ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most significant adverse reactions observed in patients treated with Efavirenz are:psychiatric symptoms [see Warnings and Precautions (5.5) ],nervous system symptoms [see Warnings and Precautions (5.6) ],rash [see Warnings and Precautions (5.8) ].hepatotoxicity [see Warnings and Precautions (5.9) ]. 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 Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com 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 AdultsThe 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-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in >=2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364a 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. Efavirenz provided as 600 mg once daily.c Median duration of treatment.d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. -- Not Specified.ZDV zidovudine, LAM=lamivudine Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenzb ZDV/LAM (n=412) 180 weeksc Efavirenzb Indinavir (n=415) 102 weeksc Indinavir ZDV/LAM (n=401) 76 weeksc Efavirenzb Nelfinavir NRTIs (n=64) 71.1 weeksc Efavirenzb 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% 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 SymptomsFor 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 Symptomsa,b Includes events reported regardless of causality.b Data from Study 006 and three Phase 2/3 studies.c Mild Symptoms which do not interfere with patients daily activities.d Moderate Symptoms which may interfere with daily activities.e Severe Events which interrupt patients usual daily activities. Percent of Patients with: Efavirenz 600 mg Once Daily (n=1008) Control Groups (n=635) Symptoms of any severity 52.7 24.6 Mild symptomsc 33.3 15.6 Moderate symptomsd 17.4 7.7 Severe symptomse 2.0 1.3 Treatment discontinuation as result of symptoms 2.1 1.1 Psychiatric SymptomsSerious 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%).RashIn 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 AbnormalitiesSelected 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 364a Efavirenz provided as 600 mg once daily.b Median duration of treatment.c Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity.d Nonfasting.ZDV zidovudine, LAM lamivudine, ULN Upper limit of normal, ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyltransferase. Study 006 LAM- NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Variable Limit Efavirenza ZDV/LAM (n=412) 180 weeksb Efavirenza Indinavir (n=415) 102 weeksb Indinavir ZDV/LAM (n=401) 76 weeksb Efavirenza Nelfinavir NRTIs (n=64) 71.1 weeksb Efavirenza 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 >=751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm3 10% 3% 5% 2% 3% 2% Patients Coinfected with Hepatitis or CLiver 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)].LipidsIncreases 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 (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. 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, malabsorption Cardiovascular: flushing, palpitationsLiver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemiaMusculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatoniaRespiratory: dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndromeSpecial Senses: abnormal vision, tinnitus.

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 InteractionsA 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. Efavirenz 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 PatientsInform patients that Efavirenz is 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. Advise patients 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 safe 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 InstructionsAdvise patients to take Efavirenz every day as prescribed. If patient forgets to take Efavirenz, 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 must always be used in combination with other antiretroviral drugs. Advise patients to take Efavirenz on an empty stomach, preferably at bedtime. Taking Efavirenz 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.For adult and pediatric patients who cannot swallow capsules or tablets, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in small amount of food or infant formula [see Dosage and Administration (2.3) and FDA-approved patient labeling (Patient Information and Instructions for Use)]. Patients should call their healthcare provider or pharmacist if they have any questions. Nervous System SymptomsInform 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 [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 is 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 SymptomsInform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have been reported in patients receiving Efavirenz [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.RashInform 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 PotentialAdvise females of reproductive potential to use effective contraception as well as barrier method during treatment with Efavirenz and for 12 weeks after discontinuing Efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, or if pregnancy is suspected during treatment with Efavirenz [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)] Pregnancy Exposure RegistryAdvise 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 RedistributionInform 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)]. Distributed by: Strides Pharma Inc. East Brunswick, NJ 08816.Revision: 05/2020Trademarks are the property of their respective owners.. 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 safe 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.

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 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).]Capsules: Administration of single 600 mg dose of efavirenz capsules with high-fat/high-caloric meal (894 kcal, 54 fat, 54% calories from fat) or reduced-fat/normal-caloric meal (440 kcal, g fat, 4% calories from fat) was associated with mean increase of 22% and 17% in efavirenz AUC and mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. [See Dosage and Administration (2) and Patient Counseling Information (17)].Bioavailability of capsule contents mixed with food vehicles:In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.DistributionEfavirenz 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.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 200 400 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). EliminationEfavirenz 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 PopulationsPediatric: 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 Patients Body weight Dose Mean AUC (0-24) M.h Mean Cmax ug/mL Mean Cmin ug/mL 3.5-5 kg 100 mg 220.52 5.81 2.43 5-7.5 kg 150 mg 262.62 7.07 2.71 7.5-10 kg 200 mg 284.28 7.75 2.87 10-15 kg 200 mg 238.14 6.54 2.32 15-20 kg 250 mg 233.98 6.47 2.3 20-25 kg 300 mg 257.56 7.04 2.55 25-32.5 kg 350 mg 262.37 7.12 2.68 32.5-40 kg 400 mg 259.79 6.96 2.69 >40 kg 600 mg 254.78 6.57 2.82 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 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 (8.5-17 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%.a Compared with atazanavir 400 mg qd alone.b Comparator dose of indinavir was 800 mg q8h 10 days.c Parallel-group design; for efavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone.d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. 95% CI.f Soft Gelatin Capsule.g Tenofovir disoproxil fumarate.h 90% CI not available.i Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days.)j Not available because of insufficient data.NA= not available Coadministered Drug (mean change) Coadministered Drug Dose Efavirenz Dose Number of Subjects Cmax (90% CI) AUC (90% CI) Cmin (90% CI) Atazanavir 400 mg qd with light meal 1-20 600 mg qd with light meal 7-20 27 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 meal 600 mg qd h after atazanavir and ritonavir 7-20 13 14%a( 17- 58%) 39%a(2-88%) 48%a(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%) Indinavir 1000 mg q8h 10 days 600 mg qd 10 days 20 After morning dose <->b 33%b(26-39%) 39%b(24-51%) After afternoon dose <->b 37%b(26-46%) 52%b(47-57%) After evening dose 29%b(11-43%) 46%b(37-54%) 57%b(50-63%) Lopinavir/ Ritonavir 400/100 mg capsule q12h 9 days 600 mg qd 9 days 11,7c <->d 19%d( 36- 3%) 39%d(3-62%) 500/125 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd 9 days 19 12%d(2-23%) <->d 10%d( 22- 4%) 600/150 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd 9 days 23 36%d(28-44%) 36%d(28-44%) 32%d(21-44%) Nelfinavir 750 mg q8h 7 days 600 mg qd 7 days 10 21% (10-33%) 20% (8-34%) <-> Metabolite AG-1402 40% (30-48%) 37% (25-48%) 43% (21-59%) Ritonavir 500 mg q12h 8 days 600 mg qd 10 days 11 After AM dose 24% (12-38%) 18% (6-33%) 42% (9-86%)e After PM dose <-> <-> 24% (3-50%)e Saquinavir SGCf 1200 mg q8h 10 days 600 mg qd 10 days 12 50% (28-66%) 62% (45-74%) 56% (16-77%)e Lamivudine 150 mg q12h 14 days 600 mg qd 14 days <-> <-> 265% (37-873%) Tenofovirg 300 mg qd 600 mg qd 14 days 29 <-> <-> <-> Zidovudine 300 mg q12h 14 days 600 mg qd 14 days <-> <-> 225% (43-640%) Maraviroc 100 mg bid 600 mg qd 12 51% (37-62%) 45% (38-51%) 45% (28-57%) Raltegravir 400 mg single dose 600 mg qd 36% (2-59%) 36% (20-48%) 21% 51- 28%) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 8% 22- 8%) 19% (11-25%) 44% (26-58%) Simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 51% 46- 56%) 71% (67-74%) 91% (88-92%) Azithromycin 600 mg single dose 400 mg qd 7 days 14 22% (4-42%) <-> NA Clarithromycin 500 mg q12h 7 days 400 mg qd 7 days 11 26% (15-35%) 39% (30-46%) 53% (42-63%) 14-OH metabolite 49% (32-69%) 34% (18-53%) 26% (9-45%) Fluconazole 200 mg 7 days 400 mg qd 7 days 10 <-> <-> <-> Itraconazole 200 mg q12h 28 days 600 mg qd 14 days 18 37% (20-51%) 39% (21-53%) 44% (27-58%) Hydroxy-itraconazole 35% (12-52%) 37% (14-55%) 43% (18-60%) Posaconazole 400 mg (oral suspension) bid 10 and 20 days 400 mg qd 10 and 20 days 11 45% (34-53%) 50% (40-57%) NA Rifabutin 300 mg qd 14 days 600 mg qd 14 days 32% (15-46%) 38% (28-47%) 45% (31-56%) Voriconazole 400 mg po q12h 1 day, then 200 mg po q12h 8 days 400 mg qd 9 days NA 61%h 77%h NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 36%i(21-49%) 55%i(45-62%) NA 400 mg po q12h days 2-7 300 mg qd 7 days NA 23%i( 1- 53%) 7%i( 23- 13%) NA Artemether/lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 Artemether 21% 51% NA dihydroartemisinin 38% 46% NA lumefantrine <-> 21% NA Atorvastatin 10 mg qd 4 days 600 mg qd 15 days 14 14% (1-26%) 43% (34-50%) 69% (49-81%) Total active (including metabolites) 15% (2-26%) 32% (21-41%) 48% (23-64%) Pravastatin 40 mg qd 4 days 600 mg qd 15 days 13 32% 59- 12%) 44% (26-57%) 19% (0-35%) Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 72% (63-79%) 68% (62-73%) 45% (20-62%) Total active (including metabolites) 68% (55-78%) 60% (52-68%) NAj Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days 600 mg qd 14 days 12 20% (15-24%) 27% (20-33%) 35% (24-44%) Epoxide metabolite <-> <-> 13% 30- 7%) Cetirizine 10 mg single dose 600 mg qd 10 days 11 24% (18-30%) <-> NA Diltiazem 240 mg 21 days 600 mg qd 14 days 13 60% (50-68%) 69% (55-79%) 63% (44-75%) Desacetyl diltiazem 64% (57-69%) 75% (59-84%) 62% (44-75%) N- monodesmethyldiltiazem 28% (7-44%) 37% (17-52%) 37% (17-52%) Ethinyl estradiol/ Norgestimate 0.035 mg/ 0.25 mg 14 days 600 mg qd 14 days Ethinyl estradiol 21 <-> <-> <-> Norelgestromin 21 46% (39-52%) 64% (62-67%) 82% (79-85%) Levonorgestrel 80% (77-83%) 83% (79-87%) 86% (80-90%) Lorazepam mg single dose 600 mg qd 10 days 12 16% (2-32%) <-> NA Methadone Stable maintenance 35- 100 mg daily 600 mg qd 14-21 days 11 45% (25-59%) 52% (33-66%) NA Bupropion 150 mg single dose (sustained-release) 600 mg qd 14 days 13 34% (21-47%) 55% (48-62%) NA Hydroxy- bupropion 50% (20-80%) <-> NA Paroxetine 20 mg qd 14 days 600 mg qd 14 days 16 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 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%.a Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule.d Tenofovir disoproxil fumarate. 90% CI not available.f Relative to steady-state administration of efavirenz (600 mg once daily for days). NA not available. Efavirenz (mean change) Coadministered Drug Dose Efavirenz Dose Number of Subjects Cmax (90% CI) AUC (90% CI) Cmin (90% CI) Indinavir 800 mg q8h 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 q8h 7 days 600 mg qd 7 days 10 12% 32- 13%)b 12% 35- 18%)b 21% 53- 33%) Ritonavir 500 mg q12h 8 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%) Tenofovird 300 mg qd 600 mg qd 14 days 30 <-> <-> <-> Boceprevir 800 mg tid 6 days 600 mg qdx16days 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 mg single dose 400 mg qd 7 days 14 <-> <-> <-> Clarithromycin 500 mg q12h 7 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 14 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 15 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 single dose 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 single dose 400 mg single dose 17 <-> <-> NA Paroxetine 20 mg qd 14 days 600 mg qd 14 days 12 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 11% (6-16%) <-> <-> 12.4 Microbiology. Mechanism of ActionEfavirenz 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 CultureThe 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. ResistanceIn cell cultureIn 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 studiesClinical 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-ResistanceCross-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.

14 CLINICAL STUDIES. 14.1 Adults. Study 006, randomized, open-label trial, compared Efavirenz (600 mg once daily) zidovudine (ZDV, 300 mg q12h) lamivudine (LAM, 150 mg q12h) or Efavirenz (600 mg once daily) indinavir (IDV, 1000 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 18-81], 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 006a Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week 168.b 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.c 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. Outcome Efavirenz ZDV +LAM (n=422) Efavirenz IDV (n=429) IDV ZDV LAM (n=415) 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 for adverse 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 For patients treated with Efavirenz zidovudine lamivudine, Efavirenz 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 18-76], 74% Caucasian, 88% male) received NRTIs in combination with Efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or Efavirenz (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 8130 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 For some patients, Week 56 data were used to confirm the status at Week 48.a Subjects achieved virologic response (two consecutive viral loads <500 copies/mL) and maintained it through Week 48.b Includes viral rebound and failure to achieve confirmed <500 copies/mL by Week 48.c See Adverse Reactions (6.1) for safety profile of these regimens.d Includes loss to follow-up, consent withdrawn, noncompliance. Outcome Efavirenz NFV NRTIs (n=65) Efavirenz 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% 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-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 1144 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 1021 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. 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. 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%.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Efavirenz tablets USP should be taken orally once daily on an empty stomach, preferably at bedtime. (2)Recommended adult dose: 600 mg. (2.2)With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2)With rifampin, increase Efavirenz dose to 800 mg once daily for patients weighing 50 kg or more. (2.2)Pediatric dosing is based on weight. (2.3). Efavirenz tablets USP should be taken orally once daily on an empty stomach, preferably at bedtime. (2). Recommended adult dose: 600 mg. (2.2). With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2). With rifampin, increase Efavirenz dose to 800 mg once daily for patients weighing 50 kg or more. (2.2). Pediatric dosing is based on weight. (2.3). 2.1 Hepatic Function. Monitor hepatic function prior to and during treatment with Efavirenz [see Warnings and Precautions (5.9)]. Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child Pugh or C) [see Warnings and Precautions (5.9) and Use in Specmc Populations (8.6)]. 2.2 Adults. The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3)]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) Adverse Reactions (6.1), and Patient Counseling Information (17)]. Efavirenz Tablets 600mg should be swallowed intact with liquid. For patients who cannot swallow tablets, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.4)]. Concomitant Antiretroviral Therapy Efavirenz must be given in combination with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.3) Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. Dosage Adjustment If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules).Efavirenz tablets must not be broken. [See Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Tables and 8)]. If Efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Efavirenz to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5) and Clinical Pharmacology (12.3, Table 8)]. 2.3 Pediatric Patients. It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. Table 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 [see Dosage and Administration (2.4)]Table 1: Efavirenz Dosing in Pediatric Patientsa Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4) ].b Tablets must not be crushed Patient Body Weight Efavirenz Daily Dose Number of Capsulesa or Tabletsb and Strength to Administer 3.5 kg to less than kg 100 mg two 50 mg capsules kg to less than 7.5 kg 150 mg three 50 mg capsules 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg one 600 mg tablet OR three 200 mg capsules 2.4 Capsule Sprinkle Method of Administration:. For pediatric patients at least months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with small amount (1 to teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into teaspoons of reconstituted room temperature infant formula in small container by carefully stirring with small spoon, and then drawing up the mixture into 10 mL oral dosing syringe for administration. After administration of the efavirenz-food or -formula mixture, an additional small amount (approximately teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining efavirenz residue, and administered to the patient. The efavirenz-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for hours after administration of efavirenz.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPeak 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).]Capsules: Administration of single 600 mg dose of efavirenz capsules with high-fat/high-caloric meal (894 kcal, 54 fat, 54% calories from fat) or reduced-fat/normal-caloric meal (440 kcal, g fat, 4% calories from fat) was associated with mean increase of 22% and 17% in efavirenz AUC and mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. [See Dosage and Administration (2) and Patient Counseling Information (17)].Bioavailability of capsule contents mixed with food vehicles:In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.DistributionEfavirenz 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.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 200 400 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). EliminationEfavirenz 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 PopulationsPediatric: 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 Patients Body weight Dose Mean AUC (0-24) M.h Mean Cmax ug/mL Mean Cmin ug/mL 3.5-5 kg 100 mg 220.52 5.81 2.43 5-7.5 kg 150 mg 262.62 7.07 2.71 7.5-10 kg 200 mg 284.28 7.75 2.87 10-15 kg 200 mg 238.14 6.54 2.32 15-20 kg 250 mg 233.98 6.47 2.3 20-25 kg 300 mg 257.56 7.04 2.55 25-32.5 kg 350 mg 262.37 7.12 2.68 32.5-40 kg 400 mg 259.79 6.96 2.69 >40 kg 600 mg 254.78 6.57 2.82 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 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 (8.5-17 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%.a Compared with atazanavir 400 mg qd alone.b Comparator dose of indinavir was 800 mg q8h 10 days.c Parallel-group design; for efavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone.d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. 95% CI.f Soft Gelatin Capsule.g Tenofovir disoproxil fumarate.h 90% CI not available.i Relative to steady-state administration of voriconazole (400 mg for day, then 200 mg po q12h for days.)j Not available because of insufficient data.NA= not available Coadministered Drug (mean change) Coadministered Drug Dose Efavirenz Dose Number of Subjects Cmax (90% CI) AUC (90% CI) Cmin (90% CI) Atazanavir 400 mg qd with light meal 1-20 600 mg qd with light meal 7-20 27 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 meal 600 mg qd h after atazanavir and ritonavir 7-20 13 14%a( 17- 58%) 39%a(2-88%) 48%a(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%) Indinavir 1000 mg q8h 10 days 600 mg qd 10 days 20 After morning dose <->b 33%b(26-39%) 39%b(24-51%) After afternoon dose <->b 37%b(26-46%) 52%b(47-57%) After evening dose 29%b(11-43%) 46%b(37-54%) 57%b(50-63%) Lopinavir/ Ritonavir 400/100 mg capsule q12h 9 days 600 mg qd 9 days 11,7c <->d 19%d( 36- 3%) 39%d(3-62%) 500/125 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd 9 days 19 12%d(2-23%) <->d 10%d( 22- 4%) 600/150 mg tablet q12h 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd 9 days 23 36%d(28-44%) 36%d(28-44%) 32%d(21-44%) Nelfinavir 750 mg q8h 7 days 600 mg qd 7 days 10 21% (10-33%) 20% (8-34%) <-> Metabolite AG-1402 40% (30-48%) 37% (25-48%) 43% (21-59%) Ritonavir 500 mg q12h 8 days 600 mg qd 10 days 11 After AM dose 24% (12-38%) 18% (6-33%) 42% (9-86%)e After PM dose <-> <-> 24% (3-50%)e Saquinavir SGCf 1200 mg q8h 10 days 600 mg qd 10 days 12 50% (28-66%) 62% (45-74%) 56% (16-77%)e Lamivudine 150 mg q12h 14 days 600 mg qd 14 days <-> <-> 265% (37-873%) Tenofovirg 300 mg qd 600 mg qd 14 days 29 <-> <-> <-> Zidovudine 300 mg q12h 14 days 600 mg qd 14 days <-> <-> 225% (43-640%) Maraviroc 100 mg bid 600 mg qd 12 51% (37-62%) 45% (38-51%) 45% (28-57%) Raltegravir 400 mg single dose 600 mg qd 36% (2-59%) 36% (20-48%) 21% 51- 28%) Boceprevir 800 mg tid 6 days 600 mg qd 16 days NA 8% 22- 8%) 19% (11-25%) 44% (26-58%) Simeprevir 150 mg qd 14 days 600 mg qd 14 days 23 51% 46- 56%) 71% (67-74%) 91% (88-92%) Azithromycin 600 mg single dose 400 mg qd 7 days 14 22% (4-42%) <-> NA Clarithromycin 500 mg q12h 7 days 400 mg qd 7 days 11 26% (15-35%) 39% (30-46%) 53% (42-63%) 14-OH metabolite 49% (32-69%) 34% (18-53%) 26% (9-45%) Fluconazole 200 mg 7 days 400 mg qd 7 days 10 <-> <-> <-> Itraconazole 200 mg q12h 28 days 600 mg qd 14 days 18 37% (20-51%) 39% (21-53%) 44% (27-58%) Hydroxy-itraconazole 35% (12-52%) 37% (14-55%) 43% (18-60%) Posaconazole 400 mg (oral suspension) bid 10 and 20 days 400 mg qd 10 and 20 days 11 45% (34-53%) 50% (40-57%) NA Rifabutin 300 mg qd 14 days 600 mg qd 14 days 32% (15-46%) 38% (28-47%) 45% (31-56%) Voriconazole 400 mg po q12h 1 day, then 200 mg po q12h 8 days 400 mg qd 9 days NA 61%h 77%h NA 300 mg po q12h days 2-7 300 mg qd 7 days NA 36%i(21-49%) 55%i(45-62%) NA 400 mg po q12h days 2-7 300 mg qd 7 days NA 23%i( 1- 53%) 7%i( 23- 13%) NA Artemether/lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over days) 600 mg qd 26 days 12 Artemether 21% 51% NA dihydroartemisinin 38% 46% NA lumefantrine <-> 21% NA Atorvastatin 10 mg qd 4 days 600 mg qd 15 days 14 14% (1-26%) 43% (34-50%) 69% (49-81%) Total active (including metabolites) 15% (2-26%) 32% (21-41%) 48% (23-64%) Pravastatin 40 mg qd 4 days 600 mg qd 15 days 13 32% 59- 12%) 44% (26-57%) 19% (0-35%) Simvastatin 40 mg qd 4 days 600 mg qd 15 days 14 72% (63-79%) 68% (62-73%) 45% (20-62%) Total active (including metabolites) 68% (55-78%) 60% (52-68%) NAj Carbamazepine 200 mg qd 3 days, 200 mg bid 3 days, then 400 mg qd 29 days 600 mg qd 14 days 12 20% (15-24%) 27% (20-33%) 35% (24-44%) Epoxide metabolite <-> <-> 13% 30- 7%) Cetirizine 10 mg single dose 600 mg qd 10 days 11 24% (18-30%) <-> NA Diltiazem 240 mg 21 days 600 mg qd 14 days 13 60% (50-68%) 69% (55-79%) 63% (44-75%) Desacetyl diltiazem 64% (57-69%) 75% (59-84%) 62% (44-75%) N- monodesmethyldiltiazem 28% (7-44%) 37% (17-52%) 37% (17-52%) Ethinyl estradiol/ Norgestimate 0.035 mg/ 0.25 mg 14 days 600 mg qd 14 days Ethinyl estradiol 21 <-> <-> <-> Norelgestromin 21 46% (39-52%) 64% (62-67%) 82% (79-85%) Levonorgestrel 80% (77-83%) 83% (79-87%) 86% (80-90%) Lorazepam mg single dose 600 mg qd 10 days 12 16% (2-32%) <-> NA Methadone Stable maintenance 35- 100 mg daily 600 mg qd 14-21 days 11 45% (25-59%) 52% (33-66%) NA Bupropion 150 mg single dose (sustained-release) 600 mg qd 14 days 13 34% (21-47%) 55% (48-62%) NA Hydroxy- bupropion 50% (20-80%) <-> NA Paroxetine 20 mg qd 14 days 600 mg qd 14 days 16 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 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%.a Parallel-group design; for efavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule.d Tenofovir disoproxil fumarate. 90% CI not available.f Relative to steady-state administration of efavirenz (600 mg once daily for days). NA not available. Efavirenz (mean change) Coadministered Drug Dose Efavirenz Dose Number of Subjects Cmax (90% CI) AUC (90% CI) Cmin (90% CI) Indinavir 800 mg q8h 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 q8h 7 days 600 mg qd 7 days 10 12% 32- 13%)b 12% 35- 18%)b 21% 53- 33%) Ritonavir 500 mg q12h 8 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%) Tenofovird 300 mg qd 600 mg qd 14 days 30 <-> <-> <-> Boceprevir 800 mg tid 6 days 600 mg qdx16days 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 mg single dose 400 mg qd 7 days 14 <-> <-> <-> Clarithromycin 500 mg q12h 7 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 14 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 15 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 single dose 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 single dose 400 mg single dose 17 <-> <-> NA Paroxetine 20 mg qd 14 days 600 mg qd 14 days 12 <-> <-> <-> Sertraline 50 mg qd 14 days 600 mg qd 14 days 13 11% (6-16%) <-> <->.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere 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 SummaryThere 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.DataHuman DataThere 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 DataEffects 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(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 tablets Read this Patient Information before you start taking Efavirenz 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 are Efavirenz tabletsEfavirenz 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:reduce the amount of HIV-1 in your blood. This is called viral load.increase the number of CD4+ (T) cells in your blood that help fight off other infectionsReducing 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 does 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: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 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 tablets Do not take Efavirenz if you are allergic to efavirenz or any of the ingredients in Efavirenz. See the end of this leaflet for complete list of ingredients in Efavirenz. Do not take Efavirenz 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: have heart conditionhave ever had mental health problemhave ever used street drugs or large amounts of alcoholhave liver problems, including hepatitis or virus infectionhave history of seizuresare 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. You should not become pregnant while taking Efavirenz and for 12 weeks after stopping treatment with Efavirenz. 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 A barrier form of birth control should be used along with another type of birth control.Barrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.Hormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with Efavirenz tablets .Talk to your doctor about forms of birth control that may be used during treatment with Efavirenz.Pregnancy 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.Do not breastfeed if you take Efavirenz tablets.You should not breastfeed if you have HIV because of the risk of passing HIV to your babyTell 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, 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.Keep list of your medicines to show your doctor and pharmacist.You can ask your doctor or pharmacist for list of medicines that interact with Efavirenz.Do 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 tabletsTake Efavirenz exactly as your doctor tells you to.Do not change your dose or stop taking Efavirenz unless your doctor tells you to.Stay under the care of your doctor during treatment with Efavirenz.Efavirenz must be used with other antiretroviral medicines.Take Efavirenz time each day.Efavirenz comes as tablet.Efavirenz tablets must not be broken.Swallow Efavirenz whole with liquid.How and when to take Efavirenz tabletsYou should take Efavirenz on an empty stomach at bedtime. Taking Efavirenz with food increases the amount of medicine in your body. Some side effects may bother you less if you take Efavirenz on an empty stomach and at bedtime.Your childs doctor will prescribe the right dose of Efavirenz based on your childs weight.If you have difficulty swallowing tablets, tell your doctor. Your doctor may recommend opening the efavirenz capsule and mixing the contents with food or infant formula.Adults and children who take efavirenz using the capsule sprinkle method should not eat for hours after taking dose of efavirenz.Babies should not be given infant formula for hours after taking dose of efavirenz using the capsule sprinkle method.Do not miss dose of Efavirenz. If you forget to take Efavirenz, 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.If you take too much Efavirenz, call your doctor or go to the nearest hospital emergency room right away.When your efavirenz supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of Efavirenz. 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 and harder to treat.What are the possible side effects of Efavirenz tablets Efavirenz tablets may cause serious side effects, including:Serious mental health problems can happen in people who take Efavirenz. Tell your doctor right away if you have any of the following symptoms:feel sad or hopelessfeel anxious or restlesshave thoughts of hurting yourself (suicide) or have tried to hurt yourself or othersare not able to tell the difference between what is true or real and what is false or unrealdo not trust other peoplehear or see things that are not realare not able to move or speak normally Nervous system symptoms are common in people who take Efavirenz and can be severe. These symptoms usually begin during the first or second day of treatment with Efavirenz 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. Symptoms may include:dizzinesstrouble sleepingtrouble concentratingdrowsinessunusual dreamslack 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.Skin rash is common with efavirenz 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:skin rash, with or without itchingfeverswelling of your faceblisters or skin lesionspeeling skinmouth soresred or inflamed eyes, like pink eye (conjunctivitis) Liver problems, including liver failure and death can happen in people who take Efavirenz. 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 and during treatment. Tell your doctor right away if you get any of the following symptoms:your skin or the white part of your eyes turns yellow (jaundice)your urine turns darkyour bowel movements (stools) turn light in coloryou dont feel like eating food for several days or longeryou feel sick to your stomach (nausea)you have lower stomach area (abdominal) pain Seizures can happen in people who take Efavirenz. 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.Changes 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.Changes 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:rashdizzinessnauseaheadachedifficulty concentratingabnormal dreamstirednesstrouble sleepingvomitingSome patients taking Efavirenz 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. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatchHow should store Efavirenz tabletsStore Efavirenz tablets at room temperature between 68F to 77F (20C to 25C).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 for condition for which it was not prescribed. Do not give Efavirenz to other people, even if they have the same symptoms that you have. It may harm them.If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Efavirenz that is written for health professionals. For more information, you can contact Strides Pharma Inc. at 1-877-244-9825 What are the ingredients in Efavirenz tablets Active ingredient: efavirenz Inactive ingredients: Efavirenz tablets: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains Instacoat Universal. Instacoat Universal contains HPMC 2910/Hypromellose, titanium dioxide, polyethylene glycol, red iron oxide, black iron oxide and yellow iron oxide. Opacode black ink contains propylene glycol, shellac glaze and ferrosoferric oxide.This Patient Information has been approved by the U.S. Food and Drug Administration. Distributed by: Strides Pharma Inc. East Brunswick, NJ 08816.Revision: 05/2020Trademarks are the property of their respective owners.. reduce the amount of HIV-1 in your blood. This is called viral load.. increase the number of CD4+ (T) cells in your blood that help fight off other infections. 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 any body fluids such as semen, vaginal secretions, or blood.. have heart condition. have ever had mental health problem. have ever used street drugs or large amounts of alcohol. have liver problems, including hepatitis or virus infection. have history of seizures. are 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. You should not become pregnant while taking Efavirenz and for 12 weeks after stopping treatment with Efavirenz. 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 A barrier form of birth control should be used along with another type of birth control.. Barrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap.. Hormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with Efavirenz tablets .. Talk to your doctor about forms of birth control that may be used during treatment with Efavirenz.. Pregnancy 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.. Do not breastfeed if you take Efavirenz tablets.. You should not breastfeed if you have HIV because of the risk of passing HIV to your baby. You can ask your doctor or pharmacist for list of medicines that interact with Efavirenz.. Do 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.. Take Efavirenz exactly as your doctor tells you to.. Do not change your dose or stop taking Efavirenz unless your doctor tells you to.. Stay under the care of your doctor during treatment with Efavirenz.. Efavirenz must be used with other antiretroviral medicines.. Take Efavirenz time each day.. Efavirenz comes as tablet.. Efavirenz tablets must not be broken.. Swallow Efavirenz whole with liquid.. You should take Efavirenz on an empty stomach at bedtime. Taking Efavirenz with food increases the amount of medicine in your body. Some side effects may bother you less if you take Efavirenz on an empty stomach and at bedtime.. Your childs doctor will prescribe the right dose of Efavirenz based on your childs weight.. If you have difficulty swallowing tablets, tell your doctor. Your doctor may recommend opening the efavirenz capsule and mixing the contents with food or infant formula.. Adults and children who take efavirenz using the capsule sprinkle method should not eat for hours after taking dose of efavirenz.. Babies should not be given infant formula for hours after taking dose of efavirenz using the capsule sprinkle method.. Do not miss dose of Efavirenz. If you forget to take Efavirenz, 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.. If you take too much Efavirenz, call your doctor or go to the nearest hospital emergency room right away.. When your efavirenz supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of Efavirenz. 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 and harder to treat.. Serious mental health problems can happen in people who take Efavirenz. Tell your doctor right away if you have any of the following symptoms:feel sad or hopelessfeel anxious or restlesshave thoughts of hurting yourself (suicide) or have tried to hurt yourself or othersare not able to tell the difference between what is true or real and what is false or unrealdo not trust other peoplehear or see things that are not realare not able to move or speak normally feel sad or hopeless. feel anxious or restless. have thoughts of hurting yourself (suicide) or have tried to hurt yourself or others. are not able to tell the difference between what is true or real and what is false or unreal. do not trust other people. hear or see things that are not real. are not able to move or speak normally. Nervous system symptoms are common in people who take Efavirenz and can be severe. These symptoms usually begin during the first or second day of treatment with Efavirenz 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. Symptoms may include:dizzinesstrouble sleepingtrouble concentratingdrowsinessunusual dreamslack of coordination or difficulty with balance dizziness. trouble sleeping. trouble concentrating. drowsiness. unusual dreams. lack of coordination or difficulty with balance. Skin rash is common with efavirenz 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:skin rash, with or without itchingfeverswelling of your faceblisters or skin lesionspeeling skinmouth soresred or inflamed eyes, like pink eye (conjunctivitis) skin rash, with or without itching. fever. swelling of your face. blisters or skin lesions. peeling skin. mouth sores. red or inflamed eyes, like pink eye (conjunctivitis). Liver problems, including liver failure and death can happen in people who take Efavirenz. 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 and during treatment. Tell your doctor right away if you get any of the following symptoms:your skin or the white part of your eyes turns yellow (jaundice)your urine turns darkyour bowel movements (stools) turn light in coloryou dont feel like eating food for several days or longeryou feel sick to your stomach (nausea)you have lower stomach area (abdominal) pain your skin or the white part of your eyes turns yellow (jaundice). your urine turns dark. your bowel movements (stools) turn light in color. you dont feel like eating food for several days or longer. you feel sick to your stomach (nausea). you have lower stomach area (abdominal) pain. Seizures can happen in people who take Efavirenz. 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.. Changes 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.. Changes 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.. rash. dizziness. nausea. headache. difficulty concentrating. abnormal dreams. tiredness. trouble sleeping. vomiting.

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 is 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). Lactation: Breastfeeding not recommended. (8.2). Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. (8.3). Hepatic impairment: Efavirenz is 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. Pregnancy Exposure RegistryThere 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 SummaryThere 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.DataHuman DataThere 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 DataEffects 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 SummaryThe 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 TestingFemales of reproductive potential should undergo pregnancy testing before initiation of Efavirenz.ContraceptionFemales 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 (7.1)].. 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.. 8.6 Hepatic 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. 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 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)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 1-2 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). 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 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). 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 1-2 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 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 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 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. 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)].. 5.6 Nervous 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.. 5.7 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 to avoid pregnancy. [See Use in Specific Populations (8.1 and 8.3).]. 5.8 Rash. 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 (eg, 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 (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 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.. 5.12 Immune 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, and Guillain-Barre syndrome and and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.. 5.13 Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and 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.