ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most significant adverse reactions observed in patients treated with efavirenz tablets are: psychiatric symptoms [see Warnings and Precautions (5.5)], nervous system symptoms [see Warnings and Precautions (5.6)], rash [see Warnings and Precautions (5.8)]. hepatotoxicity [see Warnings and Precautions (5.9)] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz tablets in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in >=2% of efavirenz tablets-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in >=2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Adverse ReactionsStudy 006LAM-, NNRTI-, and ProteaseInhibitor-Naive PatientsStudy ACTG 364NRTI-experienced, NNRTI-, andProtease Inhibitor-Naive PatientsEfavirenz tabletsb ZDV/LAM(n=412) 180 weeksc Efavirenz tabletsb Indinavir(n=415) 102 weeksc Indinavir+ZDV/LAM(n=401) 76 weeksc Efavirenz tabletsb Nelfinavir+ NRTIs(n=64) 71.1 weeksc Efavirenz tabletsb NRTIs(n=65) 70.9 weeksc Nelfinavir+ NRTIs(n=66) 62.7 weeksc Body as Whole Fatigue 8% 5% 9% 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 2% Concentration impaired 5% 3% <1% 0 Abnormal dreams 3% 1% -- -- -- Somnolence 2% 2% <1% 0 Anorexia 1% <1% <1% 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% -- -- -- Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Psychiatric Anxiety 2% 4% <1% -- -- -- Depression 5% 4% <1% 3% 5% Nervousness 2% 2% 2% 2% Skin Appendages Rashd 11% 16% 5% 9% 5% 9% Pruritus <1% 1% 1% 9% 5% 9% Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364.b Efavirenz tablets provided as 600 mg once daily. Median duration of treatment.d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. -- Not Specified. ZDV zidovudine, LAM=lamivudine. Pancreatitis has been reported, although 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 1,008 patients treated with regimens containing efavirenz tablets 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 Symptomsa,b Percent of Patients with: Efavirenz Tablets 600 mg Once Daily (n=1,008) Control Groups (n=635) Symptoms of any severity 52.7 24.6 Mild symptomsc33.3 15.6Moderate symptomsd17.47.7Severe symptomse21.3Treatment discontinuation as result of symptoms 2.11.1 Includes events reported regardless of causality. Data from Study 006 and three Phase 2/3 studies. Mild Symptoms which do not interfere with patients daily activities. Moderate Symptoms which may interfere with daily activities. Severe Events which interrupt patients usual daily activities. Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at frequency greater than 2% among patients treated with efavirenz tablets or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). Rash In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz tablets and 17% for 635 adults treated with control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade rash was 0.8% for efavirenz tablets-treated patients and 0.3% for control groups, and the frequency of Grade rash was 0.1% for efavirenz tablets and for control groups. The discontinuation rates as result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions (5.8)]. Experience with efavirenz tablets in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade to laboratory abnormalities reported in >=2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade to Laboratory Abnormalities Reported in >=2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364NRTI-experienced,NNRTI-, and ProteaseInhibitor-Naive PatientsVariable Limit Efavirenz tabletsa +ZDV/LAM(n=412) 180 weeksb Efavirenz tabletsa +Indinavir(n=415) 102 weeksb Indinavir+ZDV/LAM(n=401) 76 weeksb Efavirenz tabletsa +Nelfinavir+ NRTIs(n=64) 71.1 weeksb Efavirenz tabletsa +NRTIs(n=65) 70.9 weeksb Nelfinavir+ NRTIs (n=66) 62.7 weeksb Chemistry ALT >5 ULN 5% 8% 5% 2% 6% 3% AST >5 ULN 5% 6% 5% 6% 8% 8% GGTc >5 ULN 8% 7% 3% 5% 5% Amylase >2 ULN 4% 4% 1% 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglyceridesd 3751mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm3 10% 3% 5% 2% 3% 2% Efavirenz tablets provided as 600 mg once daily. Median duration of treatment. Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity. Nonfasting. ZDV zidovudine, LAM lamivudine, ULN upper limit of normal, ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyltransferase. Patients Coinfected with Hepatitis or 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 tablets-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 tablets arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz tablets arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz tablets-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.9)]. Lipids Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz tablets zidovudine lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz tablets indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels 240 mg/dL and 300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz tablets zidovudine lamivudine; 54% and 20%, respectively, of patients treated with efavirenz tablets indinavir; and 28% and 4%, respectively, of patients treated with indinavir zidovudine lamivudine. The effects of efavirenz tablets on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions(5.11)]. Adverse Reactions in Pediatric Patients Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz tablets in combination with other antiretroviral agents for median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 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)]. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of efavirenz tablets. 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, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia. Musculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory: dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Special Senses: abnormal vision, tinnitus.

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. AbsorptionPeak efavirenz plasma concentrations of 1.6 to 9.1 uM were attained by hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1,600 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 to hours and steady-state plasma concentrations were reached in to 10 days. In 35 patients receiving efavirenz tablets 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 1,000 kcal, 500 to 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.]DistributionEfavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz tablets 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.MetabolismStudies 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 to 400 mg per day for 10 days resulted in lower than predicted extent of accumulation (22 to 42% lower) and shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours).EliminationEfavirenz has terminal half-life of 52 to 76 hours after single doses and 40 to 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 to 34% of the radiolabel was recovered in the urine and 16 to 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. 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 StudiesEfavirenz 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 to 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 to 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%. Compared with atazanavir 400 mg qd alone. Comparator dose of indinavir was 800 mg q8h 10 days. Parallel-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. 95% CI. soft Gelatin Capsule. Tenofovir disoproxil fumarate. 90% CI not available. Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). Not available because of insufficient data. NA not available.Coadministered DrugDoseEfavirenzDoseNumber ofSubjectsCoadministered Drug(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90%CI)Atazanavir 400 mg qd with light meal 1-20 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal 300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd 11-24 (pm) (simultaneous with efavirenz) 600 mg qd qd with light meal 7-20600 mg qd h after atazanavir and ritonavir 7-20 600 mg qd withn light snack 11-24 (pm) 27 13 14 59% (49-67%) 14%a (17- 58%) 17% (8-27%) 74% (68-78%) 39%a (2-88%) <-> 93% (90-95%) 48%a (24-76%) 42% (31-51%) Indinavir 1000 mg q8hx 10 daysAfter morningDose After afternoondose After eveningdose 600 mg qd x10 days 20 <->b <->b 29%b (11-43%) 33%b (26-39%) 37%b (26-46%) 46%b (37-54%) 39%b (24-51%) 52%b (47-57%) 57%b (50-63%) Lopinavir/ritonavir 400/ 100 mgCapsules 12 9days 500/ 125 mg tabletq 12 10 dayswith efavirenzcompared to400/100 mg 12 hAlone 600/150 mg tabletQ 12 10 dayswith efavirenzcompared to400/100 mg 12 halone 600 mg qd x9 days 600 mg qd x9 days 600 mg qd x9 days 11,7c 19 23 <->d 12%d (2-23%) 36%d (28-44%) 19%d 36- 3%) <->d 36%d (28-44%) 39%d (3-62%) 10%d 22- %) 32%d (21-44%) Nelfinavir MetaboliteAG-1402 750 mg q8h 7days 600 mg qd x7 days 10 21%(10-33) 40%(30-48) 20%(8-34%) 37%(25-48%) <-> 43%(21-59%) Ritonavir 500 mg 12 8daysAfter AM dose After PM dose 600 mg qd x10 days 11 24%(12-38%) <-> 18%(6-33%) <-> 42%(9-86%)e 24%( 3-50)e SaquinavirSGCf 1200 mg q8hX 10 days 600 mg qd x10 days 12 50%(28-66%) 62%(45-74%) 56%(16-77%)e Lamivudine 150 mg 12 hx 14 days 60014 days <-> <-> 265%(37-873%) Tenofovirg 300 mg qd 600 mg qd x14 days 29 <-> <-> <-> zidovudine 300 mg 12h 600 mg qd x14 days <-> <-> 225%(43-640%) Maraviroc 100 mg bid 600 mg qd 12 51% (37-62%) 45%(38-51%) 45%(28-57%) Raltegravir 400 mg singledose 600 mg qd 36%(2-59) 36%(20-48%) 21%( 51- 28%) Boceprevir 800 mg tid 6days 600 mg qd x16 days NA 8%( 22- 8%) 19%(11-25%) 44%(26-58%) Simeprevir 150 mg qd 14days 600 mg qd x14 days 23 51%(46- 56%) 71%( 67-74% 91%(88%-92% Azithromycin 600 mg singledose 400 mg qd x7 days 14 22%(4-42%) <-> NA Clarithromycin 14-OHmetabolite 500 mg q12hX days 400 mg qd x7 days 11 26%(15-35%) 49%(32-69%) 39%(30-46%) 34%(18-53%) 53%(42-63%) 26%(9-45%) Fluconazole 200 mg x7 days 400 mg qd x7 days 10 <-> <-> <-> Itraconazole Hydroxyl-itraconazole 200 mg 12h x28 days 600 mg qd x14 days 18 37%(20-51%) 35%(12-52%) 39%(21-53%) 37%(14-55%) 44%(27-58%) 43%(18-60%) Posaconazole 400 mg (oralSuspension) bid x10 and 20 days 400 mg qd x10 and 20days 11 45%(34-53%) 50%(40-57%) NA Rifabutin 300 mg qd x14 days 600 mg qd +X14 days 32%(15-46%) 38%(28-47%) 45%(31-56%) Voriconazole 400 mg po 12h x1 day, then 200 mgPo 12h x8 days 300 mg po 12hDays 2-7 400 mg po 12hdays 2-7 400 mg qd x9 days 300 mg qd x7 days 300 mg qd x7 days NA NA NA 61%h 36%i (21-49%) 23%i 1 -53%) 77%h 55%i (45-62%) 7%i (23 13%) NA NA NA Artemether/lumefantrine Arthemetherdihydroartemisininlamefantrine Artemether20 mg /lumefantrine 120 mg tablets (6 4- tablet doses over days) 600 mg qd 26 days 12 21% 38%<-> 51% 46% 21% NANANA Atorvastatin Total active(includingmetabolites 10 mg qd x4 days 600 mg qd x15 days 14 14%(1-26%) 15%(2-26%) 43%(34-50%) 32%(21-41%) 69%(49-81%) 48%(23-64%) pravastatin 40 mg qd x4 days 600 mg qd x15 days 13 32%( 59- 12%) 44%(26-57%) 19%(0-35%) Simavastatin Total active(includingMetabolites) 40 mg qd x4 days 600 mg qd x15 days 14 72%(63-79%) 68 %(55-78 %) 68%(62-73%) 60 %(52-68 %) 45%(20-62%) NAj Carbamazepine Epoxidemetabolite 200 mg qd 3 days,200 mg bid x3 days, then 400 mgqd 29 days 600 mg qd x14 days 12 20%(15-24%) <-> 27%(20-33%) <-> 35%(24-44%) 13%( 30-7%) Cetirizine 10 mg single dose 600 mg qd x10 days 11 24%(18-30%) <-> NA Diltiazem Desacetyldiltiazem N- monodes-Methyl diltiazem 240 mg 21 days 600 mg qd x14 days 13 60%(50-68%) 64%(57-69%) 28%(7-44%) 69%(55-79%) 75%(59-84%) 37%(17-52%) 63%(44-75%) 62%(44-75%) 37%(17-52%) Ethinyl estradiol/Norgestimate Ethinylestradiol Norelgestromin Levonorgestrel 0.035 mg/0.25 mg x14 days 600 mg qd x14 days 21 21 <-> 46%(39-52%) 80%(77-83%) <-> 64%(62-67%) 83%(79-87%) <-> 82%(79-85%) 86%(80-90%) Lorazepam mg single dose 600 mg qd x10 days 12 16%(2-32%) <-> NA Methadone Stable maintenance35-100 mg daily 600 mg qd x14-21 days 11 45%(25-59%) 52%(33-66%) NA Bupropion Hydroxyl-bupropion 150 mg single dose(sustained-release) 600 mg qd x14 days 13 34%(21-47%) 50%(20-80%) 55%(48-62%) <-> NA NA Paroxetine 20 mg qd 14 days 600 mg qd x14 days 16 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd x14 days 13 29%(15-40%) 39%(27-50%) 46%(31-58%) . Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin Coadministered DrugDoseEfavirenzDoseNumber of subjectsEfavirenz (mean change)Cmax (90% CI)AUC(90% CI)Cmin (90%CI)Indinavir 800 mg q8hx 14 days 200 mg qd 14 days 11 <-> <-> <-> Lopinavir/ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11,12a <-> 16%( 38-15%) 16%( 42-20%) Nelfinavir 750 mg q8hx days 600 mg qd 7 days 10 12%( 32-13%)b 12%( 35-18%)b 21%( 53-33%) Ritonavir 500 mg q12hx days 600 mg qd 10 days 14%(4-26%) 21%(10-34%) 25%(7-46%)b Saquinavir SGCc 1200 mg q8h 10 days 600 mg qd 10 days 13 13%(5-20%) 12%(4-19%) 14%(2-24%)b Tenofovird 300 mg qd 600 mg qd 14 days 30 <-> <-> <-> Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 11%(2-20%) 20%(15-26%) NA simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 <-> 10%(5-15%) 13%(7-19%) Azithromycin 600 mgsingle dose 400 mg qd 7 days 14 <-> <-> <-> Clarithromycin 500 mg q12hx days 400 mg qd 7 days 12 11%(3-19%) <-> <-> Fluconazole 200 mg 7 days 400 mg qd 7 days 10 <-> 16%(6-26%) 22%(5-41%) Itraconazole 200 mg q12h 14 days 600 mg qd 28 days 16 <-> <-> <-> Rifabutin 300 mg qd x14 days 600 mg qd 14 days 11 <-> <-> 12%( 24-1%) Rifampin 600 mg 7 days 600 mg qd 7 days 12 20%(11-28%) 26%(15-36%) 32%(15-46%) Voriconazole 400 mg po q12h 1 day, then 200 mg po q12h 8 days 300 mg po q12h days 2-7 400 mg po q12h days 2-7 400 mg qd 9 days 300 mg qd 7 days 300 mg qd 7 days NA NA NA 38%e 14%f (7-21%) <->f <-> 44%e <->f 17%f (6-29%) NA NA NA Artemether/Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 17% NA Atorvastatin 10 mg qd 4 days 600 mg qd 15 days 14 <-> <-> <-> Pravastatin 40 mg qd 4 days 600 mg qd x15 days 11 <-> <-> <-> Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 12%( 28- 8%) <-> 12%( 25- 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 <-> <-> NA Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days 600 mg qd 35 days 14 21%(15-26%) 36%(32-40%) 47%(41-53%) Cetirizine 10 mg singleDose 600 mg qd 10 days 11 <-> <-> <-> Diltiazem 240 mg 14 days 600 mg qd 28 days 12 16%(6-26%) 11%(5-18%) 13%(1-26%) Famotidine 40 mg singleDose 400 mgsingle dose 17 <-> <-> NA Paroxetine 20 mg qd x14 days 600 mg qd 14 days 12 <-> <-> <-> Sertraline 50 mg qd x14 days 600 mg qd 14 days 13 11%(6-16%) <-> <-> Indicates increase Indicates decrease << Indicates no change or mean increase or decrease of <10%. Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule. Tenofovir disoproxil fumarate.e 90% CI not available. Relative to steady-state administration of efavirenz (600 mg once daily for days).NA not available. 12.4 Microbiology. 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 to 95% (EC90 to 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 to 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 delaviridine and nevirapine compared to baseline. Delaviridine- 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.

14 CLINICAL STUDIES. 14.1 Adults. Study 006, randomized, open-label trial, compared efavirenz tablets (600 mg once daily) zidovudine (ZDV, 300 mg q12h) lamivudine (LAM, 150 mg q12h) or efavirenz tablets (600 mg once daily) indinavir (IDV, 1,000 mg q8h) with indinavir (800 mg q8h) zidovudine (300 mg q12h) lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18 to 81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade virus. Table 9: Outcomes of Randomized Treatment through 48 and 168 Weeks, Study 006 Efaverinz tablets ZDV+ LAM(n=422) Efavirenz tablets IDV(n=429) IDV ZDV LAM(n=415) Outcome Week 48 Week 168 Week 48 Week 168 Week 48 Week 168 Respondera 69% 48% 57% 40% 50% 29% Virologic failureb 6% 12% 15% 20% 13% 19% Discontinued foradverse events 7% 8% 6% 8% 16% 20% Discontinued for other reasonsc 17% 31% 22% 32% 21% 32% CD4+ cell count (cells/mm3) Observed subjects (n) (279) (205) (256) (158) (228) (129) Mean change from baseline 190 329 191 319 180 329 Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week 168. Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy. Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients with HIV-1 RNA levels <400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication. For patients treated with efavirenz tablets zidovudine lamivudine, efavirenz tablets indinavir, or indinavir zidovudine lamivudine, the percentage of responders with HIV-1 RNA<50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400 copies/mL) suggests that both the trends of virologic response and differences in response continue through years. ACTG 364 is randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18 to 76], 74% Caucasian, 88% male) received NRTIs in combination with efavirenz tablets (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or efavirenz tablets (600 mg once daily) nelfinavir in randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm3 and mean baseline HIV-1 RNA level was 8,130 copies/mL. Upon entry into the study, all patients were assigned new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using lower limit of quantification of 500 copies/mL. Table 10: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364 Outcome Efavirenz tablets NFV+ NRTIs(n=65) Efavirenz tablets+ NRTIs(n=65) NFV NRTIs(n=66) HIV-1 RNA <500 copies/mLa 71% 63% 41% HIV-1 RNA >=500 copies/mLb CDC category Event 17%2% 34%0% 54%0% Discontinuations for adverse eventsc 3% 3% 5% Discontinuations for other reasonsd 8% 0% 0% For some patients, Week 56 data were used to confirm the status at Week 48. Subjects achieved virologic response (two consecutive viral loads <500 copies/mL) and maintained it through Week 48. Includes viral rebound and failure to achieve confirmed <500 copies/mL by Week 48. See Adverse Reactions (6.1) for safety profile of these regimens. Includes loss to follow-up, consent withdrawn, noncompliance. Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates longer duration of virologic suppression (HIV RNA <500 copies/mL) in the efavirenz tablets-containing treatment arms.. 14.2 Pediatric Patients. Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients months to years of age (median 0.7 years) were treated with efavirenz. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1,144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm3 and the median increase in CD4+ percentage was 6%. Study PACTG 1,021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients months to 21 years of age (median 9.6 years) were dosed with efavirenz tablets. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in CD4+ percentage was 13%. Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients months to 16 years of age (median 5.7 years) were treated with efavirenz tablets. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy.(7) 7.1 Potential for Efavirenz to Affect other Drugs. Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz tablets. 7.2 Potential for Other Drugs to Affect Efavirenz. Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2)]. 7.3 QT Prolonging Drugs. There is limited information available on the potential for 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. 7.4 Established and Other Potentially Significant Drug Interactions. Drug interactions with efavirenz tablets are summarized in Tables 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 Interaction Concomitant DrugClass: Drug NameEffectClinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir calcium amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir atazanavir Treatment-naive patients: When coadministered with efavirenz tablets, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz tablets and atazanavir is not recommended. Protease inhibitor: Indinavir indinavir The optimal dose of indinavir, when given in combination with efavirenz tablets, is not known. Increasing the indinavir dose to 1,000 mg every hours does not compensate for the increased indinavir metabolism due to efavirenz tablets. Protease inhibitor: Lopinavir/ritonavir lopinavir Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz tablets. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz tablets. 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 tablet is coadministered with ritonavir. Protease inhibitor: Saquinavir saquinavir Appropriate doses of the combination of efavirenz tablets and saquinavir/ritonavir with respect to safety and efficacy have not been established. NNRTI: Other NNRTIs or efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz tablets 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 agents Boceprevir boceprevir Concomitant administration of boceprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of boceprevir. Elbasvir/Grazoprevir elbasvir grazoprevir Coadministration of clopidogrel with elbasvir/grazoprevir is contraindicated [see Contraindications (4)] because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir pibrentasvir glecaprevir Coadministration of clopidogrel is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir simeprevir <->efavirenz Concomitant administration of simprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir velpatasvir Coadministration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Velpatasvir /Sofosbuvir/Voxilaprevir velpatasvir sofosbuvir Coadministration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Other agents Anticoagulant: Warfarin or warfarin Monitor INR and adjust warfarin dosage if necessary. Anticonvulsants: Carbamazepine carbamazepine efavirenz There are insufficient data to make dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital anticonvulsant efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. 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 voriconazole efavirenz Efavirenz tablets and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered with efavirenz tablets, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz tablets 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).] Itraconazole itraconazole hydroxyitraconazole Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made. Ketoconazole ketoconazole Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made. Posaconazole posaconazole 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 rifabutin Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given or times week. Rifampin efavirenz Increase efavirenz tablets to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/ lumefantrine Atovaquone/ proguanil artemether dihydroartemisinin lumefantrine atovaquone proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Concomitant administration is not recommended. Calcium channel blockers: Diltiazem diltiazem desacetyl diltiazem N-monodesmethyldiltiazem Diltiazem 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. Others (eg, felodipine,nicardipine, nifedipine,verapamil) calcium channel blocker When coadministered with efavirenz tablets, 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/ NorgestimateImplant Etonogestrel active metabolites ofnorgestimate etonogestrel 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 immunosuppressant Dose 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. The interaction between efavirenz tablets and the drug was evaluated in clinical study. All other drug interactions shown are predicted.This table is not all-inclusive.. 7.5 Drugs Without Clinically Significant Interactions with Efavirenz. No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir.. 7.6 Cannabinoid Test Interaction. Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by more specific method is recommended.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 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. Efavirenz may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication. General Information for Patients Patients should be informed 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. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. Do not share or reuse needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do 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. Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk. Dosing Instructions Patients should be advised 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. Patients should be advised 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 tablets dosing schedule for infants and young children. Patients should call their healthcare provider or pharmacist if they have any questions. Nervous System Symptoms Patients should be informed 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. Patients should be alerted to the potential for additive effects when efavirenz tablets are used concomitantly with alcohol or psychoactive drugs. Patients should be instructed that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. Psychiatric Symptoms Patients should be informed 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. Patients should be advised to inform their physician of any history of mental illness or substance abuse. Rash Patients should be informed 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, patients should be advised 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 tablets during pregnancy [see Use in Specific Populations (8.1)]. Fat Redistribution Patients should be informed 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)]. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Hetero Labs Limited. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. Manufactured by: HETEROTM HETERO LABS LIMITED 22-110, I.D.A., Jeedimetla, Hyderabad 500 055, India. Barcode Revised: February 2018. Efavirenztabcamberlogo1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPeak efavirenz plasma concentrations of 1.6 to 9.1 uM were attained by hours following single oral doses of 100 mg to 1,600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1,600 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 to hours and steady-state plasma concentrations were reached in to 10 days. In 35 patients receiving efavirenz tablets 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 1,000 kcal, 500 to 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.]DistributionEfavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz tablets 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.MetabolismStudies 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 to 400 mg per day for 10 days resulted in lower than predicted extent of accumulation (22 to 42% lower) and shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours).EliminationEfavirenz has terminal half-life of 52 to 76 hours after single doses and 40 to 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 to 34% of the radiolabel was recovered in the urine and 16 to 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. 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 StudiesEfavirenz 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 to 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 to 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%. Compared with atazanavir 400 mg qd alone. Comparator dose of indinavir was 800 mg q8h 10 days. Parallel-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. 95% CI. soft Gelatin Capsule. Tenofovir disoproxil fumarate. 90% CI not available. Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days). Not available because of insufficient data. NA not available.Coadministered DrugDoseEfavirenzDoseNumber ofSubjectsCoadministered Drug(mean change)Cmax (90% CI)AUC(90% CI)Cmin (90%CI)Atazanavir 400 mg qd with light meal 1-20 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal 300 mg qd/ritonavir 100 mg qd 1-10 (pm), then 400 mg qd 11-24 (pm) (simultaneous with efavirenz) 600 mg qd qd with light meal 7-20600 mg qd h after atazanavir and ritonavir 7-20 600 mg qd withn light snack 11-24 (pm) 27 13 14 59% (49-67%) 14%a (17- 58%) 17% (8-27%) 74% (68-78%) 39%a (2-88%) <-> 93% (90-95%) 48%a (24-76%) 42% (31-51%) Indinavir 1000 mg q8hx 10 daysAfter morningDose After afternoondose After eveningdose 600 mg qd x10 days 20 <->b <->b 29%b (11-43%) 33%b (26-39%) 37%b (26-46%) 46%b (37-54%) 39%b (24-51%) 52%b (47-57%) 57%b (50-63%) Lopinavir/ritonavir 400/ 100 mgCapsules 12 9days 500/ 125 mg tabletq 12 10 dayswith efavirenzcompared to400/100 mg 12 hAlone 600/150 mg tabletQ 12 10 dayswith efavirenzcompared to400/100 mg 12 halone 600 mg qd x9 days 600 mg qd x9 days 600 mg qd x9 days 11,7c 19 23 <->d 12%d (2-23%) 36%d (28-44%) 19%d 36- 3%) <->d 36%d (28-44%) 39%d (3-62%) 10%d 22- %) 32%d (21-44%) Nelfinavir MetaboliteAG-1402 750 mg q8h 7days 600 mg qd x7 days 10 21%(10-33) 40%(30-48) 20%(8-34%) 37%(25-48%) <-> 43%(21-59%) Ritonavir 500 mg 12 8daysAfter AM dose After PM dose 600 mg qd x10 days 11 24%(12-38%) <-> 18%(6-33%) <-> 42%(9-86%)e 24%( 3-50)e SaquinavirSGCf 1200 mg q8hX 10 days 600 mg qd x10 days 12 50%(28-66%) 62%(45-74%) 56%(16-77%)e Lamivudine 150 mg 12 hx 14 days 60014 days <-> <-> 265%(37-873%) Tenofovirg 300 mg qd 600 mg qd x14 days 29 <-> <-> <-> zidovudine 300 mg 12h 600 mg qd x14 days <-> <-> 225%(43-640%) Maraviroc 100 mg bid 600 mg qd 12 51% (37-62%) 45%(38-51%) 45%(28-57%) Raltegravir 400 mg singledose 600 mg qd 36%(2-59) 36%(20-48%) 21%( 51- 28%) Boceprevir 800 mg tid 6days 600 mg qd x16 days NA 8%( 22- 8%) 19%(11-25%) 44%(26-58%) Simeprevir 150 mg qd 14days 600 mg qd x14 days 23 51%(46- 56%) 71%( 67-74% 91%(88%-92% Azithromycin 600 mg singledose 400 mg qd x7 days 14 22%(4-42%) <-> NA Clarithromycin 14-OHmetabolite 500 mg q12hX days 400 mg qd x7 days 11 26%(15-35%) 49%(32-69%) 39%(30-46%) 34%(18-53%) 53%(42-63%) 26%(9-45%) Fluconazole 200 mg x7 days 400 mg qd x7 days 10 <-> <-> <-> Itraconazole Hydroxyl-itraconazole 200 mg 12h x28 days 600 mg qd x14 days 18 37%(20-51%) 35%(12-52%) 39%(21-53%) 37%(14-55%) 44%(27-58%) 43%(18-60%) Posaconazole 400 mg (oralSuspension) bid x10 and 20 days 400 mg qd x10 and 20days 11 45%(34-53%) 50%(40-57%) NA Rifabutin 300 mg qd x14 days 600 mg qd +X14 days 32%(15-46%) 38%(28-47%) 45%(31-56%) Voriconazole 400 mg po 12h x1 day, then 200 mgPo 12h x8 days 300 mg po 12hDays 2-7 400 mg po 12hdays 2-7 400 mg qd x9 days 300 mg qd x7 days 300 mg qd x7 days NA NA NA 61%h 36%i (21-49%) 23%i 1 -53%) 77%h 55%i (45-62%) 7%i (23 13%) NA NA NA Artemether/lumefantrine Arthemetherdihydroartemisininlamefantrine Artemether20 mg /lumefantrine 120 mg tablets (6 4- tablet doses over days) 600 mg qd 26 days 12 21% 38%<-> 51% 46% 21% NANANA Atorvastatin Total active(includingmetabolites 10 mg qd x4 days 600 mg qd x15 days 14 14%(1-26%) 15%(2-26%) 43%(34-50%) 32%(21-41%) 69%(49-81%) 48%(23-64%) pravastatin 40 mg qd x4 days 600 mg qd x15 days 13 32%( 59- 12%) 44%(26-57%) 19%(0-35%) Simavastatin Total active(includingMetabolites) 40 mg qd x4 days 600 mg qd x15 days 14 72%(63-79%) 68 %(55-78 %) 68%(62-73%) 60 %(52-68 %) 45%(20-62%) NAj Carbamazepine Epoxidemetabolite 200 mg qd 3 days,200 mg bid x3 days, then 400 mgqd 29 days 600 mg qd x14 days 12 20%(15-24%) <-> 27%(20-33%) <-> 35%(24-44%) 13%( 30-7%) Cetirizine 10 mg single dose 600 mg qd x10 days 11 24%(18-30%) <-> NA Diltiazem Desacetyldiltiazem N- monodes-Methyl diltiazem 240 mg 21 days 600 mg qd x14 days 13 60%(50-68%) 64%(57-69%) 28%(7-44%) 69%(55-79%) 75%(59-84%) 37%(17-52%) 63%(44-75%) 62%(44-75%) 37%(17-52%) Ethinyl estradiol/Norgestimate Ethinylestradiol Norelgestromin Levonorgestrel 0.035 mg/0.25 mg x14 days 600 mg qd x14 days 21 21 <-> 46%(39-52%) 80%(77-83%) <-> 64%(62-67%) 83%(79-87%) <-> 82%(79-85%) 86%(80-90%) Lorazepam mg single dose 600 mg qd x10 days 12 16%(2-32%) <-> NA Methadone Stable maintenance35-100 mg daily 600 mg qd x14-21 days 11 45%(25-59%) 52%(33-66%) NA Bupropion Hydroxyl-bupropion 150 mg single dose(sustained-release) 600 mg qd x14 days 13 34%(21-47%) 50%(20-80%) 55%(48-62%) <-> NA NA Paroxetine 20 mg qd 14 days 600 mg qd x14 days 16 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd x14 days 13 29%(15-40%) 39%(27-50%) 46%(31-58%) . Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin Coadministered DrugDoseEfavirenzDoseNumber of subjectsEfavirenz (mean change)Cmax (90% CI)AUC(90% CI)Cmin (90%CI)Indinavir 800 mg q8hx 14 days 200 mg qd 14 days 11 <-> <-> <-> Lopinavir/ritonavir 400/100 mg q12h 9 days 600 mg qd 9 days 11,12a <-> 16%( 38-15%) 16%( 42-20%) Nelfinavir 750 mg q8hx days 600 mg qd 7 days 10 12%( 32-13%)b 12%( 35-18%)b 21%( 53-33%) Ritonavir 500 mg q12hx days 600 mg qd 10 days 14%(4-26%) 21%(10-34%) 25%(7-46%)b Saquinavir SGCc 1200 mg q8h 10 days 600 mg qd 10 days 13 13%(5-20%) 12%(4-19%) 14%(2-24%)b Tenofovird 300 mg qd 600 mg qd 14 days 30 <-> <-> <-> Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 11%(2-20%) 20%(15-26%) NA simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 <-> 10%(5-15%) 13%(7-19%) Azithromycin 600 mgsingle dose 400 mg qd 7 days 14 <-> <-> <-> Clarithromycin 500 mg q12hx days 400 mg qd 7 days 12 11%(3-19%) <-> <-> Fluconazole 200 mg 7 days 400 mg qd 7 days 10 <-> 16%(6-26%) 22%(5-41%) Itraconazole 200 mg q12h 14 days 600 mg qd 28 days 16 <-> <-> <-> Rifabutin 300 mg qd x14 days 600 mg qd 14 days 11 <-> <-> 12%( 24-1%) Rifampin 600 mg 7 days 600 mg qd 7 days 12 20%(11-28%) 26%(15-36%) 32%(15-46%) Voriconazole 400 mg po q12h 1 day, then 200 mg po q12h 8 days 300 mg po q12h days 2-7 400 mg po q12h days 2-7 400 mg qd 9 days 300 mg qd 7 days 300 mg qd 7 days NA NA NA 38%e 14%f (7-21%) <->f <-> 44%e <->f 17%f (6-29%) NA NA NA Artemether/Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 17% NA Atorvastatin 10 mg qd 4 days 600 mg qd 15 days 14 <-> <-> <-> Pravastatin 40 mg qd 4 days 600 mg qd x15 days 11 <-> <-> <-> Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 12%( 28- 8%) <-> 12%( 25- 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 <-> <-> NA Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 15 days 600 mg qd 35 days 14 21%(15-26%) 36%(32-40%) 47%(41-53%) Cetirizine 10 mg singleDose 600 mg qd 10 days 11 <-> <-> <-> Diltiazem 240 mg 14 days 600 mg qd 28 days 12 16%(6-26%) 11%(5-18%) 13%(1-26%) Famotidine 40 mg singleDose 400 mgsingle dose 17 <-> <-> NA Paroxetine 20 mg qd x14 days 600 mg qd 14 days 12 <-> <-> <-> Sertraline 50 mg qd x14 days 600 mg qd 14 days 13 11%(6-16%) <-> <-> Indicates increase Indicates decrease << Indicates no change or mean increase or decrease of <10%. Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule. Tenofovir disoproxil fumarate.e 90% CI not available. Relative to steady-state administration of efavirenz (600 mg once daily for days).NA not available.

PREGNANCY SECTION.

8.1 Pregnancy. Tetratogenic Effects Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets 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 1,000 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% to 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. (8.2) Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. (8.3) Hepatic impairment: Efavirenz tablets are not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (8.6) Pediatric patients: The incidence of rash was higher than in adults. (5.8, 6.2, 8.4) 8.1 Pregnancy. Tetratogenic Effects Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets 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 1,000 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% to 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 tablets. [See Use in Specific Populations (8.1).] Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz tablets. Contraception Females of reproductive potential should use effective contraception during treatment with efavirenz tablets and for 12 weeks after discontinuing efavirenz tablets 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 (7.1)]. 8.4 Pediatric Use. The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz tablets 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 tablets 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 tablets have not been evaluated in this age group and there is risk of developing HIV resistance if efavirenz tablets are underdosed. [See Dosage and Administration (2.2)]for dosing recommendations for pediatric patients.. 8.5 Geriatric Use. Clinical studies of efavirenz tablets 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.. 8.6 Hepatic Impairment. Efavirenz tablets are 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 tablets to these patients [see Warnings and Precautions (5.9)and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. QTc 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) Do 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) Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.4) Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (5.5, 17) Nervous system symptoms (NSS): NSS are frequent and usually begin to days after initiating therapy and resolve in to weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (5.6, 6.1, 17) Embryo-Fetal Toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur. (5.7, 8.1) Hepatotoxicity: 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) Rash: Rash usually begins within to weeks after initiating therapy and resolves within weeks. Discontinue if severe rash develops.(5.8,6.1,17) Convulsions: Use caution in patients with history of seizures. (5.10) Lipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter.(5.11) Immune reconstitution syndrome: May necessitate further evaluation and treatment.(5.12) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.(5.13, 17) 5.1 Drug 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)]. 5.2 QTc 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 tablets when coadministered with drug with known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.. 5.3 Resistance. Efavirenz tablets 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.. 5.4 Coadministration with Related Products. Coadministration of efavirenz tablets with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.. 5.5 Psychiatric Symptoms. Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials of 1,008 patients treated with regimens containing efavirenz tablets 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 tablets 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 tablets and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz tablets-treated and control-treated patients. One percent of efavirenz tablets-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, psychosis-like behavior and catatonia, although causal relationship to the use of efavirenz tablets 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 tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits. [See Adverse Reactions (6.1).] 5.6 Nervous System Symptoms. Fifty-three percent (531/1,008) of patients receiving efavirenz tablets 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 1,008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2% 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 to 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 tablets 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 tablets zidovudine lamivudine, efavirenz tablets indinavir, and indinavir zidovudine lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz tablets-treated patients were generally similar to those in the indinavir-containing control arm. Patients receiving efavirenz tablets should be alerted to the potential for additive central nervous system effects when efavirenz tablets are used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.. 5.7 Embryo-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 tablets to avoid pregnancy. [See Use in Specific Populations (8.1and 8.3).] 5.8 Rash. In controlled clinical trials, 26% (266/1,008) of adult patients treated with 600 mg efavirenz tablets 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% (9/1,008) of patients treated with efavirenz tablets. The incidence of Grade rash (eg, erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with efavirenz tablets 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% (17/1,008). Rash was reported in 59 of 182 pediatric patients (32%) treated with efavirenz tablets [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 to 1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz tablets in pediatric patients should be considered. Efavirenz tablets can generally be reinitiated in patients interrupting therapy because of rash. Efavirenz tablets should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered [see Contraindications (4)]. 5.9 Hepatotoxicity. Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported in patients treated with 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.. 5.10 Convulsions. 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)]. 5.11 Lipid Elevations. Treatment with efavirenz tablets 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 tablets therapy and at periodic intervals during therapy.. 5.12 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz tablets. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.. 5.13 Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and 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.