EFAVIRENZ

Efavirenz, USP is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro4(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz,USP is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 microgram/mL). Tablets : Efavirenz USP is available as film-coated tablets for oral administration containing 600 mg of efavirenz and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains Opadry Yellow,consisting of hydroxypropylmethyl cellulose, titanium dioxide, polyethylene glycol and iron oxide yellow. efavirenz-structure

INDICATIONS & USAGE Efavirenz in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.( 1 )

DOSAGE & ADMINISTRATION • Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) • Recommended adult dose: 600 mg. ( 2.2 ) • With rifampin, increase efavirenz 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 [ see Warnings and Precautions ( 5.9 ) ]. Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [ see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.6 ) ]. 2.2 Adults The recommended dosage of efavirenz 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 be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 ), and Patient Counseling Information ( 17 )]. Efavirenz capsules or tablets should be swallowed intact with liquid. Concomitant Antiretroviral Therapy Efavirenz 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 is 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). Efavirenz tablets must not be broken. [See Drug Interactions ( 7.1 , Table 5) and Clinical Pharmacology ( 12.3 , Tables 7 and 8] . If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz 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 be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz 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 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 . Table 1: Efavirenz Dosing in Pediatric Patients Patient Body Weight Efavirenz Daily Dose Number of Capsules a or Tablets b 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 capsule 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 one 600 mg tablet OR three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4)]. b Tablets must not be crushed

• Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. • Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated [ see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 ) ]. •Patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions to any of the components of this product. ( 4 ) •Coadministration of efavirenz with elbasvir/grazoprevir

The most significant adverse reactions observed in patients treated with efavirenz 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 Macleods Pharmaceutical Ltd at 1-888-943-3210 or 1-855-926-3384 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 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-treated patients in two controlled clinical trials are presented in Table 2 Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-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 Adverse Reactions Efavirenz b + ZDV/LAM (n=412) Efavirenz b + Indinavir (n=415) Indinavir + ZDV/LAM (n=401) Efavirenz b + Nelfinavir + NRTIs (n=64) Efavirenz b + NRTIs (n=65) Nelfinavir + NRTIs (n=66) 180 weeks c 102 weeks c 76 weeks c 71.1 weeks c 70.9 weeks c 62.7 weeks c Psychiatric 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% 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% Pruritis <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 1008 patients treated with regimens containing efavirenz 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=1008) 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 of greater than 2% among patients treated with efavirenz 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 1008 adults treated with regimens containing efavirenz 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 -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups [see Warnings and Precautions ( 5.8 )]. Experience with efavirenz 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. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-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 Variable Limit EFAVI RENZ a + ZDV/ LAM (n=412) EFAVI RENZ a + Indinavir (n=415) Indina vir + ZDV/ LAM (n=401) EFAVI RENZ a + Nelfinavir + NRTIs (n=64) EFAVI RENZ a + NRTIs (n=65) Nelfi navir + NRTIs (n=66) 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% Triglyce rides d ≥751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efairenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz 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-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 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 arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz -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 10-20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + 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 + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz 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 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 [see Warnings and Precautions ( 5.13 )] 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

Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy. ( 7 ) 7.1 Potential for efavirenz to Affect other Drugs 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 7.2 Potential for Other Drugs to Affect efavirenz Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration ( 2.2 )]. 7.3 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology ( 12.2 )]. Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes. 7.4 Established and Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 5. For pharmacokinetics data, [see Clinical Pharmacology ( 12.3 )] Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations 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 tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir ↓ atazanavir * Treatment –naïve patients : When co-administered with efavirenz tablets , the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg ( once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Co-administration of efavirenz tablets and atazanavir is not recommended. Protease inhibitor: Indinavir ↓ indinavir * The optimal dose of indinavir, when given in combination with efavirenz tablets are 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 * Lopinavir/ritonavir once daily dosing is not recommended when co-administered with efavirenz. The dose of lopinavir/ritonavir must be increased when co-administered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when co-administered with efavirenz in adult and pediatric patients. Protease inhibitor: Ritonavir ↑ ritonavir * ↑ efavirenz * Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is co-administered 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. NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/ or NNRTI Combining two NNRTIs has not been shown to be beneficial. efavirenz should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full prescribing information for maraviroc for guidance on co-administration with efavirenz. Hepatitis C antiviral agents Boceprevir ↓ boceprevir* Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration o efavirenz with elbasvir/grazoprevir is contraindicated [see Contraindications ( 4 )] because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir Co-administration of efavirenz is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir Simeprevir ↓simeprevir* ↔efavirenz* Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss oftherapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir ↓ velpatasvir Co-administration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir Velpatasvir /Sofosbuvir/Voxilaprevir ↓ velpatasvir ↓ voxilaprevir Co-administration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Other agents Anticoagulant: Warfarin ↑ or ↓ warfarin Monitor INR and adjust warfarin dosage if necessary. Anticonvulsants: Carbamazepine ↓ carbamazepine * ↓ efavirenz * There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓ anticonvulsant ↓ efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressant: Bupropion Sertraline ↓bupropion* ↓ sertraline * Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose. Increases in sertraline dosage should be guided by clinical response. Antifungals: Voriconazole ↓ voriconazole * ↑ efavirenz * Efavirenz and voriconazole should not be co-administered at standard doses. When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz tablets must not be broken. [See Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 , Tables 7 and 8).] Itraconazole ↓ itraconazole * ↓ hydroxyitraconazole * Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. Ketoconazole ↓ ketoconazole Drug interaction studies with efavirenz 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. Anthelmintic: Praziquantel ↓ praziquantel Co-administration with efavirenz is not recommended due to significant decrease in plasma concentrations of praziquantel, with risk of treatment failure due to increased hepatic metabolism by efavirenz. 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 * Increase efavirenz to 800 mg once daily when co-administered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/ lumefantrine ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Atovaquone/ proguanil ↓ atovaquone ↓ proguanil Concomitant administration is not recommended. Calcium channel blockers: Diltiazem ↓ diltiazem * ↓ desacetyl diltiazem * ↓ N-monodesmethyl diltiazem * Diltiazem dose adjustments should be guided by clinical response (refer to the complete prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. Others (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker When co-administered with efavirenz, dosage adjustment of calcium channels blocker may be needed and 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. Consult the complete 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 should be used in addition to hormonal contraceptives. A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been post marketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant 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 metabolized by or stopping treatment with efavirenz. Narcotic analgesic: Methadone ↓ methadone * Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms. * The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive. 7.5 Drugs Without Clinically Significant Interactions with Efavirenz No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir. 7.6 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.