: itraconazole ↓ itraconazole ↓ hydroxy-itraconazole Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. ketoconazole ↓ ketoconazole Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. posaconazole ↓ posaconazole Avoid concomitant use unless the benefit outweighs the risks. Anti-infective: clarithromycin ↓ clarithromycin ↑ 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterial: rifabutin ↓ rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. rifampin ↓ efavirenz If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. Antimalarials: artemether/lumefantrine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. atovaquone/proguanil ↓ atovaquone ↓ proguanil Concomitant administration of atovaquone/proguanil with ATRIPLA is not recommended. Calcium channel blockers: diltiazem ↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin ↓ atorvastatin ↓ pravastatin ↓ simvastatin Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate ↓ active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. Implant: etonogestrel ↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immuno-suppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. Narcotic analgesic: methadone ↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. 7.4 Efavirenz Assay Interference Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

More information

Category Value
Authorisation number NDA021937
Agency product number OTT9J7900I
Orphan designation No
Product NDC 15584-0101
Date Last Revised 09-01-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [See USP Controlled Room Temperature]. Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
Marketing authorisation holder Gilead Sciences, LLC
Warnings WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS B ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, which are components of ATRIPLA. 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 ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.1)] . WARNING: POSTTREATMENT EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. ATRIPLA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 who have discontinued EMTRIVA or VIREAD, two of the components of ATRIPLA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)