ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz are:opsychiatric symptoms [see Warnings and Precautions (5.5) ], onervous system symptoms [see Warnings and Precautions (5.6) ], orash [see Warnings and Precautions (5.8) ], ohepatotoxicity [see Warnings and Precautions (5.9) ].. opsychiatric symptoms [see Warnings and Precautions (5.5) ], onervous system symptoms [see Warnings and Precautions (5.6) ], orash [see Warnings and Precautions (5.8) ], ohepatotoxicity [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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical 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-EmergentIncludes 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. Adverse Reactions of Moderate or Severe Intensity Reported in >= 2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364- Not Specified.ZDV zidovudine, LAM lamivudine.Study 006LAM-, NNRTI-, and Protease Inhibitor-Naive PatientsStudy ACTG 364NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive PatientsAdverse ReactionsEfavirenzEfavirenz provided as 600 mg once daily.+ZDV/LAM(n 412)180 weeksMedian duration of treatment.Efavirenz+Indinavir(n 415)102 weeksIndinavir +ZDV/LAM(n 401)76 weeksEfavirenz +Nelfinavir +NRTIs (n 64)71.1 weeksEfavirenz +NRTIs(n 65)70.9 weeksNelfinavir +NRTIs (n 66)62.7 weeksBody as Whole Fatigue8%5%9%02%3% Pain1%2%8%13%6%17%Central and Peripheral Nervous System Dizziness9%9%2%2%6%6% Headache8%5%3%5%2%3% Insomnia7%7%2%002% Concentration impaired5%3%< 1%000 Abnormal dreams3%1%0--- Somnolence2%2%< 1%000 Anorexia1%< 1%< 1%02%2%Gastrointestinal Nausea10%6%24%3%2%2% Vomiting6%3%14%--- Diarrhea3%5%6%14%3%9% Dyspepsia4%4%6%002% Abdominal pain2%2%5%3%3%3%Psychiatric Anxiety2%4%< 1%--- Depression5%4%< 1%3%05% Nervousness2%2%02%02%Skin Appendages RashIncludes 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. 11%16%5%9%5%9% Pruritus< 1%1%1%9%5%9%Pancreatitis has been reported, although causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in 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 control regimen in controlled trials, Table 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 SymptomsIncludes events reported regardless of causality. Data from Study 006 and three Phase 2/3 studies. Percent of Patients with:Efavirenz 600 mg Once Daily(n 1008)%Control Groups(n 635)%Symptoms of any severity52.724.6Mild symptomsMild Symptoms which do not interfere with patients daily activities. 33.315.6Moderate symptomsModerate Symptoms which may interfere with daily activities. 17.47.7Severe symptomsSevere Events which interrupt patients usual daily activities. 2.01.3Treatment discontinuation as result of symptoms2.11.1. Psychiatric Symptoms. Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials, psychiatric symptoms observed at frequency 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 control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade rash was 0.8% for efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade rash was 0.1% for efavirenz and for control groups. The discontinuation rates as 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 >= 2% of efavirenz-treated patients in two clinical trials are presented in Table 4.Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in >= 2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364ZDV zidovudine, LAM lamivudine, ULN upper limit of normal, ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyltransferase.Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive PatientsStudy ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive PatientsVariableLimitEfavirenzEfavirenz provided as 600 mg once daily.+ ZDV/LAM (n 412)180 weeksMedian duration of treatment.Efavirenz +Indinavir (n 415)102 weeksIndinavir +ZDV/LAM(n 401)76 weeksEfavirenz +Nelfinavir +NRTIs(n 64)71.1 weeksEfavirenz+ NRTIs (n 65) 70.9 weeksNelfinavir +NRTIs (n 66)62.7 weeksChemistry ALT> x ULN5%8%5%2%6%3% AST> x ULN5%6%5%6%8%8% GGTIsolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. 5 ULN8%7%3%5%05% Amylase> x ULN4%4%1%06%2% Glucose> 250 mg/dL3%3%3%5%2%3% TriglyceridesNonfasting. >= 751 mg/dL9%6%6%11%8%17%Hematology Neutrophils< 750/mm3 10%3%5%2%3%2%. Patients Coinfected with Hepatitis or C. Liver function tests should be monitored in patients with history of hepatitis 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 control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis (surface antigen positive) and/or (hepatitis 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 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 (i.e., more severe). Two (1.1%) pediatric patients experienced Grade rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions (5.8) ].. 6.2Postmarketing Experience The following adverse reactions have been identified during postapproval use of efavirenz. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as 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, vertigoEndocrine: gynecomastiaGastrointestinal: constipation, malabsorptionCardiovascular: flushing, palpitationsLiver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemiaMusculoskeletal: arthralgia, myalgia, myopathyPsychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatoniaRespiratory: dyspneaSkin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndromeSpecial Senses: abnormal vision, tinnitus.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose. Mutagenesis. Efavirenz tested negative in battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility. Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately <= 0.15 times that in humans at the recommended clinical dose.

OVERDOSAGE SECTION.

10 OVERDOSAGE Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions. Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patients clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 600 mg NDC 0378-2233-93Efavirenz Tablets, USP 600 mgALERT: Find out about medicines that shouldNOT be taken with Efavirenz Tablets, USP.Note to Pharmacist: Do not cover ALERT box withpharmacy label.Rx only 30 TabletsEach film-coated tablet contains:Efavirenz, USP 600 mgUsual Dosage: See accompanyingprescribing information.Keep this and all medication out ofthe reach of children.Store at 20 to 25C (68 to 77F).[See USP Controlled RoomTemperature.]Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX2233H3Dispense in original container.Keep container tightly closed.Code No.: MH/DRUGS/25/NKD/89. Efavirenz Tablets 600 mg Bottle Label.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Efavirenz is an antiviral drug [see Microbiology (12.4) ]. 12.2 Pharmacodynamics Cardiac Electrophysiology. The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 6/6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 1/1 genotype. positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B66/6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.2) ].. 12.3 Pharmacokinetics Absorption. Peak efavirenz plasma concentrations of 1.6-9.1 uM were attained by hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady-state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 +- 3.7 uM (mean +- SD), steady-state Cmin was 5.6 +- 3.2 uM, and AUC was 184 +- 73 uMoh. Effect of Food on Oral Absorption. Tablets: Administration of single 600 mg efavirenz tablet with high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with 28% increase in mean AUC of efavirenz and 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [See Dosage and Administration (2) and Patient Counseling Information (17).] Distribution. Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n 9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism. Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in lower than predicted extent of accumulation (22-42% lower) and shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours). Elimination. Efavirenz has terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. one-month mass balance/excretion study was conducted using 400 mg per day with 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.. Special Populations. Pediatric. The pharmacokinetic parameters for efavirenz at steady-state in pediatric patients were predicted by population pharmacokinetic model and are summarized in Table by weight ranges that correspond to the recommended doses.Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric PatientsBody WeightDoseMean AUC(0-24) uM.hMean Cmax ug/mLMean Cmin ug/mL3.5-5 kg100 mg220.525.812.435-7.5 kg150 mg262.627.072.717.5-10 kg200 mg284.287.752.8710-15 kg200 mg238.146.542.3215-20 kg250 mg233.986.472.320-25 kg300 mg257.567.042.5525-32.5 kg350 mg262.377.122.6832.5-40 kg400 mg259.796.962.69> 40 kg600 mg254.786.572.82. Gender and Race. The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Renal Impairment. The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic Impairment. multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects efavirenz pharmacokinetics.. Drug Interaction Studies. Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5-17 uM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 uM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the Cmax, AUC, and Cmin are summarized in Table (effect of efavirenz on other drugs) and Table (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions (7.1).Table 7: Effect of Efavirenz on Coadministered Drug Plasma Cmax, AUC, and Cmin Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of 10%.NA not available.CoadministeredDrugDoseEfavirenz DoseNumber of SubjectsCoadministered Drug(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90% CI)Atazanavir400 mg qd with light meal 1-20600 mg qd with light meal 7-2027 59%(49-67%) 74%(68-78%) 93%(90-95%)400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal600 mg qd h after atazanavir and ritonavir 7-2013 14%Compared with atazanavir 400 mg qd alone. 17- 58%) 39% (2-88%) 48% (24-76%)300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd 11-24 (pm) (simultaneous with efavirenz)600 mg qd with light snack 11-24 (pm)14 17%(8-27%)<-> 42%(31-51%)Indinavir1000 mg q8h 10 days600 mg qd 10 days20After morning dose<->Comparator dose of indinavir was 800 mg q8h 10 days. 33% (26-39%) 39% (24-51%)After afternoon dose<-> 37% (26-46%) 52% (47-57%)After evening dose 29% (11-43%) 46% (37-54%) 57% (50-63%)Lopinavir/ritonavir400/100 mg capsule q12h 9 days600 mg qd 9 days11,7Parallel-group design; for efavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone. <->Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. 19% 36- 3%) 39% (3-62%)500/125 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone600 mg qd 9 days19 12% (2-23%)<->d 10% 22- 4%)600/150 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone600 mg qd 9 days23 36% (28-44%) 36% (28-44%) 32% (21-44%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 21%(10-33%) 20%(8-34%)<-> Metabolite AG-1402 40%(30-48%) 37%(25-48%) 43%(21-59%)Ritonavir500 mg q12h 8 days600 mg qd 10 days11After AM dose 24%(12-38%) 18%(6-33%) 42%(9-86%)95% CI. After PM dose<-><-> 24%(3-50%) Saquinavir SGCSoft Gelatin Capsule. 1200 mg q8h 10 days600 mg qd 10 days12 50%(28-66%) 62%(45-74%) 56%(16-77%) Lamivudine150 mg q12h 14 days600 mg qd 14 days9<-><-> 265%(37-873%)TenofovirTenofovir disoproxil fumarate. 300 mg qd600 mg qd 14 days29<-><-><->Zidovudine300 mg q12h 14 days600 mg qd 14 days9<-><-> 225%(43-640%)Maraviroc100 mg bid600 mg qd12 51%(37-62%) 45%(38-51%) 45%(28-57%)Raltegravir400 mg single dose600 mg qd9 36%(2-59%) 36%(20-48%) 21%( 51- 28%)Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 8%( 22- 8%) 19%(11-25%) 44%(26-58%)Simeprevir150 mg qd 14 days600 mg qd 14 days23 51%( 46- 56%) 71%( 67- 74%) 91%( 88- 92%)Azithromycin600 mg single dose400 mg qd 7 days14 22%(4-42%)<->NAClarithromycin500 mg q12h 7 days400 mg qd 7 days11 26%(15-35%) 39%(30-46%) 53%(42-63%) 14-OH metabolite 49%(32-69%) 34%(18-53%) 26%(9-45%)Fluconazole200 mg 7 days400 mg qd 7 days10<-><-><->Itraconazole200 mg q12h 28 days600 mg qd 14 days18 37%(20-51%) 39%(21-53%) 44%(27-58%) Hydroxy-itraconazole 35%(12-52%) 37%(14-55%) 43%(18-60%)Posaconazole400 mg (oral suspension) bid 10 and 20 days400 mg qd 10 and 20 days1145%(34-53%) 50%(40-57%)NARifabutin300 mg qd 14 days600 mg qd 14 days9 32%(15-46%) 38%(28-47%) 45%(31-56%)Voriconazole400 mg po q12h 1 day, then 200 mg po q12h 8 days400 mg qd 9 daysNA 61%h 77%90% CI not available. NA300 mg po q12h days 2-7300 mg qd 7 daysNA 36%i (21-49%) 55%Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). (45-62%)NA400 mg po q12h days 2-7300 mg qd 7 daysNA 23%i 1- 53%) 7% 23- 13%)NAArtemether/ lumefantrineArtemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days)600 mg qd 26 days12Artemether 21% 51%NA dihydroartemisinin 38% 46%NA lumefantrine<-> 21%NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14 14%(1-26%) 43%(34-50%) 69%(49-81%) Total active (including metabolites) 15%(2-26%) 32%(21-41%) 48%(23-64%)Pravastatin40 mg qd 4 days600 mg qd 15 days13 32%( 59- 12%) 44%(26-57%) 19%(0-35%)Simvastatin40 mg qd 4 days600 mg qd 15 days14 72%(63-79%) 68%(62-73%) 45%(20-62%) Total active (including metabolites) 68%(55-78%) 60%(52-68%)NANot available because of insufficient data. Carbamazepine200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days600 mg qd 14 days12 20%(15-24%) 27%(20-33%) 35%(24-44%) Epoxide metabolite<-><-> 13%( 30- 7%)Cetirizine10 mg single dose600 mg qd 10 days11 24%(18-30%)<->NADiltiazem240 mg 21 days600 mg qd 14 days13 60%(50-68%) 69%(55-79%) 63%(44-75%) Desacetyl diltiazem 64%(57-69%) 75%(59-84%) 62%(44-75%) N-monodes-methyl diltiazem 28%(7-44%) 37%(17-52%) 37%(17-52%)Ethinyl estradiol/Norgestimate0.035 mg/0.25 mg 14 days600 mg qd 14 days Ethinyl estradiol21<-><-><-> Norelgestromin21 46%(39-52%) 64%(62-67%) 82%(79-85%) Levonorgestrel6 80%(77-83%) 83%(79-87%) 86%(80-90%)Lorazepam2 mg single dose600 mg qd 10 days12 16%(2-32%)<->NAMethadoneStable maintenance 35-100 mg daily600 mg qd 14-21 days11 45%(25-59%) 52%(33-66%)NABupropion150 mg single dose (sustained-release)600 mg qd 14 days13 34%(21-47%) 55%(48-62%)NA Hydroxy-bupropion 50%(20-80%)<->NAParoxetine20 mg qd 14 days600 mg qd 14 days16<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 29%(15-40%) 39%(27-50%) 46%(31-58%)Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of 10%.NA not available.CoadministeredDrugDoseEfavirenz DoseNumber of SubjectsEfavirenz(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90% CI)Indinavir800 mg q8h 14 days200 mg qd 14 days11<-><-><->Lopinavir/ritonavir400/100 mg q12h 9 days600 mg qd 9 days11,12Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone. <-> 16%( 38- 15%) 16%( 42- 20%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days1012%( 32- 13%)95% CI. 12%( 35- 18%) 21%( 53- 33%)Ritonavir500 mg q12h 8 days600 mg qd 10 days9 14%(4-26%) 21%(10-34%) 25%(7-46%) Saquinavir SGCSoft Gelatin Capsule. 1200 mg q8h 10 days600 mg qd 10 days13 13%(5-20%) 12%(4-19%) 14%(2-24%) TenofovirTenofovir disoproxil fumarate. 300 mg qd600 mg qd 14 days30<-><-><->Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 11%(2-20%) 20%(15-26%)NASimeprevir 150 mg qd 14 days600 mg qd 14 days23<-> 10%(5-15%) 13%(7-19%)Azithromycin600 mg single dose400 mg qd 7 days14<-><-><->Clarithromycin500 mg q12h 7 days400 mg qd 7 days12 11%(3-19%)<-><->Fluconazole200 mg 7 days400 mg qd 7 days10<-> 16%(6-26%) 22%(5-41%)Itraconazole200 mg q12h 14 days600 mg qd 28 days16<-><-><->Rifabutin300 mg qd 14 days600 mg qd 14 days11<-><-> 12%( 24- 1%)Rifampin600 mg 7 days600 mg qd 7 days12 20%(11-28%) 26%(15-36%) 32%(15-46%)Voriconazole400 mg po q12h 1 day, then 200 mg po q12h 8 days400 mg qd 9 daysNA 38%90% CI not available. 44% NA300 mg po q12h days 2-7300 mg qd 7 daysNA 14%Relative to steady-state administration of efavirenz (600 mg once daily for days). (7-21%)<-> NA400 mg po q12h days 2-7300 mg qd 7 daysNA<-> 17% (6-29%)NAArtemether/lumefantrineArtemether20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days)600 mg qd 26 days12<-> 17%NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14<-><-><->Pravastatin40 mg qd 4 days600 mg qd 15 days11<-><-><->Simvastatin40 mg qd 4 days600 mg qd 15 days14 12%( 28- 8%)<-> 12%( 25- 3%)Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg30 mL single dose400 mg single dose17<-><->NACarbamazepine200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days600 mg qd 35 days14 21%(15-26%) 36%(32-40%) 47%(41-53%)Cetirizine10 mg single dose600 mg qd 10 days11<-><-><->Diltiazem240 mg 14 days600 mg qd 28 days12 16%(6-26%) 11%(5-18%) 13%(1-26%)Famotidine40 mg single dose400 mg single dose17<-><->NAParoxetine20 mg qd 14 days600 mg qd 14 days12<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 11%(6-16%)<-><->. Metabolite AG-1402. 14-OH metabolite. Hydroxy-itraconazole. dihydroartemisinin. lumefantrine. Total active (including metabolites). Total active (including metabolites). Epoxide metabolite. Desacetyl diltiazem. N-monodes-methyl diltiazem. Ethinyl estradiol. Norelgestromin. Levonorgestrel. Hydroxy-bupropion. 12.4Microbiology Mechanism of Action. Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases , and are not inhibited by efavirenz. Antiviral Activity in Cell Culture. The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade and most non-clade isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis virus infection. Resistance. In Cell Culture. In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz (> 380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase. Clinical Studies. Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with median 88-fold change in efavirenz susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). Cross-Resistance. Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.

CLINICAL STUDIES SECTION.

Clinical Studies. Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with median 88-fold change in efavirenz susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS oEfavirenz tablets are 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.oCoadministration of efavirenz with elbasvir and grazoprevir is contraindicated [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ].. oEfavirenz tablets are 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.. oCoadministration of efavirenz with elbasvir and grazoprevir is contraindicated [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ].. oPatients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)oCoadministration of efavirenz with elbasvir/grazoprevir. (4). oPatients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4). oCoadministration of efavirenz with elbasvir/grazoprevir. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Efavirenz tablets, USP are an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C14H9ClF3NO2 and its structural formula is: Efavirenz, USP is white to slightly pink crystalline powder with molecular mass of 315.68. It is practically insoluble in water (< 10 microgram/mL). Tablets: Efavirenz is available as film-coated tablets for oral administration containing 600 mg of efavirenz and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.. Efavirenz Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oEfavirenz tablets should be taken orally once daily on an empty stomach, preferably at bedtime. (2)oRecommended adult dose: 600 mg. (2.2)oWith 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) oWith rifampin, increase efavirenz dose to 800 mg once daily for patients weighing 50 kg or more. (2.2) oPediatric dosing is based on weight. (2.3). oEfavirenz tablets should be taken orally once daily on an empty stomach, preferably at bedtime. (2). oRecommended adult dose: 600 mg. (2.2). oWith 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) oWith rifampin, increase efavirenz dose to 800 mg once daily for patients weighing 50 kg or more. (2.2) oPediatric dosing is based on weight. (2.3). 2.1Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz tablets [see Warnings and Precautions (5.9) ].Efavirenz tablets are not recommended in patients with moderate or severe hepatic impairment (Child Pugh or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.6) ].. 2.2Adults The recommended dosage of efavirenz tablets is 600 mg orally, once daily, in combination with protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz tablets be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz tablets 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 tablets should be swallowed intact with liquid.. Concomitant Antiretroviral Therapy. Efavirenz tablets 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 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)].. 2.3Pediatric Patients It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. Table describes the recommended dose of efavirenz for pediatric patients 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 small amount of food or infant formula using the capsule sprinkle method of administration.Table 1: Efavirenz Dosing in Pediatric PatientsPatient Body WeightEfavirenz Daily DoseNumber of CapsulesCapsules can be administered intact or as sprinkles. or TabletsTablets must not be crushed. and Strength to Administer3.5 kg to less than kg100 mgtwo 50 mg capsules5 kg to less than 7.5 kg150 mgthree 50 mg capsules7.5 kg to less than 15 kg200 mgone 200 mg capsule15 kg to less than 20 kg250 mgone 200 mg one 50 mg capsule20 kg to less than 25 kg300 mgone 200 mg two 50 mg capsules25 kg to less than 32.5 kg350 mgone 200 mg three 50 mg capsules32.5 kg to less than 40 kg400 mgtwo 200 mg capsulesat least 40 kg600 mgone 600 mg tablet OR three 200 mg capsules.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Efavirenz Tablets, USP are available containing 600 mg of efavirenz, USP. oThe 600 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with MYLAN on one side of the tablet and 233 on the other side.. oThe 600 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with MYLAN on one side of the tablet and 233 on the other side.. oTablets: 600 mg. (3) oTablets: 600 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oCoadministration 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) oCoadministration 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) 7.1Potential 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) ].. 7.3QT Prolonging Drugs There is limited information available on the potential for 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 drug with known risk of Torsade de Pointes.. 7.4Established and Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3) Tables 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 InteractionThis table is not all-inclusive.Concomitant Drug Class: Drug NameEffectClinical CommentHIV antiviral agentsProtease inhibitor: Fosamprenavir calcium amprenavirFosamprenavir (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 is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.Protease inhibitor: Atazanavir atazanavirThe interaction between efavirenz and the drug was evaluated in clinical study. All other drug interactions shown are predicted. Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended.Protease inhibitor: Indinavir indinavir The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 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 coadministered with efavirenz. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered 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 coadministered 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 NNRTICombining 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 coadministration with efavirenz.Hepatitis antiviral agentsBoceprevir boceprevir Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir.Elbasvir/Grazoprevir elbasvir grazoprevirCoadministration of efavirenz with elbasvir/grazoprevir is contraindicated [see Contraindications (4) because it may lead to loss of virologic response to elbasvir/grazoprevir.Pibrentasvir/Glecaprevir pibrentasvir glecaprevirCoadministration 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 of therapeutic effect of simeprevir.Velpatasvir/Sofosbuvir velpatasvirCoadministration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir.Velpatasvir/Sofosbuvir/Voxilaprevir velpatasvir voxilaprevirCoadministration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.Other agentsAnticoagulant: Warfarin or warfarinMonitor INR and adjust warfarin dosage if necessary.Anticonvulsants: Carbamazepine Phenytoin Phenobarbital carbamazepine efavirenz anticonvulsant efavirenzThere are insufficient data to make dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.Antidepressants: 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 Itraconazole Ketoconazole Posaconazole voriconazole efavirenz itraconazole hydroxyitraconazole ketoconazole posaconazole Efavirenz and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered 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 and 8).] Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made. Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made. Avoid concomitant use unless the benefit outweighs the risks.Anti-infective: Clarithromycin clarithromycin 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.Antimycobacterials: Rifabutin Rifampin rifabutin efavirenz Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given or times week. Increase efavirenz to 800 mg once daily when coadministered 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 proguanilConcomitant administration is not recommended.Calcium channel blockers: Diltiazem Others (e.g., felodipine, nicardipine, nifedipine, verapamil) diltiazem desacetyl diltiazem N-monodesmethyl diltiazem calcium channel blockerDiltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. When coadministered 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 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 etonogestrelA 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 postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A immunosuppressantDose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least weeks (until stable concentrations are reached) is recommended when starting 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.. 7.5Drugs 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.. 7.6Cannabinoid 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 more specific method is recommended.

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.2Tablets Efavirenz Tablets, USP are available containing 600 mg of efavirenz, USP. The 600 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with MYLAN on one side of the tablet and 233 on the other side. They are available as follows:NDC 0378-2233-93bottles of 30 tablets. 16.3Storage Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Dispense in original container.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Drug Interactions: statement to patients and healthcare providers is included on the products bottle labels: ALERT: Find out about medicines that should NOT be taken with Efavirenz Tablets, USP. Efavirenz tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription or nonprescription medication. General Information for Patients: Inform patients that efavirenz tablets are not cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician while taking efavirenz tablets. Advise patients to avoid doing things that can spread HIV-1 infection to others.oDo not share or reuse needles or other injection equipment.oDo not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.oDo not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.oDo not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.Dosing Instructions: Advise patients to take efavirenz tablets every day as prescribed. If patient forgets to take efavirenz tablets, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask healthcare provider if he/she needs help in planning the best times to take his/her medicine. Efavirenz tablets must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration (2) and Adverse Reactions (6.1)]. Healthcare providers should assist parents or caregivers in determining the best efavirenz dosing schedule for infants and young children.Patients should call their healthcare provider or pharmacist if they have any questions.Nervous System Symptoms: Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz tablets [see Warnings and Precautions (5.6)]. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Alert patients to the potential for additive effects when efavirenz tablets are used concomitantly with alcohol or psychoactive drugs. Instruct patients that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. Inform patients that there is risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz therapy [see Warnings and Precautions (5.6) ]. Psychiatric Symptoms: Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz tablets [see Warnings and Precautions (5.5) ]. If they experience severe psychiatric adverse experiences they should seek immediate medical evaluation. Advise patients to inform their physician of any history of mental illness or substance abuse.Rash: Inform patients that common side effect is rash [see Warnings and Precautions (5.8)]. Rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs. Hepatotoxicity: Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions (5.9) and Adverse Reactions (6.1) ].Females of Reproductive Potential: Advise females of reproductive potential to use effective contraception as well as barrier method during treatment with efavirenz tablets and for 12 weeks after discontinuing efavirenz tablets. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz tablets [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3) ].Pregnancy Exposure Registry: Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy [see Use in Specific Populations (8.1) ].Fat Redistribution: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.13)].. oDo not share or reuse needles or other injection equipment.. oDo not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.. oDo not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.. oDo not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Efavirenz is an antiviral drug [see Microbiology (12.4) ].

MICROBIOLOGY SECTION.

12.4Microbiology Mechanism of Action. Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases , and are not inhibited by efavirenz. Antiviral Activity in Cell Culture. The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade and most non-clade isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis virus infection. Resistance. In Cell Culture. In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz (> 380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase. Clinical Studies. Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with median 88-fold change in efavirenz susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). Cross-Resistance. Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose. Mutagenesis. Efavirenz tested negative in battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility. Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately <= 0.15 times that in humans at the recommended clinical dose. 13.2 Animal Toxicology Nonsustained convulsions were observed in of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.10)].

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients months to 21 years of age in three open-label clinical trials [see Adverse Reactions (6.2), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of higher frequency of rash, including higher frequency of Grade or rash, in pediatric patients compared to adults [see Warnings and Precautions (5.8) and Adverse Reactions (6.2)].Use of efavirenz in patients younger than months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of efavirenz have not been evaluated in this age group and there is risk of developing HIV resistance if efavirenz is underdosed. See Dosage and Administration (2.2)for dosing recommendations for pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Cardiac Electrophysiology. The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 6/6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 1/1 genotype. positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B66/6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.2) ].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. Peak efavirenz plasma concentrations of 1.6-9.1 uM were attained by hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady-state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 +- 3.7 uM (mean +- SD), steady-state Cmin was 5.6 +- 3.2 uM, and AUC was 184 +- 73 uMoh. Effect of Food on Oral Absorption. Tablets: Administration of single 600 mg efavirenz tablet with high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with 28% increase in mean AUC of efavirenz and 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [See Dosage and Administration (2) and Patient Counseling Information (17).] Distribution. Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n 9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism. Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in lower than predicted extent of accumulation (22-42% lower) and shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours). Elimination. Efavirenz has terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. one-month mass balance/excretion study was conducted using 400 mg per day with 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.. Special Populations. Pediatric. The pharmacokinetic parameters for efavirenz at steady-state in pediatric patients were predicted by population pharmacokinetic model and are summarized in Table by weight ranges that correspond to the recommended doses.Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric PatientsBody WeightDoseMean AUC(0-24) uM.hMean Cmax ug/mLMean Cmin ug/mL3.5-5 kg100 mg220.525.812.435-7.5 kg150 mg262.627.072.717.5-10 kg200 mg284.287.752.8710-15 kg200 mg238.146.542.3215-20 kg250 mg233.986.472.320-25 kg300 mg257.567.042.5525-32.5 kg350 mg262.377.122.6832.5-40 kg400 mg259.796.962.69> 40 kg600 mg254.786.572.82. Gender and Race. The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Renal Impairment. The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic Impairment. multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects efavirenz pharmacokinetics.. Drug Interaction Studies. Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5-17 uM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 uM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the Cmax, AUC, and Cmin are summarized in Table (effect of efavirenz on other drugs) and Table (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions (7.1).Table 7: Effect of Efavirenz on Coadministered Drug Plasma Cmax, AUC, and Cmin Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of 10%.NA not available.CoadministeredDrugDoseEfavirenz DoseNumber of SubjectsCoadministered Drug(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90% CI)Atazanavir400 mg qd with light meal 1-20600 mg qd with light meal 7-2027 59%(49-67%) 74%(68-78%) 93%(90-95%)400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal600 mg qd h after atazanavir and ritonavir 7-2013 14%Compared with atazanavir 400 mg qd alone. 17- 58%) 39% (2-88%) 48% (24-76%)300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd 11-24 (pm) (simultaneous with efavirenz)600 mg qd with light snack 11-24 (pm)14 17%(8-27%)<-> 42%(31-51%)Indinavir1000 mg q8h 10 days600 mg qd 10 days20After morning dose<->Comparator dose of indinavir was 800 mg q8h 10 days. 33% (26-39%) 39% (24-51%)After afternoon dose<-> 37% (26-46%) 52% (47-57%)After evening dose 29% (11-43%) 46% (37-54%) 57% (50-63%)Lopinavir/ritonavir400/100 mg capsule q12h 9 days600 mg qd 9 days11,7Parallel-group design; for efavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone. <->Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. 19% 36- 3%) 39% (3-62%)500/125 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone600 mg qd 9 days19 12% (2-23%)<->d 10% 22- 4%)600/150 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone600 mg qd 9 days23 36% (28-44%) 36% (28-44%) 32% (21-44%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 21%(10-33%) 20%(8-34%)<-> Metabolite AG-1402 40%(30-48%) 37%(25-48%) 43%(21-59%)Ritonavir500 mg q12h 8 days600 mg qd 10 days11After AM dose 24%(12-38%) 18%(6-33%) 42%(9-86%)95% CI. After PM dose<-><-> 24%(3-50%) Saquinavir SGCSoft Gelatin Capsule. 1200 mg q8h 10 days600 mg qd 10 days12 50%(28-66%) 62%(45-74%) 56%(16-77%) Lamivudine150 mg q12h 14 days600 mg qd 14 days9<-><-> 265%(37-873%)TenofovirTenofovir disoproxil fumarate. 300 mg qd600 mg qd 14 days29<-><-><->Zidovudine300 mg q12h 14 days600 mg qd 14 days9<-><-> 225%(43-640%)Maraviroc100 mg bid600 mg qd12 51%(37-62%) 45%(38-51%) 45%(28-57%)Raltegravir400 mg single dose600 mg qd9 36%(2-59%) 36%(20-48%) 21%( 51- 28%)Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 8%( 22- 8%) 19%(11-25%) 44%(26-58%)Simeprevir150 mg qd 14 days600 mg qd 14 days23 51%( 46- 56%) 71%( 67- 74%) 91%( 88- 92%)Azithromycin600 mg single dose400 mg qd 7 days14 22%(4-42%)<->NAClarithromycin500 mg q12h 7 days400 mg qd 7 days11 26%(15-35%) 39%(30-46%) 53%(42-63%) 14-OH metabolite 49%(32-69%) 34%(18-53%) 26%(9-45%)Fluconazole200 mg 7 days400 mg qd 7 days10<-><-><->Itraconazole200 mg q12h 28 days600 mg qd 14 days18 37%(20-51%) 39%(21-53%) 44%(27-58%) Hydroxy-itraconazole 35%(12-52%) 37%(14-55%) 43%(18-60%)Posaconazole400 mg (oral suspension) bid 10 and 20 days400 mg qd 10 and 20 days1145%(34-53%) 50%(40-57%)NARifabutin300 mg qd 14 days600 mg qd 14 days9 32%(15-46%) 38%(28-47%) 45%(31-56%)Voriconazole400 mg po q12h 1 day, then 200 mg po q12h 8 days400 mg qd 9 daysNA 61%h 77%90% CI not available. NA300 mg po q12h days 2-7300 mg qd 7 daysNA 36%i (21-49%) 55%Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). (45-62%)NA400 mg po q12h days 2-7300 mg qd 7 daysNA 23%i 1- 53%) 7% 23- 13%)NAArtemether/ lumefantrineArtemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days)600 mg qd 26 days12Artemether 21% 51%NA dihydroartemisinin 38% 46%NA lumefantrine<-> 21%NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14 14%(1-26%) 43%(34-50%) 69%(49-81%) Total active (including metabolites) 15%(2-26%) 32%(21-41%) 48%(23-64%)Pravastatin40 mg qd 4 days600 mg qd 15 days13 32%( 59- 12%) 44%(26-57%) 19%(0-35%)Simvastatin40 mg qd 4 days600 mg qd 15 days14 72%(63-79%) 68%(62-73%) 45%(20-62%) Total active (including metabolites) 68%(55-78%) 60%(52-68%)NANot available because of insufficient data. Carbamazepine200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days600 mg qd 14 days12 20%(15-24%) 27%(20-33%) 35%(24-44%) Epoxide metabolite<-><-> 13%( 30- 7%)Cetirizine10 mg single dose600 mg qd 10 days11 24%(18-30%)<->NADiltiazem240 mg 21 days600 mg qd 14 days13 60%(50-68%) 69%(55-79%) 63%(44-75%) Desacetyl diltiazem 64%(57-69%) 75%(59-84%) 62%(44-75%) N-monodes-methyl diltiazem 28%(7-44%) 37%(17-52%) 37%(17-52%)Ethinyl estradiol/Norgestimate0.035 mg/0.25 mg 14 days600 mg qd 14 days Ethinyl estradiol21<-><-><-> Norelgestromin21 46%(39-52%) 64%(62-67%) 82%(79-85%) Levonorgestrel6 80%(77-83%) 83%(79-87%) 86%(80-90%)Lorazepam2 mg single dose600 mg qd 10 days12 16%(2-32%)<->NAMethadoneStable maintenance 35-100 mg daily600 mg qd 14-21 days11 45%(25-59%) 52%(33-66%)NABupropion150 mg single dose (sustained-release)600 mg qd 14 days13 34%(21-47%) 55%(48-62%)NA Hydroxy-bupropion 50%(20-80%)<->NAParoxetine20 mg qd 14 days600 mg qd 14 days16<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 29%(15-40%) 39%(27-50%) 46%(31-58%)Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of 10%.NA not available.CoadministeredDrugDoseEfavirenz DoseNumber of SubjectsEfavirenz(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90% CI)Indinavir800 mg q8h 14 days200 mg qd 14 days11<-><-><->Lopinavir/ritonavir400/100 mg q12h 9 days600 mg qd 9 days11,12Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone. <-> 16%( 38- 15%) 16%( 42- 20%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days1012%( 32- 13%)95% CI. 12%( 35- 18%) 21%( 53- 33%)Ritonavir500 mg q12h 8 days600 mg qd 10 days9 14%(4-26%) 21%(10-34%) 25%(7-46%) Saquinavir SGCSoft Gelatin Capsule. 1200 mg q8h 10 days600 mg qd 10 days13 13%(5-20%) 12%(4-19%) 14%(2-24%) TenofovirTenofovir disoproxil fumarate. 300 mg qd600 mg qd 14 days30<-><-><->Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 11%(2-20%) 20%(15-26%)NASimeprevir 150 mg qd 14 days600 mg qd 14 days23<-> 10%(5-15%) 13%(7-19%)Azithromycin600 mg single dose400 mg qd 7 days14<-><-><->Clarithromycin500 mg q12h 7 days400 mg qd 7 days12 11%(3-19%)<-><->Fluconazole200 mg 7 days400 mg qd 7 days10<-> 16%(6-26%) 22%(5-41%)Itraconazole200 mg q12h 14 days600 mg qd 28 days16<-><-><->Rifabutin300 mg qd 14 days600 mg qd 14 days11<-><-> 12%( 24- 1%)Rifampin600 mg 7 days600 mg qd 7 days12 20%(11-28%) 26%(15-36%) 32%(15-46%)Voriconazole400 mg po q12h 1 day, then 200 mg po q12h 8 days400 mg qd 9 daysNA 38%90% CI not available. 44% NA300 mg po q12h days 2-7300 mg qd 7 daysNA 14%Relative to steady-state administration of efavirenz (600 mg once daily for days). (7-21%)<-> NA400 mg po q12h days 2-7300 mg qd 7 daysNA<-> 17% (6-29%)NAArtemether/lumefantrineArtemether20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days)600 mg qd 26 days12<-> 17%NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14<-><-><->Pravastatin40 mg qd 4 days600 mg qd 15 days11<-><-><->Simvastatin40 mg qd 4 days600 mg qd 15 days14 12%( 28- 8%)<-> 12%( 25- 3%)Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg30 mL single dose400 mg single dose17<-><->NACarbamazepine200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days600 mg qd 35 days14 21%(15-26%) 36%(32-40%) 47%(41-53%)Cetirizine10 mg single dose600 mg qd 10 days11<-><-><->Diltiazem240 mg 14 days600 mg qd 28 days12 16%(6-26%) 11%(5-18%) 13%(1-26%)Famotidine40 mg single dose400 mg single dose17<-><->NAParoxetine20 mg qd 14 days600 mg qd 14 days12<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 11%(6-16%)<-><->. Metabolite AG-1402. 14-OH metabolite. Hydroxy-itraconazole. dihydroartemisinin. lumefantrine. Total active (including metabolites). Total active (including metabolites). Epoxide metabolite. Desacetyl diltiazem. N-monodes-methyl diltiazem. Ethinyl estradiol. Norelgestromin. Levonorgestrel. Hydroxy-bupropion.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.. Risk Summary. There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to fetus.. Data. Human Data. There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester.Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4%-3.6%). One of these prospectively reported defects with first-trimester exposure was neural tube defect. single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have known association with anophthalmia.. Animal Data. Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days to 18) or from gestation day through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Efavirenz Tablets, USP(ef vir enz)Important: Ask your doctor or pharmacist about medicines that should not be taken with efavirenz tablets. For more information, see the section What should tell my doctor before taking efavirenz tabletsRead this Patient Information before you start taking efavirenz tablets and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.What is efavirenzEfavirenz is prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection in adults and in children who are at least months old and who weigh at least pounds 12 ounces (3.5 kg). HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).It is not known if efavirenz is safe and effective in children younger than months of age or who weigh less than pounds 12 ounces (3.5 kg).When used with other antiretroviral medicines to treat HIV-1 infection, efavirenz may help:oreduce the amount of HIV-1 in your blood. This is called viral load.oincrease the number of CD4+ (T) cells in your blood that help fight off other infections.Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).Efavirenz tablets do not cure HIV-1 infection or AIDS. You should keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.Avoid doing things that can spread HIV-1 infection to others:oDo not share or reuse needles or other injection equipment.oDo not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.oDo not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.Ask your doctor if you have any questions about how to prevent passing HIV to other people.Who should not take efavirenz tabletsDo not take efavirenz tablets if you are allergic to efavirenz or any of the ingredients in efavirenz tablets. See the end of this leaflet for complete list of ingredients in efavirenz tablets.Do not take efavirenz tablets if you are currently taking elbasvir and grazoprevir (ZEPATIER(R)).What should tell my doctor before taking efavirenz tabletsBefore taking efavirenz tablets, tell your doctor if you have any medical conditions and in particular, if you:ohave heart conditionohave ever had mental health problemohave ever used street drugs or large amounts of alcoholohave liver problems, including hepatitis or virus infectionohave history of seizuresoare pregnant or plan to become pregnant. Efavirenz may harm your unborn baby. If you are able to become pregnant your healthcare provider should do pregnancy test before you start efavirenz tablets. You should not become pregnant while taking efavirenz tablets and for 12 weeks after stopping treatment with efavirenz tablets. Females who are able to become pregnant should use effective forms of birth control during treatment and for 12 weeks after stopping treatment with efavirenz tablets. barrier form of birth control should always be used along with another type of birth control.oBarrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.oHormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with efavirenz tablets.oTalk to your doctor about forms of birth control that may be used during treatment with efavirenz tablets. oPregnancy Registry. There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry. oDo not breastfeed if you take efavirenz tablets.oYou should not breastfeed if you have HIV because of the risk of passing HIV to your baby.Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Efavirenz tablets may affect the way other medicines work, and other medicines may affect how efavirenz tablets work, and may cause serious side effects. If you take certain medicines with efavirenz tablets, the amount of efavirenz in your body may be too low and it may not work to help control your HIV infection. The HIV virus in your body may become resistant to efavirenz or other HIV medicines that are like it.You should not take efavirenz tablets if you take ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate) unless your doctor tells you to.Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with efavirenz tablets.Keep list of your medicines to show your doctor and pharmacist.oYou can ask your doctor or pharmacist for list of medicines that interact with efavirenz tablets.oDo not start taking new medicine without telling your doctor. Your doctor can tell you if it is safe to take efavirenz tablets with other medicines.How should take efavirenz tabletsoTake efavirenz tablets exactly as your doctor tells you to.oDo not change your dose or stop taking efavirenz tablets unless your doctor tells you to.oStay under the care of your doctor during treatment with efavirenz tablets.oEfavirenz tablets must be used with other antiretroviral medicines.oTake efavirenz tablets time each day.oEfavirenz comes as tablets.oEfavirenz tablets must not be broken.oSwallow efavirenz tablets whole with liquid.How and when to take efavirenz tablets:oYou should take efavirenz tablets on an empty stomach at bedtime. Taking efavirenz tablets with food increases the amount of medicine in your body. Some side effects may bother you less if you take efavirenz tablets on an empty stomach and at bedtime.oYour childs doctor will prescribe the right dose of efavirenz based on your childs weight.oIf you have difficulty swallowing tablets, tell your doctor.oDo not miss dose of efavirenz tablets. If you forget to take efavirenz tablets, take the missed dose right away, unless it is almost time for your next dose. Do not take doses at one time. Just take your next dose at your regularly scheduled time. If you need help in planning the best times to take your medicine, ask your doctor or pharmacist.oIf you take too many efavirenz tablets, call your doctor or go to the nearest hospital emergency room right away.oWhen your efavirenz tablets supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of efavirenz tablets. The amount of HIV-1 in your blood may increase if the medicine is stopped for even short time. The virus may become resistant to efavirenz tablets and harder to treat.What are the possible side effects of efavirenz tabletsEfavirenz tablets may cause serious side effects, including:oSerious mental health problems can happen in people who take efavirenz tablets. Tell your doctor right away if you have any of the following symptoms:ofeel sad or hopelessofeel anxious or restlessohave thoughts of hurting yourself (suicide) or have tried to hurt yourself or othersoare not able to tell the difference between what is true or real and what is false or unrealodo not trust other peopleohear or see things that are not realoare not able to move or speak normallyoNervous system symptoms are common in people who take efavirenz tablets and can be severe. These symptoms usually begin during the first or second day of treatment with efavirenz tablets and usually go away after to weeks of treatment. Some symptoms may occur months to years after beginning efavirenz therapy. These symptoms may become worse if you drink alcohol, take medicine for mental health problems, or use certain street drugs during treatment with efavirenz tablets. Symptoms may include:odizzinessotrouble sleepingounusual dreamsotrouble concentratingodrowsiness olack of coordination or difficulty with balance If you have dizziness, trouble concentrating or drowsiness, do not drive car, use machinery, or do anything that needs you to be alert. Some nervous system symptoms (e.g., confusion, slow thoughts and physical movement, and delusions [false beliefs] or hallucinations [seeing or hearing things that others do not see or hear]) may occur months to years after beginning efavirenz therapy. Promptly contact your health care provider should any of these symptoms occur.oSkin rash is common with efavirenz tablets but can sometimes be severe. Skin rash usually goes away without any change in treatment. If you develop rash with any of the following symptoms, tell your doctor right away:oskin rash, with or without itchingofeveroswelling of your faceoblisters or skin lesionsopeeling skinomouth soresored or inflamed eyes, like pink eye (conjunctivitis)oLiver problems, including liver failure and death can happen in people who take efavirenz tablets. Liver problems can happen in people without history of liver problems. Your doctor will do blood tests to check your liver before you start efavirenz tablets and during treatment. Tell your doctor right away if you get any of the following symptoms:oyour skin or the white part of your eyes turns yellow (jaundice)oyour urine turns darkoyour bowel movements (stools) turn light in coloroyou dont feel like eating food for several days or longeroyou feel sick to your stomach (nausea)oyou have lower stomach area (abdominal) painoSeizures can happen in people who take efavirenz tablets. Seizures are more likely to happen if you have had seizures in the past. Tell your doctor if you have had seizure or if you take medicine to help prevent seizures.oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your doctor if you start having new symptoms after starting your HIV-1 medicine.oChanges in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known.The most common side effects of efavirenz tablets include:orashodizzinessonauseaoheadacheodifficulty concentratingoabnormal dreamsotirednessotrouble sleepingovomitingSome patients taking efavirenz tablets have experienced increased levels of lipids (cholesterol and triglycerides) in the blood. Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of efavirenz tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store efavirenz tabletsoStore efavirenz tablets at room temperature between 20 to 25C (68 to 77F).Keep efavirenz tablets and all medicines out of the reach of children.General information about efavirenz tabletsMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use efavirenz tablets for condition for which they were not prescribed. Do not give efavirenz tablets to other people, even if they have the same symptoms that you have. They may harm them.If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about efavirenz tablets that is written for health professionals. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).What are the ingredients in efavirenz tabletsActive ingredient: efavirenzInactive ingredients:Efavirenz Tablets: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, red iron oxide, sodium lauryl sulfate, titanium dioxide and yellow iron oxide.This Patient Information has been approved by the U.S. Food and Drug Administration.The brands listed are trademarks of their respective owners.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India 750XXXXX Revised: 10/2021MX:EFV:RX1. oreduce the amount of HIV-1 in your blood. This is called viral load.. oincrease the number of CD4+ (T) cells in your blood that help fight off other infections.. oDo not share or reuse needles or other injection equipment.. oDo not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.. oDo not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.. ohave heart condition. ohave ever had mental health problem. ohave ever used street drugs or large amounts of alcohol. ohave liver problems, including hepatitis or virus infection. ohave history of seizures. oare pregnant or plan to become pregnant. Efavirenz may harm your unborn baby. If you are able to become pregnant your healthcare provider should do pregnancy test before you start efavirenz tablets. You should not become pregnant while taking efavirenz tablets and for 12 weeks after stopping treatment with efavirenz tablets. Females who are able to become pregnant should use effective forms of birth control during treatment and for 12 weeks after stopping treatment with efavirenz tablets. barrier form of birth control should always be used along with another type of birth control.oBarrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.oHormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with efavirenz tablets.oTalk to your doctor about forms of birth control that may be used during treatment with efavirenz tablets. oPregnancy Registry. There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry. oBarrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.. oHormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with efavirenz tablets.. oTalk to your doctor about forms of birth control that may be used during treatment with efavirenz tablets. oPregnancy Registry. There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.. oDo not breastfeed if you take efavirenz tablets.. oYou should not breastfeed if you have HIV because of the risk of passing HIV to your baby.. oYou can ask your doctor or pharmacist for list of medicines that interact with efavirenz tablets.. oDo not start taking new medicine without telling your doctor. Your doctor can tell you if it is safe to take efavirenz tablets with other medicines.. oTake efavirenz tablets exactly as your doctor tells you to.. oDo not change your dose or stop taking efavirenz tablets unless your doctor tells you to.. oStay under the care of your doctor during treatment with efavirenz tablets.. oEfavirenz tablets must be used with other antiretroviral medicines.. oTake efavirenz tablets time each day.. oEfavirenz comes as tablets.. oEfavirenz tablets must not be broken.. oSwallow efavirenz tablets whole with liquid.. oYou should take efavirenz tablets on an empty stomach at bedtime. Taking efavirenz tablets with food increases the amount of medicine in your body. Some side effects may bother you less if you take efavirenz tablets on an empty stomach and at bedtime.. oYour childs doctor will prescribe the right dose of efavirenz based on your childs weight.. oIf you have difficulty swallowing tablets, tell your doctor.. oDo not miss dose of efavirenz tablets. If you forget to take efavirenz tablets, take the missed dose right away, unless it is almost time for your next dose. Do not take doses at one time. Just take your next dose at your regularly scheduled time. If you need help in planning the best times to take your medicine, ask your doctor or pharmacist.. oIf you take too many efavirenz tablets, call your doctor or go to the nearest hospital emergency room right away.. oWhen your efavirenz tablets supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of efavirenz tablets. The amount of HIV-1 in your blood may increase if the medicine is stopped for even short time. The virus may become resistant to efavirenz tablets and harder to treat.. oSerious mental health problems can happen in people who take efavirenz tablets. Tell your doctor right away if you have any of the following symptoms:. ofeel sad or hopeless. ofeel anxious or restless. ohave thoughts of hurting yourself (suicide) or have tried to hurt yourself or others. oare not able to tell the difference between what is true or real and what is false or unreal. odo not trust other people. ohear or see things that are not real. oare not able to move or speak normally. oNervous system symptoms are common in people who take efavirenz tablets and can be severe. These symptoms usually begin during the first or second day of treatment with efavirenz tablets and usually go away after to weeks of treatment. Some symptoms may occur months to years after beginning efavirenz therapy. These symptoms may become worse if you drink alcohol, take medicine for mental health problems, or use certain street drugs during treatment with efavirenz tablets. Symptoms may include:. odizziness. otrouble sleeping. ounusual dreams. otrouble concentrating. odrowsiness olack of coordination or difficulty with balance. If you have dizziness, trouble concentrating or drowsiness, do not drive car, use machinery, or do anything that needs you to be alert. Some nervous system symptoms (e.g., confusion, slow thoughts and physical movement, and delusions [false beliefs] or hallucinations [seeing or hearing things that others do not see or hear]) may occur months to years after beginning efavirenz therapy. Promptly contact your health care provider should any of these symptoms occur.. oSkin rash is common with efavirenz tablets but can sometimes be severe. Skin rash usually goes away without any change in treatment. If you develop rash with any of the following symptoms, tell your doctor right away:. oskin rash, with or without itching. ofever. oswelling of your face. oblisters or skin lesions. opeeling skin. omouth sores. ored or inflamed eyes, like pink eye (conjunctivitis). oLiver problems, including liver failure and death can happen in people who take efavirenz tablets. Liver problems can happen in people without history of liver problems. Your doctor will do blood tests to check your liver before you start efavirenz tablets and during treatment. Tell your doctor right away if you get any of the following symptoms:. oyour skin or the white part of your eyes turns yellow (jaundice). oyour urine turns dark. oyour bowel movements (stools) turn light in color. oyou dont feel like eating food for several days or longer. oyou feel sick to your stomach (nausea). oyou have lower stomach area (abdominal) pain. oSeizures can happen in people who take efavirenz tablets. Seizures are more likely to happen if you have had seizures in the past. Tell your doctor if you have had seizure or if you take medicine to help prevent seizures.. oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your doctor if you start having new symptoms after starting your HIV-1 medicine.. oChanges in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known.. orash. odizziness. onausea. oheadache. odifficulty concentrating. oabnormal dreams. otiredness. otrouble sleeping. ovomiting. oStore efavirenz tablets at room temperature between 20 to 25C (68 to 77F).

SPL UNCLASSIFIED SECTION.

2.1Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz tablets [see Warnings and Precautions (5.9) ].Efavirenz tablets are not recommended in patients with moderate or severe hepatic impairment (Child Pugh or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.6) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Breastfeeding not recommended. (8.2)oFemales and males of reproductive potential: Pregnancy testing and contraception are recommended. (8.3) oHepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (8.6) oPediatric patients: The incidence of rash was higher than in adults. (5.8, 6.2, 8.4). oLactation: Breastfeeding not recommended. (8.2). oFemales and males of reproductive potential: Pregnancy testing and contraception are recommended. (8.3) oHepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (8.6) oPediatric patients: The incidence of rash was higher than in adults. (5.8, 6.2, 8.4). 8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.. Risk Summary. There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to fetus.. Data. Human Data. There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester.Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4%-3.6%). One of these prospectively reported defects with first-trimester exposure was neural tube defect. single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have known association with anophthalmia.. Animal Data. Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days to 18) or from gestation day through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.. 8.2 Lactation Risk Summary. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission in breastfed infants, advise women not to breastfeed. 8.3 Females and Males of Reproductive Potential Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz. [See Use in Specific Populations (8.1).]. Pregnancy Testing. Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz.. Contraception. Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness [see Drug Interactions (7.4)].. 8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients months to 21 years of age in three open-label clinical trials [see Adverse Reactions (6.2), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of higher frequency of rash, including higher frequency of Grade or rash, in pediatric patients compared to adults [see Warnings and Precautions (5.8) and Adverse Reactions (6.2)].Use of efavirenz in patients younger than months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of efavirenz have not been evaluated in this age group and there is risk of developing HIV resistance if efavirenz is underdosed. See Dosage and Administration (2.2)for dosing recommendations for pediatric patients.. 8.5 Geriatric Use Clinical studies of efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. 8.6Hepatic Impairment Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering efavirenz to these patients [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oQTc prolongation: Consider alternatives to efavirenz in patients taking other medications with known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. (5.2)oDo not use as single agent or add on as sole agent to failing regimen. Consider potential for cross-resistance when choosing other agents. (5.3) oNot recommended with ATRIPLA(R), which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.4) oSerious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (5.5, 17) oNervous system symptoms (NSS): NSS are frequent and usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (5.6, 6.1, 17) oEmbryo-Fetal toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur. (5.7, 8.1)oHepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis or coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, few occurred in patients with no pre-existing hepatic disease. (5.9, 6.1, 8.6)oRash: Rash usually begins within 1-2 weeks after initiating therapy and resolves within weeks. Discontinue if severe rash develops. (5.8, 6.1, 17) oConvulsions: Use caution in patients with history of seizures. (5.10) oLipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. (5.11) oImmune reconstitution syndrome: May necessitate further evaluation and treatment. (5.12)oRedistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.13, 17). oQTc prolongation: Consider alternatives to efavirenz in patients taking other medications with known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. (5.2). oDo not use as single agent or add on as sole agent to failing regimen. Consider potential for cross-resistance when choosing other agents. (5.3) oNot recommended with ATRIPLA(R), which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.4) oSerious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (5.5, 17) oNervous system symptoms (NSS): NSS are frequent and usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (5.6, 6.1, 17) oEmbryo-Fetal toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur. (5.7, 8.1). oHepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis or coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, few occurred in patients with no pre-existing hepatic disease. (5.9, 6.1, 8.6). oRash: Rash usually begins within 1-2 weeks after initiating therapy and resolves within weeks. Discontinue if severe rash develops. (5.8, 6.1, 17) oConvulsions: Use caution in patients with history of seizures. (5.10) oLipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. (5.11) oImmune reconstitution syndrome: May necessitate further evaluation and treatment. (5.12). oRedistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.13, 17). 5.1Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6 [see Dosage and Administration (2.2) and Drug Interactions (7.1)]. 5.2QTc Prolongation QTc prolongation has been observed with the use of efavirenz [see Drug Interactions (7.3, 7.4) and Clinical Pharmacology (12.2) ]. Consider alternatives to efavirenz when coadministered with drug with known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.. 5.3Resistance Efavirenz must not be used as single agent to treat HIV-1 infection or added on as sole agent to failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance. 5.4Coadministration with Related Products Coadministration of efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients. 5.5Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for mean of 2.1 years and 635 patients treated with control regimens for mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz 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 group in multifactorial analysis of data from Study 006, treatment with efavirenz 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 study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients 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 causal relationship to the use of efavirenz cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz 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 efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits. [See Adverse Reactions (6.1) .] 5.6Nervous System Symptoms Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens [see Adverse Reactions (6.1, Table 3) ]. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients; and 2.1% of patients discontinued therapy as result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with 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) ]. Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz zidovudine lamivudine, efavirenz indinavir, and indinavir zidovudine lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients 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 efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels despite standard dosing of efavirenz. 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 efavirenz use, and whether discontinuation of efavirenz is warranted.Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is 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. 5.7Embryo-Fetal Toxicity Efavirenz may cause fetal harm when administered during the first trimester to pregnant woman. Advise females of reproductive potential who are receiving efavirenz to avoid pregnancy. [See Use in Specific Populations (8.1 and 8.3).]. 5.8Rash In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups [see Adverse Reactions (6.1) ]. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1008). Rash was reported in 59 of 182 pediatric patients (32%) treated with efavirenz [see Adverse Reactions (6.2)]. Two pediatric patients experienced Grade rash (confluent rash with fever, generalized rash), and four patients had Grade rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered. Efavirenz can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz 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 life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered [see Contraindications (4)].. 5.9Hepatotoxicity Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with efavirenz. Reports have included patients with underlying hepatic disease, including coinfection with hepatitis or C, and patients without pre-existing hepatic disease or other identifiable risk factors.Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Careful monitoring is recommended for patients with mild hepatic impairment receiving efavirenz [see Adverse Reactions (6.1) and Use in Specific Populations (8.6) ].Monitoring of liver enzymes before and during treatment is recommended for all patients [see Dosage and Administration (2.1) ]. Consider discontinuing efavirenz in patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range.Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation.. 5.10Convulsions Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2) ]. Caution should be taken in any patient with 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 [see Drug Interactions (7.1) ].. 5.11Lipid Elevations Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1) ]. Cholesterol and triglyceride testing should be performed before initiating efavirenz therapy and at periodic intervals during therapy. 5.12Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. 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 jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre 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.. 5.13Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.