EFAVIRENZ, EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE

Efavirenz, emtricitabine and tenofovir disoproxil fumarate is a fixed-dose combination tablet containing EFV, FTC, and TDF. EFV is a non-nucleoside reverse transcriptase inhibitor (NNRTI). FTC is a synthetic nucleoside analog of cytidine. TDF, which is converted in vivo to tenofovir, is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are for oral administration. Each film coated tablet contains efavirenz, USP 600 mg; emtricitabine, USP 200 mg and tenofovir disoproxil fumarate 300 mg equivalent to 245 mg of tenofovir disoproxil as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide. Efavirenz : EFV is chemically described as ( S )-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2 H -3,1-benzoxazin-2-one. Its molecular formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz, USP is a white to off white powder with a molecular mass of 315.67. It is practically insoluble in water (less than 10 mcg/mL). Emtricitabine : The chemical name of FTC is 5-Fluoro-1-[(2 R ,5 S )-2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine. FTC 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 247.30. It has the following structural formula: Emtricitabine, USP is a white to almost white crystalline powder. It is freely soluble in water. Tenofovir DF : TDF is a fumaric acid salt of the bis -isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[( R )-2[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P●C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: TDF is a white to off white powder. It is slightly soluble in water at 25°C. efavirenz-structure emtricitabine-structure tenofovir-structure

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are a three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. ( 1 )

Testing: Consult Full Prescribing Information for important testing recommendations prior to initiation and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. ( 2.1 ) Recommended dosage in adults and pediatric patients weighing at least 40 kg: One tablet once daily taken orally on an empty stomach, preferably at bedtime. ( 2.2 ) Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL/min. ( 2.3 ) Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment. ( 2.4 ) Dosage adjustment with rifampin coadministration: An additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. ( 2.5 ) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate Tablets Prior to or when initiating efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1 )] . Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, 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 (5.7) ] . Monitor hepatic function prior to and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.3) ] . Perform pregnancy testing before initiation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adolescents and adults of childbearing potential [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1 , 8.3 )] . 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology (12.3) ] . 2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions (5.7) , Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] . 2.5 Dosage Adjustment with Rifampin If efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are co-administered with rifampin in patients weighing 50 kg or more, take one tablet of efavirenz, emtricitabine and tenofovir disoproxil fumarate once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] .

Efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.2) ]. Efavirenz, emtricitabine and tenofovir disoproxil fumarate is contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. ( 4 ) Coadministration with voriconazole. ( 4 ) Coadministration with elbasvir/grazoprevir. ( 4 )

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) ] . Rash [see Warnings and Precautions (5.2) ] . Hepatotoxicity [see Warnings and Precautions (5.3) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] . Nervous System Symptoms [see Warnings and Precautions (5.6) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.7) ] . Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.9) ] . Convulsions [see Warnings and Precautions (5.10) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.11) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.12) ] . Fat Redistribution [see Warnings and Precautions (5.13) ] . Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of EFV, FTC, and TDF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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. Clinical Trials in Adult Subjects Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either FTC + TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (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 Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Either Treatment Group in Study 934 (0 to 144 Weeks) a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash Event c 7% 9% Headache 6% 5% Insomnia 5% 7% Anxiety 5% 4% Nasopharyngitis 5% 3% Vomiting 2% 5% In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or TDF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents. Efavirenz: The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms [see Warnings and Precautions (5.6) ], psychiatric symptoms [see Warnings and Precautions (5.5) ], and rash [see Warnings and Precautions (5.2) ] . Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-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 EFV has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with EFV 600 mg than in control subjects. Skin discoloration has been reported with higher frequency among FTC-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 who received EFV 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 (5.2) ] . Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). 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 TDF (N=81) were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions (5.9) ] . 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 to 144 Weeks) a. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. FTC+TDF+EFV a 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/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. Hepatic Events : In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV 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 EFV, FTC, and TDF 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 (5.3) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF. 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 Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [see Warnings and Precautions (5.13) ] , hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, encephalopathy, 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.

Consult Full Prescribing Information prior to and during treatment for important potential drug interactions. ( 4 , 5.4 , 7 ) HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV, resulting in lowered plasma concentrations [see Dosage and Administration (2.2) ] . There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology (12.2) ] . Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate when coadministered with a drug with a known risk of Torsade de Pointes. 7.2 Drugs Affecting Renal Function FTC and tenofovir are primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ] . Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. 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 (5.7) ] . Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir. 7.3 Established and Potentially Significant Drug Interactions Other important drug interaction information for efavirenz, emtricitabine and tenofovir disoproxil fumarate is summarized in Table 3. The drug interactions described are based on trials conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate, the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, or TDF) as individual agents, or are potential drug interactions [see Clinical Pharmacology (12.3) ] . Table 3 Established and Potentially Significant a Drug Interactions Concomitant Drug Class: Drug Name Effect Clinical Comment a. This table is not all inclusive. HIV antiviral agents Protease inhibitor: atazanavir ↓atazanavir ↑tenofovir Coadministration of atazanavir with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended. The combined effect of EFV plus TDF on atazanavir plasma concentrations is not known. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with efavirenz, emtricitabine and tenofovir disoproxil fumarate. Protease inhibitor: fosamprenavir calcium ↓amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: indinavir ↓indinavir The optimal dose of indinavir, when given in combination with EFV, is not known. Increasing the indinavir dose to 1,000 mg every 8 hours does not compensate for the increased indinavir metabolism due to EFV. Protease inhibitor: darunavir/ritonavir lopinavir/ritonavir ↑tenofovir ↓lopinavir ↑tenofovir Monitor patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with EFV. Refer to the Full Prescribing Information for lopinavir/ritonavir for guidance on coadministration with EFV- or tenofovir-containing regimens, such as efavirenz, emtricitabine and tenofovir disoproxil fumarate. Patients should be monitored for tenofovir-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Protease inhibitor: ritonavir ↑ritonavir ↑efavirenz When ritonavir 500 mg every 12 hours was coadministered with EFV 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate is used in combination with ritonavir. Protease inhibitor: saquinavir ↓saquinavir Appropriate doses of the combination of EFV and saquinavir/ritonavir with respect to safety and efficacy have not been established. CCR5 co-receptor antagonist: maraviroc ↓maraviroc Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz, emtricitabine and tenofovir disoproxil fumarate. NRTI: didanosine ↑didanosine Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with efavirenz, emtricitabine and tenofovir disoproxil fumarate. When coadministered, efavirenz, emtricitabine and tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz, emtricitabine and tenofovir disoproxil fumarate contains EFV and should not be coadministered with other NNRTIs. Integrase strand transfer inhibitor: raltegravir ↓ raltegravir The clinical significance of this interaction has not been directly assessed. Hepatitis C antiviral agents boceprevir ↓ boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with EFV, which may result in loss of therapeutic effect. The combination should be avoided. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with elbasvir/grazoprevir is contraindicated [ see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir. glecaprevir/pibrentasvir ↓ glecaprevir ↓ pibrentasvir Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended because it may lead to reduced therapeutic effect of glecaprevir/pibrentasvir. ledipasvir/sofosbuvir ↑ tenofovir Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and HARVONI ® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with TDF. simeprevir ↓ simeprevir ↔ efavirenz Concomitant administration of simeprevir with EFV is not recommended because it may result in loss of therapeutic effect of simeprevir. sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ↑ tenofovir ↓ velpatasvir ↓ voxilaprevir Coadministration of EFV-containing regimens and EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) is not recommended. Other agents Anticoagulant: warfarin ↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by EFV. Anticonvulsants: carbamazepine ↓ carbamazepine ↓ efavirenz There are insufficient data to make a dose recommendation for efavirenz, emtricitabine and tenofovir disoproxil fumarate. Alternative anticonvulsant treatment should be used. phenytoin phenobarbital ↓ anticonvulsant ↓efavirenz Potential for reduction in anticonvulsant and/or EFV plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressants: bupropion ↓ bupropion The effect of EFV 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate 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. voriconazole ↓ voriconazole ↑ efavirenz Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with voriconazole is contraindicated [see Contraindications (4) ] because it may lead to reduced therapeutic effect of voriconazole and increased risk of EFV-associated adverse reactions 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of EFV is recommended. Antimalarials: artemether/ lumefantrine atovaquone/proguanil ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine ↓ atovaquone ↓ proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions (5.4) ] . Concomitant administration of atovaquone/proguanil with efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate 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 EFV 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 EFV. Consult the Full Prescribing Information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate Implant: etonogestrel ↓ active metabolites of norgestimate ↓ etonogestrel 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 EFV plasma concentrations was observed. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in EFV-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 EFV. These immunosuppressants are not anticipated to affect exposure of EFV. 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 efavirenz, emtricitabine and tenofovir disoproxil fumarate. Narcotic analgesic: methadone ↓ methadone Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in 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 EFV. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.