EFAVIRENZ: 7,893 Adverse Event Reports & Safety Profile

Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet 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 tablet contains 600 mg of EFV, 200 mg of FTC, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: Croscarmellose sodium, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, microcrystalline cellulose, magnesium stearate, red iron oxide, sodium lauryl sulfate. The tablets are film-coated with a coating material opadry AMB 80W54485 pink containing polyvinyl alcohol-part, hydrolyzed, titanium dioxide, talc, lecithin (soya), xanthan gum, iron oxide yellow, iron oxide red and opadry AMB 80W56843 brown containing polyvinyl alcohol-part, hydrolyzed, titanium dioxide, talc, lecithin (soya), xanthan gum, iron oxide red. 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 is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (less than 10 µg/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 247.24. It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25°C. 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 crystalline powder with a solubility of 13.4 mg/mL in water at 25°C.

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AND USAGE 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 )

AND ADMINISTRATION Efavirenz capsules should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) Recommended adult dose: 600 mg. ( 2.2 ) With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2) With rifampin, increase efavirenz capsules dose to 800 mg once daily for patients weighing 50 kg or more. (2.2) Pediatric dosing is based on weight. (2.3)

2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz capsules <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> . Efavirenz capsules are not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) and Use in Specific Populations (8.6) ]</span> .

2.2 Adults The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Dosing at bedtime may improve the tolerability of nervous system symptoms <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , and Patient Counseling Information (17) ]</span>. Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span>.

Concomitant Antiretroviral Therapy

Efavirenz capsules must be given in combination with other antiretroviral medications [see Indications and Usage (1) , Warnings and Precautions (5.3) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ] .

Dosage

Adjustment If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5 ) and Clinical Pharmacology (12.3, Table 8) ].

2.3 Pediatric Patients It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime.

Table

1 describes the recommended dose of efavirenz capsules for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3) ] . The recommended dosage of efavirenz capsules for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.4) ].

Table

1: Efavirenz Capsules Dosing in Pediatric Patients Patient Body Weight Efavirenz Capsules Daily Dose Number of Capsules a and Strength to Administer 3.5 kg to less than 5 kg 100 mg two 50 mg capsules 5 kg to less than 7.5 kg 150 mg three 50 mg capsules 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4) ].

2.4 Capsule Sprinkle Method of Administration For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons of reconstituted room temperature infant formula in a small container by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the efavirenz capsules-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining efavirenz residue, and administered to the patient. The efavirenz capsules-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of efavirenz capsules. Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use ).

4 CONTRAINDICATIONS

• Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are 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 tablets are 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 )

REACTIONS The most significant adverse reactions observed in patients treated with efavirenz tablets are:

• psychiatric symptoms [see Warnings and Precautions ( 5.5 )] ,
• nervous system symptoms [see Warnings and Precautions ( 5.6 )] ,
• rash [see Warnings and Precautions ( 5.8 )] .
• hepatotoxicity [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact XLCare Pharmaceuticals, Inc. at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.

Adverse

Reactions in Adults The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz tablets in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz tablets-treated patients in two controlled clinical trials are presented in Table 2.

Table

2: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenz tablets b + ZDV/LAM (n=412) Efavirenz tablets b + Indinavir (n=415) Indinavir + ZDV/LAM (n=401) Efavirenz tablets b + Nelfinavir + NRTIs (n=64) Efavirenz tablets b + NRTIs (n=65) Nelfinavir + NRTIs (n=66)

Adverse Reactions

180 weeks c 102 weeks c 76 weeks c 71.1 weeks c 70.9 weeks c 62.7 weeks c Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Psychiatric Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritus <1% 1% 1% 9% 5% 9% a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz tablets provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. Pancreatitis has 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 patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities ).

Nervous System Symptoms For

1,008 patients treated with regimens containing efavirenz tablets and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions ( 5.6 )] . The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2.

Table

3: Percent of Patients with One or More Selected Nervous System Symptoms a,b Percent of Patients with: Efavirenz Tablets 600 mg Once Daily (n=1,008) % Control Groups (n=635) % Symptoms of any severity 52.7

24.6 Mild symptoms c 33.3

15.6 Moderate symptoms d 17.4

7.7 Severe symptoms e 2.0

1.3 Treatment discontinuation as a result of symptoms 2.1 1.1 a Includes events reported regardless of causality. b Data from Study 006 and three Phase 2/3 studies. c “Mild” = Symptoms which do not interfere with patient’s daily activities. d “Moderate” = Symptoms which may interfere with daily activities. e “Severe” = Events which interrupt patient’s usual daily activities.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz tablets or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). Rash In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz tablets and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz tablets-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz tablets and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions ( 5.8 )] . Experience with efavirenz tablets in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash.

Laboratory Abnormalities Selected Grade

3 to 4 laboratory abnormalities reported in ≥2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.

Table

4: Selected Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenz tablets a +ZDV/LAM (n=412) Efavirenz tablets a +Indinavir (n=415) Indinavir +ZDV/LAM (n=401) Efavirenz tablets a +Nelfinavir + NRTIs (n=64) Efavirenz tablets a + NRTIs (n=65) Nelfinavir + NRTIs (n=66)

Variable Limit

180 weeks b 102 weeks b 76 weeks b 71.1 weeks b 70.9 weeks b 62.7 weeks b Chemistry ALT >5 x ULN 5% 8% 5% 2% 6% 3% AST >5 x ULN 5% 6% 5% 6% 8% 8% GGT c >5 x ULN 8% 7% 3% 5% 0 5% Amylase >2 x ULN 4% 4% 1% 0 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglycerides d ³751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efavirenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity. d Nonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase.

Patients

Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz tablets-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz tablets arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz tablets arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz tablets-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions ( 5.9 )] .

Lipids

Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz tablets + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz tablets + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels 240 mg/dL and 300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz tablets + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz tablets + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz tablets on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions ( 5.11 )] .

Adverse

Reactions in Pediatric Patients Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz tablets in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions ( 5.8 )] .

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of efavirenz tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole : allergic reactions, asthenia, redistribution/accumulation of body fat <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.13 )]</span> Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia. Musculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory: dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Special Senses: abnormal vision, tinnitus

AND PRECAUTIONS Rash: Discontinue if severe rash develops. ( 5.2 , 6.1 ) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease. ( 5.3 , 6.2 , 8.7 ) Risk of adverse reactions or loss of virologic response due to drug interactions: Consult full prescribing information prior to and during treatment for important potential drug interactions. Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. ( 5.4 ) Serious psychiatric symptoms: Immediate medical evaluation is recommended. ( 5.5 , 6.1 ) Nervous system symptoms (NSS): NSS are frequent, usually begin 1 to 2 days after initiating therapy, and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 2.2 , 5.6 ) New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Avoid administering efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.7 ) Embryo fetal toxicity: Fetal harm may occur when administered to a pregnant woman during the first trimester. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and for 12 weeks after discontinuation. ( 5.8 , 8.1 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathological fracture or other risk factors for osteoporosis or bone loss. ( 5.9 ) Convulsions: Use caution in patients with a history of seizures. ( 5.10 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.11 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.12 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.13 )

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Rash In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets can be reinitiated in patients interrupting therapy because of rash. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. Experience with EFV in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with EFV. Nine of these subjects developed mild-to-moderate rash while receiving therapy with EFV, and two of these subjects discontinued because of rash. Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3 to 1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in pediatric patients should be considered.

5.3 Hepatotoxicity Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with EFV, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1) ]</span> . Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 ) and Use in Specific Populations ( 8.7 )]</span>. Monitoring of liver enzymes before and during treatment is recommended for all patients <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1) ]</span> . Consider discontinuing efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>.

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and other drugs may result in potentially significant drug interactions <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Drug Interactions ( 7.3 )]</span> , some of which may lead to: Loss of therapeutic effect of concomitant drug or efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and possible development of resistance. Possible clinically significant adverse reaction from greater exposures of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets or concomitant drug. QTc prolongation has been observed with the use of EFV <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2 )]</span> . Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

See Table

3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet therapy and review concomitant medications during efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet therapy [see Dosage and Administration ( 2.5 ), Contraindications ( 4 ), and Drug Interactions ( 7 )].

5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. In controlled trials of 1,008 subjects treated with regimens containing EFV for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received EFV or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006, NCT00002410), a Phase 3 randomized, open-label trial of EFV-containing regimens versus controls in 1,266 subjects (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with EFV + zidovudine + lamivudine, EFV + indinavir, and indinavir + zidovudine + lamivudine, respectively), treatment with EFV was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at trial entry; similar associations were observed in both the EFV and control treatment groups.

In Study

006, onset of new serious psychiatric symptoms occurred throughout the trial for both EFV-treated and control-treated subjects. One percent of EFV-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased EFV exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions ( 6 )].

5.6 Nervous System Symptoms Fifty-three percent (531/1,008) of subjects receiving EFV in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1,008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy.

After

4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing EFV and from 3% to 5% in subjects treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions ( 5.5 )]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration ( 2.2 )]. Analysis of long-term data from Study 006 showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among EFV-treated subjects were generally similar to those in the indinavir-containing control arm. Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning EFV therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased EFV levels despite standard dosing of EFV. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to EFV use, and whether discontinuation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is warranted. Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be alerted to the potential for additive central nervous system effects when efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

5.7 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are principally eliminated by the kidney; however, EFV is not. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. 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. 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). Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span>. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.8 Embryo-Fetal Toxicity Efavirenz may cause fetal harm when administered during the first trimester of pregnancy. Advise adults and adolescents of childbearing potential who are receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets to avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets and for 12 weeks after discontinuation <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.1 , 8.3 )]</span>.

5.9 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in HIV-1 infected adults, TDF (a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis-B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions ( 6.2 )]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions ( 5.7 )].

5.10 Convulsions Convulsions have been observed in adult and pediatric patients receiving EFV, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span>.

5.11 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. Treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.12 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [ PCP ] , or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.13 Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &quot;cushingoid appearance,&quot; has been observed in patients receiving antiretroviral therapy, including EFV. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

INTERACTIONS 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 tablets 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 tablets 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Consider alternatives to efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 )]</span> . 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 tablets is summarized in Table 3. The drug interactions described are based on trials conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets (EFV, FTC, or TDF) as individual agents, or are potential drug interactions <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

Table

3: Established and Potentially Significant a Drug Interactions Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: atazanavir ↓ atazanavir Coadministration of atazanavir with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets. ↑ tenofovir Protease inhibitor: fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are 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 1000 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 tablets concomitantly with ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets. Patients should be monitored for tenofovir-associated adverse reactions. Discontinue efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in patients who develop TDF-associated adverse reactions. Protease inhibitor: ritonavir ↑ ritonavir 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 tablets are used in combination with ritonavir. ↑ efavirenz 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 tablets. NRTI: didanosine ↑ didanosine Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets. 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 tablets. When coadministered, efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets contain 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 tablets 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 tablets is not recommended because it may lead to reduced therapeutic effect of glecaprevir/pibrentasvir. ledipasvir/sofosbuvir ↑ tenofovir ↓ velpatasvir Patients receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 There are insufficient data to make a dose recommendation for efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Alternative anticonvulsant treatment should be used. ↓ efavirenz phenytoin phenobarbital ↓ anticonvulsant Potential for reduction in anticonvulsant and/or EFV plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. ↓ efavirenz Antidepressants: bupropion sertraline ↓ bupropion ↓ sertraline 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. Increases in sertraline dose should be guided by clinical response. Antifungals: itraconazole ↓ itraconazole Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. ↓ hydroxy- itraconazole ketoconazole ↓ ketoconazole Drug interaction trials with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets 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 tablets are coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of EFV is recommended. Antimalarials: artemether/ lumefantrine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions (5.4)] . atovaquone/proguanil ↓ atovaquone ↓ proguanil Concomitant administration of atovaquone/proguanil with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets 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 tablets 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 ↓ 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 EFV plasma concentrations was observed. Implant: etonogestrel ↓ etonogestrel 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 tablets. Narcotic analgesic: methadone ↓ methadone Coadministration of EFV 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. a This table is not all inclusive.

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.