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The US Food and Drug Administration (FDA) has approved a fixed-dose combination of the antiretroviral drug darunavir (800 mg) and the pharmacokinetic enhancer cobicistat (150 mg) for HIV"...
Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Severe Acute Exacerbations of Hepatitis B [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Psychiatric Symptoms [See WARNINGS AND PRECAUTIONS].
- Nervous System Symptoms [See WARNINGS AND PRECAUTIONS].
- New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
- Rash [See WARNINGS AND PRECAUTIONS].
- Hepatotoxicity [See WARNINGS AND PRECAUTIONS].
- Bone Effects of Tenofovir DF [See WARNINGS AND PRECAUTIONS].
- Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].
- Drug Interactions [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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.
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 was an open-label active-controlled trial in which 511 antiretroviral-naive 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 2).
Table 2 : Selected Treatment-Emergent Adverse
Reactionsa (Grades 2–4) Reported in ≥ 5% in Either
Treatment Group in Study 934 (0–144 Weeks)
|FTC + TDF + EFVb
|AZT/3TC + EFV
|General Disorders and Administration Site Condition|
|Infections and Infestations|
|Upper respiratory tract infections||8%||5%|
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, regardless of relationship to study
b From 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.
c Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.
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 Disoproxil Fumarate
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.
The most significant adverse reactions observed in subjects treated with efavirenz are nervous system symptoms [See WARNINGS AND PRECAUTIONS], psychiatric symptoms [See WARNINGS AND PRECAUTIONS], and rash [See WARNINGS AND PRECAUTIONS].
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 Disoproxil Fumarate
Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include 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
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]. For additional information, please consult the SUSTIVA prescribing information.
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 Disoproxil Fumarate
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].
Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 3).
Table 3 : Significant Laboratory Abnormalities
Reported in ≥ 1% of Subjects in Either Treatment Group in Study 934
|FTC + TDF + EFVa
|AZT/3TC + EFV
|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%|
|3 Neutrophils ( < 750/mm³)||3%||5%|
|Fasting Triglycerides ( > 750 mg/dL)||4%||2%|
|a From 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.|
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 3), Grade 3/4 laboratory abnormalities of increased bilirubin (greater than 2.5 x upper limit of normal (ULN)), increased pancreatic amylase (greater than 2.0 x ULN), increased or decreased serum glucose (less than 40 or greater than 250 mg/dL), and increased serum lipase (greater than 2.0 x ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.
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].
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.
Ear and Labyrinth Disorders
General Disorders and Administration Site Conditions
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
Metabolism and Nutrition Disorders
Redistribution/accumulation of body fat [See WARNINGS AND PRECAUTIONS], 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
Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide
Respiratory, Thoracic and Mediastinal Disorders
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 Disoproxil Fumarate
Immune System Disorders
Allergic reaction, including angioedema
Metabolism and Nutrition Disorders
Lactic acidosis, hypokalemia, hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders
Pancreatitis, increased amylase, abdominal pain
Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT)
Skin and Subcutaneous Tissue Disorders
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
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.
Read the Atripla (efavirenz, emtricitabine, and tenofovir disoproxil fumarate) Side Effects Center for a complete guide to possible side effects
This section describes clinically relevant drug interactions with ATRIPLA. Drug interaction trials are described elsewhere in the labeling [See CLINICAL PHARMACOLOGY].
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].
Emtricitabine And Tenofovir Disoproxil Fumarate
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].
Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosineassociated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions [for didanosine dosing adjustment recommendations, see Table 4]. 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 (Pgp) 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 [See Table 4].
Coadministration of atazanavir with ATRIPLA is not recommended since 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 [See Table 4].
Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate
Other important drug interaction information for ATRIPLA is summarized in Table 1 and Table 4. The drug interactions described are based on trials conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction trials have been conducted using ATRIPLA [for pharmacokinetics data see CLINICAL PHARMACOLOGY, Tables 5-8]. The tables include potentially significant interactions, but are not all inclusive.
Table 4 : Established and Other Potentially
Significanta Drug Interactions: Alterationin 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
|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
|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
|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: telaprevir||↓telaprevir
|Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.|
|Anticoagulant: warfarin||↑ or ↓ warfarin||Plasma concentrations and effects potentially increased or decreased by efavirenz.|
|There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.|
|Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.|
|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. Increases in sertraline dose should be guided by clinical response.|
|Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. Avoid concomitant use unless the benefit outweighs the risks.|
|Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.|
|Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. 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
|Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.|
|Calcium channel blockers: diltiazem Others (e.g., felodipine, nicardipine, nifedipine, verapamil)||↓ diltiazem
↓ desacetyl diltiazem
↓ calcium channel blocker
|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. 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:
|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.
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||↓immunosuppressant||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.|
|a This table is not all inclusive.|
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.
Read the Atripla Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/13/2015
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