ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most significant adverse reactionsobserved in patients treated with SUSTIVA are:psychiatric symptoms [see Warnings and Precautions (5.4) ],nervous system symptoms [see Warnings and Precautions (5.5) ],rash [see Warnings and Precautions (5.7) ].The most common (>5% in either efavirenz treatment group)adverse reactions of at least moderate severity among patients in Study 006treated with SUSTIVA in combination with zidovudine/lamivudine or indinavirwere rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.. psychiatric symptoms [see Warnings and Precautions (5.4) ],. nervous system symptoms [see Warnings and Precautions (5.5) ],. rash [see Warnings and Precautions (5.7) ].. Mostcommon adverse reactions (>5%, moderate-severe) are rash, dizziness, nausea,headache, fatigue, insomnia, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience in Adults. Because clinical studies are conductedunder widely varying conditions, the adverse reaction rates reported cannotbe directly compared to rates in other clinical studies and may not reflectthe rates observed in clinical practice.Selectedclinical adverse reactions of moderate or severe intensity observed in >=2%of SUSTIVA-treated patients in two controlled clinical trials are presentedin Table 3.Table 3:Selected Treatment-Emergenta AdverseReactions of Moderate or Severe Intensity Reported in >=2% of SUSTIVA-TreatedPatients in Studies 006 and ACTG 364Study 006 LAM-,NNRTI-, and Protease Inhibitor-Naive PatientsStudy ACTG 364 NRTI-experienced,NNRTI-, and Protease Inhibitor-Naive PatientsAdverse ReactionsSUSTIVAb +ZDV/LAM(n=412)SUSTIVAb +Indinavir(n=415)Indinavir+ZDV/LAM(n=401)SUSTIVAb Nelfinavir+ NRTIs (n=64)SUSTIVAb NRTIs(n=65)Nelfinavir+NRTIs(n=66)180 weeksc 102 weeksc 76 weeksc 71.1 weeksc 70.9 weeksc 62.7 weeksc Includes adverse events at leastpossibly related to study drug or of unknown relationship for Study 006. Includesall adverse events regardless of relationship to study drug for Study ACTG364.b SUSTIVA provided as 600 mg oncedaily.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, andpruritus for ACTG 364.-- Not Specified.ZDV zidovudine, LAM lamivudine.Body as Whole Fatigue8%5%9%02%3% Pain1%2%8%13%6%17%Central and Peripheral Nervous System Dizziness9%9%2%2%6%6% Headache8%5%3%5%2%3% Insomnia7%7%2%002% Concentration impaired5%3%<1%000 Abnormal dreams3%1%0------ Somnolence2%2%<1%000 Anorexia1%<1%<1%02%2%Gastrointestinal Nausea10%6%24%3%2%2% Vomiting6%3%14%------ Diarrhea3%5%6%14%3%9% Dyspepsia4%4%6%002% Abdominal pain2%2%5%3%3%3%Psychiatric Anxiety2%4%<1%------ Depression5%4%<1%3%05% Nervousness2%2%02%02%Skin Appendages Rashd 11%16%5%9%5%9% Pruritus<1%1%1%9%5%9%Pancreatitis has been reported, although causalrelationship with efavirenz has not been established. Asymptomatic increasesin serum amylase levels were observed in significantly higher number ofpatients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities).. Nervous System Symptoms For 1008 patients treated with regimenscontaining SUSTIVA and 635 patients treated with control regimen in controlledtrials, Table lists the frequency of symptoms of different degrees of severityand gives the discontinuation rates for one or more of the following nervoussystem symptoms: dizziness, insomnia, impaired concentration, somnolence,abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations,stupor, abnormal thinking, and depersonalization [see Warnings andPrecautions (5.5) ]. The frequenciesof specific central and peripheral nervous system symptoms are provided in Table 3.Table 4:Percent of Patients with One or More Selected Nervous SystemSymptomsa,b Percent of Patientswith:SUSTIVA600 mg Once Daily(n=1008)ControlGroups(n=635)%%a Includes eventsreported regardless of causality.b Data from Study006 and three Phase 2/3 studies.c Mild Symptomswhich do not interfere with patients daily activities.d Moderate Symptomswhich may interfere with daily activities.e Severe Eventswhich interrupt patients usual daily activities.Symptoms of any severity52.724.6Mild symptomsc 33.315.6Moderate symptomsd 17.47.7Severe symptomse 2.01.3Treatment discontinuation asa result of symptoms2.11.1. Psychiatric Symptoms. Serious psychiatric adverse experienceshave been reported in patients treated with SUSTIVA. In controlled trials,psychiatric symptoms observed at frequency of >2% among patients treatedwith SUSTIVA or control regimens, respectively, were depression (19%, 16%),anxiety (13%, 9%), and nervousness (7%, 2%).. Rash. For 1008 adult and 57 pediatricpatients treated with regimens containing SUSTIVA and 635 patients treatedwith control regimen in controlled trials, the frequency of rash by NCIgrade and the discontinuation rates as result of rash in clinical studiesare provided in Table [see Warnings and Precautions (5.7) ].Table 5:Percent of Patients with Treatment-Emergent Rasha,b Percent of Patients with:Description of Rash Gradec SUSTIVA600 mg Once Daily Adults(n=1008)SUSTIVAPediatricPatients(n=57)ControlGroupsAdults(n=635)%%%a Includes eventsreported regardless of causality.b Data from Study006 and three Phase 2/3 studies.c NCI Grading System.Rash of any grade--26.345.617.5Grade rashErythema, pruritus10.78.89.8Grade rashDiffuse maculopapular rash, dry desquamation14.731.67.4Grade rashVesiculation, moist desquamation,ulceration0.81.80.3Grade rashErythema multiforme, Stevens-Johnsonsyndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliativedermatitis0.13.50.0Treatment discontinuationas result of rash--1.78.80.3As seen in Table 5, rash is more common in pediatricpatients and more often of higher grade (ie, more severe) [see Warningsand Precautions (5.7) ].Experience with SUSTIVA in patients who discontinued other antiretroviralagents of the NNRTI class is limited. Nineteen patients who discontinued nevirapinebecause of rash have been treated with SUSTIVA. Nine of these patients developedmild-to-moderate rash while receiving therapy with SUSTIVA, and two of thesepatients discontinued because of rash.. Laboratory Abnormalities. Selected Grade 3-4 laboratory abnormalitiesreported in >=2% of SUSTIVA-treated patients in two clinical trials are presentedin Table 6.Table 6:Selected Grade 3-4 Laboratory Abnormalities Reported in >=2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-,NNRTI-, and ProteaseInhibitor-Naive PatientsStudy ACTG 364 NRTI-experienced,NNRTI-, and ProteaseInhibitor-Naive PatientsVariableLimitSUSTIVAa ZDV/LAM(n=412)SUSTIVAa Indinavir(n=415)Indinavir+ ZDV/LAM(n=401)SUSTIVAa Nelfinavir+ NRTIs(n=64)SUSTIVAa NRTIs(n=65)Nelfinavir+ NRTIs(n=66)180 weeksb 102 weeksb 76 weeksb 71.1 weeksb 70.9 weeksb 62.7 weeksb SUSTIVA providedas 600 mg once daily.b Median durationof treatment.c Isolated elevationsof GGT in patients receiving SUSTIVA may reflect enzyme induction not associatedwith liver toxicity.d Nonfasting.ZDV zidovudine, LAM lamivudine,ULN Upper limit of normal, ALT alanine aminotransferase,AST aspartate aminotransferase, GGT gamma-glutamyltransferase.Chemistry ALT>5 ULN5%8%5%2%6%3% AST>5 ULN5%6%5%6%8%8% GGTc >5 ULN8%7%3%5%05% Amylase>2 ULN4%4%1%06%2% Glucose>250 mg/dL3%3%3%5%2%3% Triglyceridesd >=751 mg/dL9%6%6%11%8%17%Hematology Neutrophils<750/mm3 10%3%5%2%3%2%. Patients Coinfected with Hepatitis or C. Liver function tests should be monitored in patients with history of hepatitis and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median durationof therapy, 68 weeks) and 84 treated with control regimen (median duration,56 weeks) were seropositive at screening for hepatitis (surface antigenpositive) and/or (hepatitis antibody positive). Among these coinfectedpatients, elevations in AST to greater than five times ULN developed in 13%of patients in the SUSTIVA arms and 7% of those in the control arm, and elevationsin ALT to greater than five times ULN developed in 20% of patients in theSUSTIVA arms and 7% of patients in the control arm. Among coinfected patients,3% of those treated with SUSTIVA-containing regimens and 2% in the controlarm discontinued from the study because of liver or biliary system disorders[see Warnings and Precautions (5.8) ].. Lipids. Increases from baseline in totalcholesterol of 10-20% have been observed in some uninfected volunteers receivingSUSTIVA. In patients treated with SUSTIVA zidovudine lamivudine, increasesfrom baseline in nonfasting total cholesterol and HDL of approximately 20%and 25%, respectively, were observed. In patients treated with SUSTIVA indinavir,increases from baseline in nonfasting cholesterol and HDL of approximately40% and 35%, respectively, were observed. Nonfasting total cholesterol levels >=240 mg/dL and >=300 mg/dL were reported in 34% and 9%, respectively, of patientstreated with SUSTIVA zidovudine lamivudine; 54% and 20%, respectively,of patients treated with SUSTIVA indinavir; and 28% and 4%, respectively,of patients treated with indinavir zidovudine lamivudine. The effectsof SUSTIVA on triglycerides and LDL in this study were not well characterizedsince samples were taken from nonfasting patients. The clinical significanceof these findings is unknown [see Warnings and Precautions (5.10) ].. 6.2 Clinical Trial Experience in Pediatric Patients Clinical adverse experiences observedin >=10% of 57 pediatric patients aged to 16 years who received SUSTIVA capsules,nelfinavir, and one or more NRTIs in Study ACTG 382 [see Use In SpecificPopulations (8.4) were rash (46%),diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting(16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%).The incidence of nervous system symptoms was 18% (10/57). One patient experiencedGrade rash, two patients had Grade rash, and five patients (9%) discontinuedbecause of rash [see Warnings and Precautions (5.7) and AdverseReactions (6.1, Table 5) ].. 6.3 Postmarketing Experience The following adverse reactions havebeen identified during postapproval use of SUSTIVA. Because these reactionsare reported voluntarily from population of unknown size, it is not alwayspossible to reliably estimate their frequency or establish causal relationshipto drug exposure. Body as Whole: allergicreactions, asthenia, redistribution/accumulation of body fat [see Warningsand Precautions (5.12) ]Central and Peripheral Nervous System: abnormalcoordination, ataxia, 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. few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by fulminant course, progressing in some cases to transplantation or death.Metabolic andNutritional: hypercholesterolemia, hypertriglyceridemiaMusculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation,delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicideRespiratory: dyspnea Skinand Appendages: erythema multiforme, photoallergic dermatitis, Stevens-JohnsonsyndromeSpecial Senses: abnormalvision, tinnitus.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology. Nonsustained convulsions were observed in of 20 monkeys receiving efavirenz at doses yielding plasma AUC values4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9) ].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Efavirenz is an antiviral drug[see Clinical Pharmacology (12.4) ]. 12.3 Pharmacokinetics. Absorption. Peak efavirenz plasma concentrationsof 1.6-9.1 uM were attained by hours following single oral doses of 100mg to 1600 mg administered to uninfected volunteers. Dose-related increasesin Cmax and AUC were seen for doses up to 1600 mg;the increases were less than proportional suggesting diminished absorptionat higher doses. In HIV-1-infected patients atsteady state, mean Cmax, mean Cmin,and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg dailydoses. Time-to-peak plasma concentrations were approximately 3-5 hours andsteady-state plasma concentrations were reached in 6-10 days. In 35 patientsreceiving SUSTIVA 600 mg once daily, steady-state Cmax was12.9 +- 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:. Capsules: Administrationof single 600-mg dose of efavirenz capsules with high-fat/high-caloricmeal (894 kcal, 54 fat, 54% calories from fat) or reduced-fat/normal-caloricmeal (440 kcal, g fat, 4% calories from fat) was associated with meanincrease of 22% and 17% in efavirenz AUC and meanincrease of 39% and 51% in efavirenz Cmax, respectively,relative to the exposures achieved when given under fasted conditions. See Dosageand Administration (2) and PatientCounseling Information (17.3) .Tablets: Administration of single 600-mg efavirenztablet with high-fat/high-caloric meal (approximately 1000 kcal, 500-600kcal from fat) was associated with 28% increase in mean AUC ofefavirenz and 79% increase in mean Cmax of efavirenzrelative to the exposures achieved under fasted conditions. See Dosageand Administration (2) and PatientCounseling Information (17.3) .. Distribution. Efavirenz is highly bound (approximately99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infectedpatients (n=9) who received SUSTIVA 200 to 600 mg once daily for at leastone month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean0.69%) of the corresponding plasma concentration. This proportion is approximately3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.. Metabolism. Studies in humans and in vitro studiesusing human liver microsomes have demonstrated that efavirenz is principallymetabolized by the cytochrome P450 system to hydroxylated metabolites withsubsequent glucuronidation of these hydroxylated metabolites. These metabolitesare essentially inactive against HIV-1. The in vitro studiessuggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenzmetabolism. Efavirenz has been shown to induceCYP enzymes, resulting in the induction of its own metabolism. Multiple dosesof 200-400 mg per day for 10 days resulted in lower than predicted extentof accumulation (22-42% lower) and shorter terminal half-life of 40-55 hours(single dose half-life 52-76 hours). Elimination. Efavirenz has terminal half-lifeof 52-76 hours after single doses and 40-55 hours after multiple doses. Aone-month mass balance/excretion study was conducted using 400 mg per daywith 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 radiolabeleddrug was in the form of metabolites. Efavirenz accounted for the majorityof the total radioactivity measured in feces.. Special Populations. Gender and race: Thepharmacokinetics of efavirenz in patients appear to be similar between menand women and among the racial groups studied.Renalimpairment: The pharmacokinetics of efavirenz have not been studiedin patients with renal insufficiency; however, less than 1% of efavirenz isexcreted unchanged in the urine, so the impact of renal impairment on efavirenzelimination should be minimal.Hepatic impairment: multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects efavirenz pharmacokinetics.. Drug Interaction Studies. Efavirenz has been shown invivo to cause hepatic enzyme induction, thus increasing the biotransformationof some drugs metabolized by CYP3A and CYP2B6. In vitro studies haveshown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values(8.5-17 uM) in the range of observed efavirenz plasma concentrations. In invitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6and CYP1A2 (Ki values 82-160 uM) only at concentrationswell above those achieved clinically. The inhibitory effect on CYP3A is expectedto be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministrationof efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymesmay result in altered plasma concentrations of the coadministered drug. Drugswhich induce CYP3A activity would be expected to increase the clearance ofefavirenz resulting in lowered plasma concentrations.Druginteraction studies were performed with efavirenz and other drugs likely tobe 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 ofefavirenz on other drugs) and Table (effect of other drugs on efavirenz).For information regarding clinical recommendations see Contraindications (4.2) and Drug Interactions (7.1) .Table 8:Effect of Efavirenz on Coadministered Drug Plasma Cmax,AUC, and Cmin CoadministeredDrugDoseEfavirenzDoseNumber of SubjectsCoadministeredDrug(mean change)Cmax (90%CI)AUC(90%CI)Cmin (90%CI) Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of <10%.a Compared with atazanavir 400mg qd alone.b Comparator dose of indinavirwas 800 mg q8h 10 days.c Parallel-group design; forefavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone.d Values are for lopinavir;the pharmacokinetics of ritonavir in this study were unaffected by concurrentefavirenz.e 95% CI.f Soft Gelatin Capsule.g Tenofovir disoproxil fumarate.h 90% CI not available.i Relative to steady-state administrationof voriconazole (400 mg for day, then 200 mg po q12h for days).j Not available becauseof insufficient data.NA not available.Atazanavir400 mg qd with alight meal 1-20600 mg qd with alight meal 7-2027 59%(49-67%) 74%(68-78%) 93%(90-95%) 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal600 mg qd h after atazanavir andritonavir 7-2013 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%)Indinavir1000 mg q8h 10 days600 mg qd 10 days20 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/ ritonavir400/100 mg capsuleq12hx days600 mg qd 9 days11,7c <->d 19%d 36- 3%) 39%d (3-62%) 600/150 mg tabletq12hx 10 days withefavirenz compared to400/100 mg q12halone600 mg qd 9 days23 36%d (28-44%) 36%d (28-44%) 32%d (21-44%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 21%(10-33%) 20%(8-34%)<-> Metabolite AG-1402 40%(30-48%) 37%(25-48%) 43%(21-59%)Ritonavir500 mg q12h 8 days600 mg qd 10 days11 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 days600 mg qd 10 days12 50%(28-66%) 62%(45-74%) 56%(16-77%)e Lamivudine150 mg q12h 14 days600 mg qd 14 days9<-><-> 265%(37-873%)Tenofovirg 300 mg qd600 mg qd 14 days29<-><-><->Zidovudine300 mg q12h 14 days600 mg qd 14 days9<-><-> 225%(43-640%)Maraviroc100 mg bid600 mg qd12 51%(37-62%) 45%(38-51%) 45%(28-57%)Raltegravir400 mg single dose600 mg qd9 36%(2-59%) 36%(20-48%) 21%( 51- 28%)Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 8%( 22- 8%) 19%(11-25%) 44%(26-58%)Telaprevir750 mg q8h 10 days600 mg qd 20 days21 9%( 18- 2%) 26%(16-35%) 47%(35-56%)Azithromycin600 mg single dose400 mg qd 7 days14 22%(4-42%)<->NAClarithromycin500 mg q12h 7 days400 mg qd 7 days11 26%(15-35%) 39%(30-46%) 53%(42-63%) 14-OH metabolite 49%(32-69%) 34%(18-53%) 26%(9-45%)Fluconazole200 mg 7 days400 mg qd 7 days10<-><-><->Itraconazole200 mg q12h 28 days600 mg qd 14 days18 37%(20-51%) 39%(21-53%) 44%(27-58%) Hydroxy-itraconazole 35%(12-52%) 37%(14-55%) 43%(18-60%)Posaconazole400 mg (oral suspension) bid 10 and 20 days400 mg qd 10 and 20 days11 45%(34-53%) 50%(40-57%)NARifabutin300 mg qd 14 days600 mg qd 14 days9 32%(15-46%) 38%(28-47%) 45%(31-56%)Voriconazole400 mg po q12h 1 day, then 200mg po q12h 8 days400 mg qd 9 daysNA 61%h 77%h NA 300 mg po q12h days 2-7300 mg qd 7 daysNA 36%i (21-49%) 55%i (45-62%)NA 400 mg po q12h days 2-7300 mg qd 7 daysNA 23%i 1- 53%) 7%i 23- 13%)NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14 14%(1-26%) 43%(34-50%) 69%(49-81%) Total active (including metabolites) 15%(2-26%) 32%(21-41%) 48%(23-64%)Pravastatin40 mg qd 4 days600 mg qd 15 days13 32%( 59- 12%) 44%(26-57%) 19%(0-35%)Simvastatin40 mg qd 4 days600 mg qd 15 days14 72%(63-79%) 68%(62-73%) 45%(20-62%) Total active (including metabolites) 68%(55-78%) 60%(52-68%)NAj Carbamazepine200 mg qd 3 days,200 mg bid 3 days, then 400 mg qd 29 days600 mg qd 14 days12 20%(15-24%) 27%(20-33%) 35%(24-44%)Epoxide metabolite <-><-> 13%( 30- 7%)Cetirizine10 mg single dose600 mg qd 10 days11 24%(18-30%)<->NADiltiazem240 mg 21 days600 mg qd 14 days13 60%(50-68%) 69%(55-79%) 63%(44-75%) Desacetyl diltiazem 64%(57-69%) 75%(59-84%) 62%(44-75%) N- monodesmethyl diltiazem 28%(7-44%) 37%(17-52%) 37%(17-52%)Ethinyl estradiol/ Norgestimate0.035 mg/0.25 mg 14 days600 mg qd 14 days Ethinyl estradiol 21<-><-><-> Norelgestromin 21 46%(39-52%) 64%(62-67%) 82%(79-85%) Levonorgestrel 80%(77-83%) 83%(79-87%) 86%(80-90%)Lorazepam2 mg single dose600 mg qd 10 days12 16%(2-32%)<->NAMethadoneStablemaintenance35-100 mg daily600 mg qd 14-21 days11 45%(25-59%) 52%(33-66%)NABupropion150 mg single dose(sustained-release)600 mg qd 14 days13 34%(21-47%) 55%(48-62%)NA Hydroxy- bupropion 50%(20-80%)<->NAParoxetine20 mg qd 14 days600 mg qd 14 days16<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 29%(15-40%) 39%(27-50%) 46%(31-58%)Table 9:Effect of Coadministered Drug on Efavirenz Plasma Cmax,AUC, and Cmin Efavirenz(mean change)Coadministered DrugDoseEfavirenz DoseNumber of SubjectsCmax (90% CI)AUC(90% CI)Cmin (90% CI) Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of <10%.a Parallel-group design; forefavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule.d Tenofovir disoproxil fumarate.e 90% CI not available.f Relative to steady-state administrationof efavirenz (600 mg once daily for days).NA not available.Indinavir800 mg q8h 14 days200 mg qd 14 days11<-><-><->Lopinavir/ ritonavir400/100 mg q12h x9 days600 mg qd 9 days11,12a <-> 16%( 38- 15%) 16%( 42- 20%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 12%( 32- 13%)b 12%( 35- 18%)b 21%( 53- 33%)Ritonavir500 mg q12h 8 days600 mg qd 10 days9 14%(4-26%) 21%(10-34%) 25%(7-46%)b Saquinavir SGCc 1200 mg q8h 10 days600 mg qd 10 days13 13%(5-20%) 12%(4-19%) 14%(2-24%)b Tenofovird 300 mg qd600 mg qd 14 days30<-><-><->Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 11%(2-20%) 20%(15-26%)NATelaprevir750 mg q8h 10 days600 mg qd 20 days21 16%(7-24%) 7%(2-13%) 2%( 6- 2%)Telaprevir, coadministered with tenofovir disoproxil fumarate (TDF)1125 mg q8h 7 days600 mg efavirenz/300 mg TDF qd 7 days15 24%(15-32%) 18%(10-26%) 10%( 19- 1%)1500 mg q12h 7 days600 mg efavirenz/300 mg TDF qd 7 days16 20%(14-26%) 15%(9-21%) 11%(4-18%)Azithromycin600 mg single dose400 mg qd 7 days14<-><-><->Clarithromycin500 mg q12h 7 days400 mg qd 7 days12 11%(3-19%)<-><->Fluconazole200 mg x7 days400 mg qd 7 days10<-> 16%(6-26%) 22%(5-41%)Itraconazole200 mg q12h 14 days600 mg qd 28 days16<-><-><->Rifabutin300 mg qd 14 days600 mg qd 14 days11<-><-> 12%( 24- 1%)Rifampin600 mg x7 days600 mg qd 7 days12 20%(11-28%) 26%(15-36%) 32%(15-46%)Voriconazole400 mg po q12hx1 day, then 200 mg po q12hx days400 mg qd 9 daysNA 38%e 44%e NA 300 mg po q12h days2-7300 mg qd 7 daysNA 14%f (7-21%)<->f NA 400 mg po q12h days2-7300 mg qd 7 daysNA<->f 17%f (6-29%)NAAtorvastatin10 mg qd x4 days600 mg qd 15 days14<-><-><->Pravastatin40 mg qd x4 days600 mg qd 15 days11<-><-><->Simvastatin40 mg qd x4 days600 mg qd 15 days14 12%( 28- 8%)<-> 12%( 25- 3%)Aluminum hydroxide400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg30 mL single dose400 mg single dose17<-><->NACarbamazepine200 mg qd 3 days,200 mgbid 3 days, then 400 mg qd 15 days600 mg qd 35 days14 21%(15-26%) 36%(32-40%) 47%(41-53%)Cetirizine10 mg single dose600 mg qd 10 days11<-><-><->Diltiazem240 mg x14 days600 mg qd 28 days12 16%(6-26%) 11%(5-18%) 13%(1-26%)Famotidine40 mg single dose400 mg single dose17<-><->NAParoxetine20 mg qd 14 days600 mg qd 14 days12<-><-><->Sertraline50 mg qd x14 days600 mg qd 14 days13 11%(6-16%)<-><->. 12.4 Microbiology. Mechanism of Action. Efavirenz (EFV) is an NNRTI of HIV-1.EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases , and are not inhibited by EFV. Antiviral Activity in Cell Culture. The concentration of EFV inhibitingreplication of wild-type laboratory adapted strains and clinical isolatesin cell culture by 90-95% (EC90-95) ranged from 1.7to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells(PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activityagainst clade and most non-clade isolates (subtypes A, AE, AG, C, D, F,G, J, N), but had reduced antiviral activity against group viruses. EFVdemonstrated additive antiviral activity without cytotoxicity against HIV-1in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine(NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine,tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV],lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide.EFV demonstrated additive to antagonistic antiviral activity in cell culturewith atazanavir. EFV was not antagonistic with adefovir, used for the treatmentof hepatitis virus infection, or ribavirin, used in combination with interferonfor the treatment of hepatitis virus infection. Resistance. In cell culture. In cell culture, HIV-1 isolates withreduced susceptibility to EFV (>380-fold increase in EC90 value)emerged rapidly in the presence of drug. Genotypic characterization of theseviruses identified single amino acid substitutions L100I or V179D, doublesubstitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C inRT.. Clinical studies. Clinical isolates with reduced susceptibilityin cell culture to EFV have been obtained. One or more RT substitutions atamino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 wereobserved in patients failing treatment with EFV in combination with IDV, orwith ZDV plus LAM. The mutation K103N was the most frequently observed. Long-termresistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28matching baseline and virologic failure isolates. Sixty-one percent (17/28)of these failure isolates had decreased EFV susceptibility in cell culturewith median 88-fold change in EFV susceptibility (EC50 value)from reference. The most frequent NNRTI substitution to develop in these patientisolates was K103N (54%). Other NNRTI substitutions that developed includedL100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), andM230I/L (11%).. Cross-Resistance. Cross-resistance among NNRTIs has beenobserved. Clinical isolates previously characterized as EFV-resistant werealso phenotypically resistant in cell culture to DLV and NVP compared to baseline.DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associatedsubstitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X,P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture.Greater than 90% of NRTI-resistant clinical isolates tested in cell cultureretained susceptibility to EFV.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Study 006, randomized, open-label trial, compared SUSTIVA (600 mg once daily) zidovudine (ZDV, 300 mg q12h) lamivudine (LAM, 150 mg q12h) or SUSTIVA (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 10. 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 10:Outcomes of Randomized Treatment Through 48 and 168 Weeks,Study 006 SUSTIVA+ ZDV+ LAM(n=422) SUSTIVA+ IDV(n=429) IDV+ ZDV LAM(n=415)OutcomeWeek 48Week 168Week 48Week 168Week 48Week 168a Patients achievedand maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week168.b Includes patientswho rebounded, patients who were on study at Week 48 and failed to achieveconfirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patientswho discontinued due to lack of efficacy.c Includes consentwithdrawn, 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 phasesof the study were censored at date of last dose of study medication.Respondera 69%48%57%40%50%29%Virologic failureb 6%12%15%20%13%19%Discontinued for adverse events7%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 changefrom baseline190329191319180329For patients treated with SUSTIVA zidovudine lamivudine,SUSTIVA indinavir, or indinavir zidovudine lamivudine, the percentageof 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.A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400copies/mL) suggests that both the trends of virologic response and differencesin response continue through years.ACTG364 is randomized, double-blind, placebo-controlled, 48-week studyin NRTI-experienced patients who had completed two prior ACTG studies. One-hundredninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male)received NRTIs in combination with SUSTIVA (efavirenz) (600 mg once daily),or nelfinavir (NFV, 750 mg three times daily), or SUSTIVA (600 mg once daily)+ nelfinavir in randomized, double-blinded manner. The mean baseline CD4+cell count was 389 cells/mm3 and mean baselineHIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patientswere assigned new open-label NRTI regimen, which was dependent on theirprevious NRTI treatment experience. There was no significant difference inthe mean CD4+ cell count among treatment groups; the overall mean increasewas approximately 100 cells at 48 weeks among patients who continued on studyregimens. Treatment outcomes are shown in Table 11. Plasma HIV RNA levelswere quantified with the AMPLICOR HIV-1 MONITOR assay using lower limitof quantification of 500 copies/mL.Table 11:Outcomes of Randomized Treatment Through 48 Weeks, StudyACTG 364OutcomeSUSTIVA +NFV +NRTIs(n=65)SUSTIVA NRTIs(n=65)NFV NRTIs(n=66) For some patients, Week 56 datawere used to confirm the status at Week 48.a Subjects achievedvirologic response (two consecutive viral loads <500 copies/mL) and maintainedit through Week 48.b Includes viral reboundand failure to achieve confirmed <500 copies/mL by Week 48.c See AdverseReactions (6.1) for safety profileof these regimens.d Includes loss tofollow-up, consent withdrawn, noncompliance.HIV-1 RNA <500 copies/mLa 71%63%41%HIV-1 RNA >=500 copies/mLb 17%34%54%CDC Category Event2%0%0%Discontinuationsfor adverse eventsc 3%3%5%Discontinuationsfor other reasonsd 8%0%0%A Kaplan-Meier analysis of time to treatment failurethrough 72 weeks demonstrates longer duration of virologic suppression (HIVRNA <500 copies/mL) in the SUSTIVA-containing treatment arms.

SPL UNCLASSIFIED SECTION.

17.1 Drug Interactions. statement to patients and healthcareproviders is included on the products bottle labels: ALERT: Findout about medicines that should NOT be taken with SUSTIVA. SUSTIVA may interact with some drugs; therefore, patients shouldbe advised to report to their doctor the use of any other prescription, nonprescriptionmedication, or herbal products, particularly St. Johns wort.

STORAGE AND HANDLING SECTION.

16.3 Storage. SUSTIVA capsules and SUSTIVA tabletsshould be stored at 25 (77 F); excursions permitted to 15-30 (59-86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Women should avoid pregnancy duringSUSTIVA therapy and for 12 weeks after discontinuation. (5.6) Nursing mothers: Women infected with HIV shouldbe instructed not to breast-feed. (8.3) Hepatic impairment: SUSTIVA 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 washigher than in adults. (5.7, 6.1, 6.2, 8.4) Pregnancy: Women should avoid pregnancy duringSUSTIVA therapy and for 12 weeks after discontinuation. (5.6) Nursing mothers: Women infected with HIV shouldbe instructed not to breast-feed. (8.3) Hepatic impairment: SUSTIVA 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 washigher than in adults. (5.7, 6.1, 6.2, 8.4) 8.1 Pregnancy. Pregnancy Category D: See Warnings and Precautions (5.6) .Antiretroviral Pregnancy Registry: To monitor fetaloutcomes of pregnant women exposed to SUSTIVA, an Antiretroviral PregnancyRegistry has been established. Physicians are encouraged to register patientsby calling 1-800-258-4263.As of July 2010, theAntiretroviral Pregnancy Registry has received prospective reports of 792pregnancies exposed to efavirenz-containing regimens, nearly all of whichwere first-trimester exposures (718 pregnancies). Birth defects occurred in17 of 604 live births (first-trimester exposure) and of 69 live births (second/third-trimesterexposure). 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; however, this case included severe oblique facial clefts and amniotic banding, known association with anophthalmia. There have been six retrospective reports of findings consistentwith neural tube defects, including meningomyelocele. All mothers were exposedto efavirenz-containing regimens in the first trimester. Although causalrelationship of these events to the use of SUSTIVA has not been established,similar defects have been observed in preclinical studies of efavirenz.. Animal Data. Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses 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, microophthalmia 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.. 8.3 Nursing Mothers. The Centers for Disease Controland Prevention recommend that HIV-infected mothers not breast-feed theirinfants to avoid risking postnatal transmission of HIV. Although it is notknown if efavirenz is secreted in human milk, efavirenz is secreted into themilk of lactating rats. Because of the potential for HIV transmission andthe potential for serious adverse effects in nursing infants, mothers shouldbe instructed not to breast-feed if they are receiving SUSTIVA.. 8.4 Pediatric Use. ACTG 382 is an ongoing, open-labelstudy in 57 NRTI-experienced pediatric patients to characterize the safety,pharmacokinetics, and antiviral activity of SUSTIVA in combination with nelfinavir(20-30 mg/kg three times daily) and NRTIs. Mean age was years (range 3-16).SUSTIVA has not been studied in pediatric patients below years of age orwho weigh less than 13 kg. At 48 weeks, the type and frequency of adverseexperiences was generally similar to that of adult patients with the exceptionof higher incidence of rash, which was reported in 46% (26/57) of pediatricpatients compared to 26% of adults, and higher frequency of Grade or 4rash reported in 5% (3/57) of pediatric patients compared to 0.9% of adults[see Warnings and Precautions (5.7) and AdverseReactions (6.1, Table 5; 6.2) ].The starting dose of SUSTIVA was600 mg once daily adjusted to body size, based on weight, targeting AUC levelsin the range of 190-380 uMoh [see Dosage and Administration (2.2) ]. The pharmacokinetics of efavirenzin pediatric patients were similar to the pharmacokinetics in adults who received600-mg daily doses of SUSTIVA. In 48 pediatric patients receiving the equivalentof 600-mg dose of SUSTIVA, steady-state Cmax was14.2 +- 5.8 uM (mean +- SD), steady-state Cmin was 5.6 +- 4.1 uM, and AUC was 218 +- 104 uMoh.. 8.5 Geriatric Use. Clinical studies of SUSTIVA didnot include sufficient numbers of subjects aged 65 years and over to determinewhether they respond differently from younger subjects. In general, dose selectionfor an elderly patient should be cautious, reflecting the greater frequencyof decreased hepatic, renal, or cardiac function and of concomitant diseaseor other therapy.. 8.6 Hepatic Impairment. SUSTIVA 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 SUSTIVA to these patients [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Do not use as single agent or add on as soleagent to failing regimen. Consider potential for cross resistance when choosingother agents. (5.2)Not recommended with ATRIPLA, which contains efavirenz, emtricitabine,and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.3) Serious psychiatric symptoms: Immediate medicalevaluation is recommended for serious psychiatric symptoms such as severedepression or suicidal ideation. (5.4, 17.5) Nervous system symptoms (NSS): NSS are frequent,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 onsetof psychiatric symptoms. (5.5, 6.1, 17.4) Pregnancy: Fetal harm can occur when administeredto pregnant woman during the first trimester. Women should be apprised ofthe potential harm to the fetus. (5.6, 17.7) Pregnancy registry is available. (8.1) Hepatotoxicity: Monitor liver function tests beforeand 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. (5.8, 6.1, 8.6) Rash: Rash usually begins within 1-2 weeks afterinitiating therapy and resolves within weeks. Discontinue if severe rashdevelops. (5.7, 6.1, 17.6) Convulsions: Use caution in patients with historyof seizures. (5.9) Lipids: Total cholesterol and triglyceride elevations.Monitor before therapy and periodically thereafter. (5.10)Immune reconstitution syndrome: May necessitatefurther evaluation and treatment. (5.11) Redistribution/accumulation of body fat: Observedin patients receiving antiretroviral therapy. (5.12, 17.8) Do not use as single agent or add on as soleagent to failing regimen. Consider potential for cross resistance when choosingother agents. (5.2). Not recommended with ATRIPLA, which contains efavirenz, emtricitabine,and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.3) Serious psychiatric symptoms: Immediate medicalevaluation is recommended for serious psychiatric symptoms such as severedepression or suicidal ideation. (5.4, 17.5) Nervous system symptoms (NSS): NSS are frequent,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 onsetof psychiatric symptoms. (5.5, 6.1, 17.4) Pregnancy: Fetal harm can occur when administeredto pregnant woman during the first trimester. Women should be apprised ofthe potential harm to the fetus. (5.6, 17.7) Pregnancy registry is available. (8.1) Hepatotoxicity: Monitor liver function tests beforeand 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. (5.8, 6.1, 8.6) Rash: Rash usually begins within 1-2 weeks afterinitiating therapy and resolves within weeks. Discontinue if severe rashdevelops. (5.7, 6.1, 17.6) Convulsions: Use caution in patients with historyof seizures. (5.9) Lipids: Total cholesterol and triglyceride elevations.Monitor before therapy and periodically thereafter. (5.10). Immune reconstitution syndrome: May necessitatefurther evaluation and treatment. (5.11) Redistribution/accumulation of body fat: Observedin patients receiving antiretroviral therapy. (5.12, 17.8) 5.1 Drug Interactions. Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenzmay alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6 [see Contraindications (4.2) and Drug Interactions (7.1) ].. 5.2 Resistance. SUSTIVA must not be used as singleagent 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 efavirenzshould take into consideration the potential for viral cross-resistance.. 5.3 Coadministration with Related Products. Coadministration of SUSTIVA 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.. 5.4 Psychiatric Symptoms. Serious psychiatric adverse experienceshave been reported in patients treated with SUSTIVA. In controlled trialsof 1008 patients treated with regimens containing SUSTIVA for mean of 2.1years and 635 patients treated with control regimens for mean of 1.5 years,the frequency (regardless of causality) of specific serious psychiatric eventsamong patients who received SUSTIVA or control regimens, respectively, weresevere depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicideattempts (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 similarto those noted above were combined and evaluated as group in multifactorialanalysis of data from Study 006, treatment with efavirenz was associated withan increase in the occurrence of these selected psychiatric symptoms. Otherfactors associated with an increase in the occurrence of these psychiatricsymptoms were history of injection drug use, psychiatric history, and receiptof psychiatric medication at study entry; similar associations were observedin both the SUSTIVA and control treatment groups. In Study 006, onset of newserious psychiatric symptoms occurred throughout the study for both SUSTIVA-treatedand control-treated patients. One percent of SUSTIVA-treated patients discontinuedor interrupted treatment because of one or more of these selected psychiatricsymptoms. There have also been occasional postmarketing reports of death bysuicide, delusions, and psychosis-like behavior, although causal relationshipto the use of SUSTIVA cannot be determined from these reports. Patients withserious psychiatric adverse experiences should seek immediate medical evaluationto assess the possibility that the symptoms may be related to the use of SUSTIVA,and if so, to determine whether the risks of continued therapy outweigh thebenefits. See Adverse Reactions (6.1) .. 5.5 Nervous System Symptoms. Fifty-three percent (531/1008) ofpatients receiving SUSTIVA in controlled trials reported central nervous systemsymptoms (any grade, regardless of causality) compared to 25% (156/635) ofpatients receiving control regimens [see Adverse Reactions (6.1, Table 4) ]. These symptoms included, butwere 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 usuallybegin during the first or second day of therapy and generally resolve afterthe first 2-4 weeks of therapy. After weeks of therapy, the prevalence ofnervous system symptoms of at least moderate severity ranged from 5% to 9%in patients treated with regimens containing SUSTIVA and from 3% to 5% inpatients treated with control regimen. Patients should be informed thatthese common symptoms were likely to improve with continued therapy and werenot predictive of subsequent onset of the less frequent psychiatric symptoms[see Warnings and Precautions (5.4) ].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 180weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA zidovudine+ lamivudine, SUSTIVA indinavir, and indinavir zidovudine lamivudine,respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onsetnervous system symptoms among SUSTIVA-treated patients were generally similarto those in the indinavir-containing control arm.Patientsreceiving SUSTIVA should be alerted to the potential for additive centralnervous system effects when SUSTIVA is used concomitantly with alcohol orpsychoactive drugs.Patients who experience centralnervous system symptoms such as dizziness, impaired concentration, and/ordrowsiness should avoid potentially hazardous tasks such as driving or operatingmachinery.. 5.6 Reproductive Risk Potential. Pregnancy Category D. Efavirenz may cause fetal harm when administered during the first trimester to pregnantwoman. Pregnancy should be avoided in women receiving SUSTIVA. Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of SUSTIVA is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of SUSTIVA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm tothe fetus.There are no adequate and well-controlled studies in pregnant women. SUSTIVA should be used duringpregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options. [See Use in Specific Populations (8.1) .]. 5.7 Rash. In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg SUSTIVA experienced new-onset skinrash compared with 17% (111/635) of patients treated in control groups [see Adverse Reactions (6.1, Table 5) ]. Rash associated with blistering, moist desquamation, or ulceration occurredin 0.9% (9/1008) of patients treated with SUSTIVA. The incidence of Grade rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treatedwith SUSTIVA in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first2 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 clinical trials was 1.7% (17/1008). SUSTIVA can be reinitiatedin patients interrupting therapy because of rash. SUSTIVA 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 also Contraindications (4.1) ]. Rash was reported in 26 of 57 pediatric patients (46%) treated with SUSTIVA capsules [see Adverse Reactions (6.1, 6.2) ]. One pediatric patient experienced Grade rash (confluent rash with fever), and two patients had Grade rash (erythema multiforme). The median time to onset of rash in pediatric patients was days. Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.. 5.8 Hepatotoxicity. Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis or infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.6) ]. few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors [see Adverse Reactions (6.3) ]. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with SUSTIVA needs to be weighed against the unknown risks of significant liver toxicity. 5.9 Convulsions. Convulsions have been observed inpatients receiving efavirenz, generally in the presence of known medical historyof seizures [see Nonclinical Toxicology (13.2) ].Caution must be taken in any patient with history of seizures. Patientswho are receiving concomitant anticonvulsant medications primarily metabolizedby the liver, such as phenytoin and phenobarbital, may require periodic monitoringof plasma levels [see Drug Interactions (7.1) ]. 5.10 Lipid Elevations. Treatment with SUSTIVA has resultedin increases in the concentration of total cholesterol and triglycerides [see AdverseReactions (6.1) ]. Cholesterol andtriglyceride testing should be performed before initiating SUSTIVA therapyand at periodic intervals during therapy.. 5.11 Immune Reconstitution Syndrome. Immune reconstitution syndrome hasbeen reported in patients treated with combination antiretroviral therapy,including SUSTIVA. During the initial phase of combination antiretroviraltreatment, patients whose immune system responds may develop an inflammatoryresponse to indolent or residual opportunistic infections [such as Mycobacteriumavium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluationand treatment.Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.. 5.12 Fat Redistribution. Redistribution/accumulation of bodyfat including central obesity, dorsocervical fat enlargement (buffalo hump),peripheral wasting, facial wasting, breast enlargement, and cushingoid appearancehave been observed in patients receiving antiretroviral therapy. The mechanismand long-term consequences of these events are currently unknown. causalrelationship has not been established.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. SUSTIVA is contraindicated in patients with previously demonstratedhypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxicskin eruptions) to any of the components of this product. (4.1) For some drugs, competition for CYP3A by efavirenz could resultin inhibition of their metabolism and create the potential for serious and/orlife-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation,or respiratory depression). (4.2) SUSTIVA is contraindicated in patients with previously demonstratedhypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxicskin eruptions) to any of the components of this product. (4.1) For some drugs, competition for CYP3A by efavirenz could resultin inhibition of their metabolism and create the potential for serious and/orlife-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation,or respiratory depression). (4.2) 4.1 Hypersensitivity. SUSTIVA is contraindicated in patientswith previously demonstrated clinically significant hypersensitivity (eg,Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) toany of the components of this product.. 4.2 Contraindicated Drugs. For some drugs, competition for CYP3Aby efavirenz could result in inhibition of their metabolism and create thepotential for serious and/or life-threatening adverse reactions (eg, cardiacarrhythmias, prolonged sedation, or respiratory depression). Drugs that arecontraindicated with SUSTIVA are listed in Table 2.Table 2:Drugs That Are Contraindicated or Not Recommended for UseWith SUSTIVADrugClass: Drug NameClinicalCommentAntimigraine: ergot derivatives (dihydroergotamine,ergonovine, ergotamine, methylergonovine)Potential for serious and/or life-threateningreactions such as acute ergot toxicity characterized by peripheral vasospasmand ischemia of the extremities and other tissues.Benzodiazepines: midazolam, triazolamPotential for serious and/or life-threateningreactions such as prolonged or increased sedation or respiratory depression.Calcium channel blocker:bepridilPotential for seriousand/or life-threatening reactions such as cardiac arrhythmias.GI motility agent: cisapridePotential for serious and/or life-threateningreactions such as cardiac arrhythmias.Neuroleptic: pimozidePotential for serious and/or life-threateningreactions such as cardiac arrhythmias.St. Johns wort (Hypericumperforatum) May lead to lossof virologic response and possible resistance to efavirenz or to the classof non-nucleoside reverse transcriptase inhibitors (NNRTIs).

DESCRIPTION SECTION.

11 DESCRIPTION. SUSTIVA(R) (efavirenz)is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI).Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.Its empirical formula is C14H9ClF3NO2 andits structural formula is:Efavirenz is white to slightly pink crystalline powderwith molecular mass of 315.68. It is practically insoluble in water (<10microgram/mL).Capsules: SUSTIVA isavailable as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate,magnesium stearate, sodium lauryl sulfate, and sodium starch glycolate. Thecapsule shell contains the following inactive ingredients and dyes: gelatin,sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide. The capsuleshells may also contain silicon dioxide. The capsules are printed with inkcontaining carmine 40 blue, FD&C Blue No. 2, and titanium dioxide.Tablets: SUSTIVAis available as film-coated tablets for oral administration containing 600mg of efavirenz and the following inactive ingredients: croscarmellose sodium,hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystallinecellulose, and sodium lauryl sulfate. The film coating contains Opadry Yellowand Opadry Clear. The tablets are polished with carnauba wax and printed withpurple ink, Opacode WB.. efavirenz chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . SUSTIVA should be taken orally once daily on an empty stomach, preferablyat bedtime. (2) Recommended adult dose: 600 mg. (2.1) With voriconazole, increase voriconazole maintenance dose to 400mg every 12 hours and decrease SUSTIVA dose to 300 mg once daily using thecapsule formulation. (2.1) With rifampin, increase SUSTIVA dose to 800 mg once daily for patients weighing 50 kg or more. (2.1) Pediatric Patients at Least Years and at Least 10 kg (2.2) kglbsdosekglbsdose10- <1522- <33200mg25- <32.555- <71.5350mg15- <2033- <44250mg32.5- <4071.5- <88400mg20- <2544- <55300mgatleast 40atleast 88600mg. SUSTIVA should be taken orally once daily on an empty stomach, preferablyat bedtime. (2) Recommended adult dose: 600 mg. (2.1) With voriconazole, increase voriconazole maintenance dose to 400mg every 12 hours and decrease SUSTIVA dose to 300 mg once daily using thecapsule formulation. (2.1) With rifampin, increase SUSTIVA dose to 800 mg once daily for patients weighing 50 kg or more. (2.1) 2.1 Adults. The recommended dosage of SUSTIVA(efavirenz) is 600 mg orally, once daily, in combination with protease inhibitorand/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It isrecommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.The increased efavirenz concentrations observed following administration ofSUSTIVA 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 (5.5),Adverse Reactions (6.1) and PatientCounseling Information (17.4) ]. Concomitant Antiretroviral Therapy. SUSTIVA must be given in combinationwith other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2),Drug Interactions (7.1) and ClinicalPharmacology (12.3) ].. Dosage Adjustment. If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules orsix 50-mg capsules). SUSTIVA tablets should not be broken. See Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Tables and 9).If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Table 9) ].. 2.2 Pediatric Patients. It is recommended that SUSTIVA betaken on an empty stomach, preferably at bedtime. Table describes the recommendeddose of SUSTIVA for pediatric patients years of age or older and weighingbetween 10 and 40 kg [see Use in Specific Populations (8.4) ]. The recommended dosage of SUSTIVA for pediatric patients weighinggreater than 40 kg is 600 mg once daily.Table 1:Pediatric Dose to be Administered Once DailyBody WeightSUSTIVA Dose(mg)kglbs10 to less than1522 to less than3320015 to less than 2033 to less than 4425020 to less than 2544 to less than 5530025 to less than 32.555 to less than 71.535032.5 to less than 4071.5 to less than 88400at least 40at least 88600.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules 200-mg capsules are gold color, reverse printed with SUSTIVA on the body and imprinted 200 mg on the cap. 50-mg capsules aregold color and white, printed with SUSTIVA on the gold color cap and reverseprinted 50 mg on the white body.o Tablets 600-mg tablets are yellow,capsular-shaped, film-coated tablets, with SUSTIVA printed on both sides.. Capsules: 200 mg and 50 mg. (3) Tablets: 600 mg. (3) Capsules: 200 mg and 50 mg. (3) Tablets: 600 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration of efavirenz can alter the concentrations ofother drugs and other drugs may alter the concentrations of efavirenz. Thepotential for drug-drug interactions must be considered before and duringtherapy. (4.2, 7.1, 12.3) 7.1 Drug-Drug Interactions. Efavirenz has been shown invivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6may have decreased plasma concentrations when coadministered with SUSTIVA. Invitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19,and 3A4 isozymes in the range of observed efavirenz plasma concentrations.Coadministration of efavirenz with drugs primarily metabolized by these isozymesmay result in altered plasma concentrations of the coadministered drug. Therefore,appropriate dose adjustments may be necessary for these drugs.Drugs that induce CYP3A activity (eg, phenobarbital, rifampin,rifabutin) would be expected to increase the clearance of efavirenz resultingin lowered plasma concentrations. Drug interactions with SUSTIVA are summarizedin Tables and [forpharmacokinetics data see Clinical Pharmacology (12.3, Tables and 9)].The tables include potentially significant interactions, but are not all inclusive.Table 7:Established and Other Potentially Significant DrugInteractions: Alteration in Dose or Regimen May Be Recommended Based on DrugInteraction Studies or Predicted InteractionConcomitantDrug Class: Drug NameEffectClinicalComment The interaction between SUSTIVA and the drug was evaluated in clinical study. All other drug interactions shown are predicted.This table is not all-inclusive.HIV antiviral agentsProtease inhibitor: Fosamprenavir calcium amprenavirFosamprenavir(unboosted): Appropriate doses of the combinations with respect to safetyand efficacy have not been established.Fosamprenavir/ritonavir:An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVAis administered with fosamprenavir/ritonavir once daily. No change in theritonavir dose is required when SUSTIVA is administered with fosamprenavirplus ritonavir twice daily.Protease inhibitor: Atazanavir sulfate atazanavir Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.Protease inhibitor: Indinavir indinavir The optimal doseof indinavir, when given in combination with SUSTIVA, is not known. Increasingthe indinavir dose to 1000 mg every hours does not compensate for the increasedindinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mgevery hours) was given with SUSTIVA (600 mg once daily), the indinavir AUCand Cmin were decreased on average by 33-46% and 39-57%,respectively, compared to when indinavir (800 mg every hours) was givenalone.Protease inhibitor: Lopinavir/ritonavir lopinavir Lopinavir/ritonavirtablets should not be administered once daily in combination with SUSTIVA.In antiretroviral-naive patients, lopinavir/ritonavir tablets can be usedtwice daily in combination with SUSTIVA with no dose adjustment. dose increaseof lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may beconsidered when used in combination with SUSTIVA in treatment-experiencedpatients where decreased susceptibility to lopinavir is clinically suspected(by treatment history or laboratory evidence). dose increase of lopinavir/ritonaviroral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommendedwhen used in combination with SUSTIVA.Protease inhibitor: Ritonavir ritonavir efavirenz When ritonavir500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combinationwas associated with higher frequency of adverse clinical experiences (eg,dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liverenzymes). Monitoring of liver enzymes is recommended when SUSTIVA is usedin combination with ritonavir.Protease inhibitor: Saquinavir saquinavir Should not be used as sole protease inhibitor in combination with SUSTIVA.NNRTI: Other NNRTIs or efavirenzand/or NNRTICombining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.CCR5 co-receptor antagonist: Maraviroc maraviroc Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.Integrase strand transfer inhibitor: Raltegravir raltegravir SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.Hepatitis antiviral agentsProtease inhibitor: Boceprevir boceprevir Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.Protease inhibitor: Telaprevir telaprevir efavirenz Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.Other agentsAnticoagulant: Warfarin or warfarinPlasma concentrationsand effects potentially increased or decreased by SUSTIVA.Anticonvulsants: Carbamazepine carbamazepine efavirenz There are insufficientdata to make dose recommendation for efavirenz. Alternative anticonvulsanttreatment should be used. Phenytoin Phenobarbital anticonvulsant efavirenzPotential forreduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoringof anticonvulsant plasma levels should be conducted.Antidepressants: Bupropion bupropion The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. Sertraline sertraline Increases in sertralinedosage should be guided by clinical response.Antifungals: Voriconazole voriconazole efavirenz SUSTIVA and voriconazolemust not be coadministered at standard doses. Efavirenz significantly decreasesvoriconazole plasma concentrations, and coadministration may decrease thetherapeutic effectiveness of voriconazole. Also, voriconazole significantlyincreases efavirenz plasma concentrations, which may increase the risk ofSUSTIVA-associated side effects. When voriconazole is coadministered withSUSTIVA, voriconazole maintenance dose should be increased to 400 mg every12 hours and SUSTIVA dose should be decreased to 300 mg once daily using thecapsule formulation. SUSTIVA tablets should not be broken. [See Dosageand Administration (2.1) and ClinicalPharmacology (12.3, Tables and 9).] Itraconazole itraconazole hydroxyitraconazole Since no dose recommendationfor itraconazole can be made, alternative antifungal treatment should be considered. Ketoconazole ketoconazoleDrug interactionstudies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA hasthe potential to decrease plasma concentrations of ketoconazole. Posaconazole posaconazole Avoid concomitant use unless the benefit outweighs the risks.Anti-infective: Clarithromycin clarithromycin 14-OHmetabolite Plasma concentrationsdecreased by SUSTIVA; clinical significance unknown. In uninfected volunteers,46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustmentof SUSTIVA is recommended when given with clarithromycin. Alternatives toclarithromycin, such as azithromycin, should be considered (see Other Drugs, following table). Othermacrolide antibiotics, such as erythromycin, have not been studied in combinationwith SUSTIVA.Antimycobacterials: Rifabutin rifabutin Increase daily dose of rifabutinby 50%. Consider doubling the rifabutin dose in regimens where rifabutin isgiven or times week. Rifampin efavirenz If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.Calcium channel blockers: Diltiazem diltiazem desacetyl diltiazem N-monodesmethyl diltiazem Diltiazem dose adjustments shouldbe guided by clinical response (refer to the full prescribing informationfor diltiazem). No dose adjustment of efavirenz is necessary when administeredwith diltiazem.Others (eg, felodipine,nicardipine, nifedipine, verapamil) calciumchannel blockerNo data are availableon the potential interactions of efavirenz with other calcium channel blockersthat are substrates of CYP3A. The potential exists for reduction in plasmaconcentrations of the calcium channel blocker. Dose adjustments should beguided by clinical response (refer to the full prescribing informationfor the calcium channel blocker).HMG-CoA reductaseinhibitors: Atorvastatin Pravastatin Simvastatin atorvastatin pravastatin simvastatin Plasma concentrationsof atorvastatin, pravastatin, and simvastatin decreased. Consult the fullprescribing information for the HMG-CoA reductase inhibitor for guidance onindividualizing the dose.Hormonal contraceptives: Oral Ethinylestradiol/ Norgestimate active metabolitesof norgestimate reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. Implant Etonogestrel etonogestrelA reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A immunosuppressantDecreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz. Narcotic analgesic: Methadone methadone Coadministrationin HIV-infected individuals with history of injection drug use resultedin decreased plasma levels of methadone and signs of opiate withdrawal. Methadonedose was increased by mean of 22% to alleviate withdrawal symptoms. Patientsshould be monitored for signs of withdrawal and their methadone dose increasedas required to alleviate withdrawal symptoms.. Other Drugs Based on the results of drug interactionstudies [see Clinical Pharmacology (12.3, Tables and 9)],no dosage adjustment is recommended when SUSTIVA (efavirenz) is given withthe following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine,famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovirdisoproxil fumarate, and zidovudine. Specificdrug interaction studies have not been performed with SUSTIVA and NRTIs otherthan lamivudine and zidovudine. Clinically significant interactions wouldnot be expected since the NRTIs are metabolized via different route thanefavirenz and would be unlikely to compete for the same metabolic enzymesand elimination pathways.. 7.2 Cannabinoid Test Interaction. Efavirenz does not bind to cannabinoidreceptors. False-positive urine cannabinoid test results have been observedin non-HIV-infected volunteers receiving SUSTIVA when the Microgenics CEDIADAU Multi-Level THC assay was used for screening. Negative results were obtainedwhen more specific confirmatory testing was performed with gas chromatography/massspectrometry.Of the three assays analyzed (MicrogenicsCEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [DiagnosticReagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAUMulti-Level THC assay showed false-positive results. The other two assaysprovided true-negative results. The effects of SUSTIVA on cannabinoid screeningtests other than these three are unknown. The manufacturers of cannabinoidassays should be contacted for additional information regarding the use oftheir assays with patients receiving efavirenz.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of SUSTIVA didnot include sufficient numbers of subjects aged 65 years and over to determinewhether they respond differently from younger subjects. In general, dose selectionfor an elderly patient should be cautious, reflecting the greater frequencyof decreased hepatic, renal, or cardiac function and of concomitant diseaseor other therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 Capsules. SUSTIVA(R) (efavirenz)capsules are available as follows:Capsules200 mg are gold color, reverse printed with SUSTIVA on the body and imprinted 200 mg on the cap.Capsules 50mg are gold color and white, printed with SUSTIVA on the gold colorcap and reverse printed 50 mg on the white body.. 16.2 Tablets. SUSTIVA(R) (efavirenz) tablets are availableas follows:Tablets 600 mg areyellow, capsular-shaped, film-coated tablets, with SUSTIVA printed on bothsides. Bottles of 30 NDC 54868-4668-0. 16.3 Storage. SUSTIVA capsules and SUSTIVA tabletsshould be stored at 25 (77 F); excursions permitted to 15-30 (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. SUSTIVA(R) (efavirenz) in combinationwith other antiretroviral agents is indicated for the treatment of human immunodeficiencyvirus type (HIV-1) infection. This indication is based on two clinical trialsof at least one year duration that demonstrated prolonged suppression of HIVRNA [see Clinical Studies (14) ].. SUSTIVAis non-nucleoside reverse transcriptase inhibitor indicated in combinationwith other antiretroviral agents for the treatment of human immunodeficiencyvirus type infection. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information).. 17.1 Drug Interactions. statement to patients and healthcareproviders is included on the products bottle labels: ALERT: Findout about medicines that should NOT be taken with SUSTIVA. SUSTIVA may interact with some drugs; therefore, patients shouldbe advised to report to their doctor the use of any other prescription, nonprescriptionmedication, or herbal products, particularly St. Johns wort.. 17.2 General Information for Patients. Patients should be informed that SUSTIVA is not cure for HIV-1 infection and patients may continue to experienceillnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of physician while taking SUSTIVA.Patients should be advised to avoid doing things that can spread HIV-1 infection to others.Do not share 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 breast-feed. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.. Do not share 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 breast-feed. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.. 17.3 Dosing Instructions. Patients should be advised to take SUSTIVAevery day as prescribed. SUSTIVA must always be used in combination with otherantiretroviral drugs. Patients should be advised to take SUSTIVA on an emptystomach, preferably at bedtime. Taking SUSTIVA with food increases efavirenzconcentrations and may increase the frequency of adverse reactions. Dosingat bedtime may improve the tolerability of nervous system symptoms [see Dosageand Administration (2) and AdverseReactions (6.1) ].. 17.4 Nervous System Symptoms. Patients should be informed that centralnervous system symptoms (NSS) including dizziness, insomnia, impaired concentration,drowsiness, and abnormal dreams are commonly reported during the first weeksof therapy with SUSTIVA [see Warnings and Precautions (5.5) ].Dosing at bedtime may improve the tolerability of these symptoms, which arelikely to improve with continued therapy. Patients should be alerted to thepotential for additive effects when SUSTIVA is used concomitantly with alcoholor psychoactive drugs. Patients should be instructed that if they experienceNSS they should avoid potentially hazardous tasks such as driving or operatingmachinery.. 17.5 Psychiatric Symptoms. Patients should be informed that seriouspsychiatric symptoms including severe depression, suicide attempts, aggressivebehavior, delusions, paranoia, and psychosis-like symptoms have been reportedin patients receiving SUSTIVA [see Warnings and Precautions (5.4) ]. If they experience severepsychiatric adverse experiences they should seek immediate medical evaluation.Patients should be advised to inform their physician of any history of mentalillness or substance abuse.. 17.6 Rash. Patients should be informed that acommon side effect is rash [see Warnings and Precautions (5.7) ]. Rashes usually go away without any change in treatment. However,since rash may be serious, patients should be advised to contact their physicianpromptly if rash occurs.. 17.7 Reproductive Risk Potential. Women receiving SUSTIVA should beinstructed to avoid pregnancy [see Warnings and Precautions (5.6) ]. reliable form of barriercontraception must always be used in combination with other methods of contraception,including oral or other hormonal contraception. Because of the long half-lifeof efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuationof SUSTIVA is recommended. Women should be advised to notify their physicianif they become pregnant or plan to become pregnant while taking SUSTIVA. Ifthis drug is used during the first trimester of pregnancy, or if the patientbecomes pregnant while taking this drug, she should be apprised of the potentialharm to the fetus.. 17.8 Fat Redistribution. Patients should be informed that redistributionor accumulation of body fat may occur in patients receiving antiretroviraltherapy and that the cause and long-term health effects of these conditionsare not known [see Warnings and Precautions (5.12) ].

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action. Efavirenz (EFV) is an NNRTI of HIV-1.EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases , and are not inhibited by EFV. Antiviral Activity in Cell Culture. The concentration of EFV inhibitingreplication of wild-type laboratory adapted strains and clinical isolatesin cell culture by 90-95% (EC90-95) ranged from 1.7to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells(PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activityagainst clade and most non-clade isolates (subtypes A, AE, AG, C, D, F,G, J, N), but had reduced antiviral activity against group viruses. EFVdemonstrated additive antiviral activity without cytotoxicity against HIV-1in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine(NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine,tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV],lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide.EFV demonstrated additive to antagonistic antiviral activity in cell culturewith atazanavir. EFV was not antagonistic with adefovir, used for the treatmentof hepatitis virus infection, or ribavirin, used in combination with interferonfor the treatment of hepatitis virus infection. Resistance. In cell culture. In cell culture, HIV-1 isolates withreduced susceptibility to EFV (>380-fold increase in EC90 value)emerged rapidly in the presence of drug. Genotypic characterization of theseviruses identified single amino acid substitutions L100I or V179D, doublesubstitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C inRT.. Clinical studies. Clinical isolates with reduced susceptibilityin cell culture to EFV have been obtained. One or more RT substitutions atamino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 wereobserved in patients failing treatment with EFV in combination with IDV, orwith ZDV plus LAM. The mutation K103N was the most frequently observed. Long-termresistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28matching baseline and virologic failure isolates. Sixty-one percent (17/28)of these failure isolates had decreased EFV susceptibility in cell culturewith median 88-fold change in EFV susceptibility (EC50 value)from reference. The most frequent NNRTI substitution to develop in these patientisolates was K103N (54%). Other NNRTI substitutions that developed includedL100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), andM230I/L (11%).. Cross-Resistance. Cross-resistance among NNRTIs has beenobserved. Clinical isolates previously characterized as EFV-resistant werealso phenotypically resistant in cell culture to DLV and NVP compared to baseline.DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associatedsubstitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X,P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture.Greater than 90% of NRTI-resistant clinical isolates tested in cell cultureretained susceptibility to EFV.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0,25, 75, 150, or 300 mg/kg/day for years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.. Mutagenesis. Efavirenz tested negative in battery of invitro and in vivo genotoxicity assays. These included bacterialmutation assays in S. typhimurium and E. coli,mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.. Impairment of Fertility. Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately <=0.15 times that in humans at the recommended clinical dose. 13.2 Animal Toxicology. Nonsustained convulsions were observed in of 20 monkeys receiving efavirenz at doses yielding plasma AUC values4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9) ].

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. The Centers for Disease Controland Prevention recommend that HIV-infected mothers not breast-feed theirinfants to avoid risking postnatal transmission of HIV. Although it is notknown if efavirenz is secreted in human milk, efavirenz is secreted into themilk of lactating rats. Because of the potential for HIV transmission andthe potential for serious adverse effects in nursing infants, mothers shouldbe instructed not to breast-feed if they are receiving SUSTIVA.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Some patients accidentally taking600 mg twice daily have reported increased nervous system symptoms. One patientexperienced involuntary muscle contractions.Treatmentof overdose with SUSTIVA should consist of general supportive measures, includingmonitoring of vital signs and observation of the patients clinical status.Administration of activated charcoal may be used to aid removal of unabsorbeddrug. There is no specific antidote for overdose with SUSTIVA. Since efavirenzis highly protein bound, dialysis is unlikely to significantly remove thedrug from blood.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

NDC 54868-4668-0 30 TabletsSUSTIVA(R) Rx only (efavirenz) tablets 600 mgEach tablet contains 600 mg of efavirenz. DOSAGE: For dosage and full prescribinginformation, read accompanying packageinsert. Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines thatshould NOT be taken with SUSTIVA(R). PRINCIPAL DISPLAY PANEL 600 mg Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. ACTG 382 is an ongoing, open-labelstudy in 57 NRTI-experienced pediatric patients to characterize the safety,pharmacokinetics, and antiviral activity of SUSTIVA in combination with nelfinavir(20-30 mg/kg three times daily) and NRTIs. Mean age was years (range 3-16).SUSTIVA has not been studied in pediatric patients below years of age orwho weigh less than 13 kg. At 48 weeks, the type and frequency of adverseexperiences was generally similar to that of adult patients with the exceptionof higher incidence of rash, which was reported in 46% (26/57) of pediatricpatients compared to 26% of adults, and higher frequency of Grade or 4rash reported in 5% (3/57) of pediatric patients compared to 0.9% of adults[see Warnings and Precautions (5.7) and AdverseReactions (6.1, Table 5; 6.2) ].The starting dose of SUSTIVA was600 mg once daily adjusted to body size, based on weight, targeting AUC levelsin the range of 190-380 uMoh [see Dosage and Administration (2.2) ]. The pharmacokinetics of efavirenzin pediatric patients were similar to the pharmacokinetics in adults who received600-mg daily doses of SUSTIVA. In 48 pediatric patients receiving the equivalentof 600-mg dose of SUSTIVA, steady-state Cmax was14.2 +- 5.8 uM (mean +- SD), steady-state Cmin was 5.6 +- 4.1 uM, and AUC was 218 +- 104 uMoh.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. Peak efavirenz plasma concentrationsof 1.6-9.1 uM were attained by hours following single oral doses of 100mg to 1600 mg administered to uninfected volunteers. Dose-related increasesin Cmax and AUC were seen for doses up to 1600 mg;the increases were less than proportional suggesting diminished absorptionat higher doses. In HIV-1-infected patients atsteady state, mean Cmax, mean Cmin,and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg dailydoses. Time-to-peak plasma concentrations were approximately 3-5 hours andsteady-state plasma concentrations were reached in 6-10 days. In 35 patientsreceiving SUSTIVA 600 mg once daily, steady-state Cmax was12.9 +- 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:. Capsules: Administrationof single 600-mg dose of efavirenz capsules with high-fat/high-caloricmeal (894 kcal, 54 fat, 54% calories from fat) or reduced-fat/normal-caloricmeal (440 kcal, g fat, 4% calories from fat) was associated with meanincrease of 22% and 17% in efavirenz AUC and meanincrease of 39% and 51% in efavirenz Cmax, respectively,relative to the exposures achieved when given under fasted conditions. See Dosageand Administration (2) and PatientCounseling Information (17.3) .Tablets: Administration of single 600-mg efavirenztablet with high-fat/high-caloric meal (approximately 1000 kcal, 500-600kcal from fat) was associated with 28% increase in mean AUC ofefavirenz and 79% increase in mean Cmax of efavirenzrelative to the exposures achieved under fasted conditions. See Dosageand Administration (2) and PatientCounseling Information (17.3) .. Distribution. Efavirenz is highly bound (approximately99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infectedpatients (n=9) who received SUSTIVA 200 to 600 mg once daily for at leastone month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean0.69%) of the corresponding plasma concentration. This proportion is approximately3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.. Metabolism. Studies in humans and in vitro studiesusing human liver microsomes have demonstrated that efavirenz is principallymetabolized by the cytochrome P450 system to hydroxylated metabolites withsubsequent glucuronidation of these hydroxylated metabolites. These metabolitesare essentially inactive against HIV-1. The in vitro studiessuggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenzmetabolism. Efavirenz has been shown to induceCYP enzymes, resulting in the induction of its own metabolism. Multiple dosesof 200-400 mg per day for 10 days resulted in lower than predicted extentof accumulation (22-42% lower) and shorter terminal half-life of 40-55 hours(single dose half-life 52-76 hours). Elimination. Efavirenz has terminal half-lifeof 52-76 hours after single doses and 40-55 hours after multiple doses. Aone-month mass balance/excretion study was conducted using 400 mg per daywith 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 radiolabeleddrug was in the form of metabolites. Efavirenz accounted for the majorityof the total radioactivity measured in feces.. Special Populations. Gender and race: Thepharmacokinetics of efavirenz in patients appear to be similar between menand women and among the racial groups studied.Renalimpairment: The pharmacokinetics of efavirenz have not been studiedin patients with renal insufficiency; however, less than 1% of efavirenz isexcreted unchanged in the urine, so the impact of renal impairment on efavirenzelimination should be minimal.Hepatic impairment: multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class or C) affects efavirenz pharmacokinetics.. Drug Interaction Studies. Efavirenz has been shown invivo to cause hepatic enzyme induction, thus increasing the biotransformationof some drugs metabolized by CYP3A and CYP2B6. In vitro studies haveshown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values(8.5-17 uM) in the range of observed efavirenz plasma concentrations. In invitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6and CYP1A2 (Ki values 82-160 uM) only at concentrationswell above those achieved clinically. The inhibitory effect on CYP3A is expectedto be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministrationof efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymesmay result in altered plasma concentrations of the coadministered drug. Drugswhich induce CYP3A activity would be expected to increase the clearance ofefavirenz resulting in lowered plasma concentrations.Druginteraction studies were performed with efavirenz and other drugs likely tobe 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 ofefavirenz on other drugs) and Table (effect of other drugs on efavirenz).For information regarding clinical recommendations see Contraindications (4.2) and Drug Interactions (7.1) .Table 8:Effect of Efavirenz on Coadministered Drug Plasma Cmax,AUC, and Cmin CoadministeredDrugDoseEfavirenzDoseNumber of SubjectsCoadministeredDrug(mean change)Cmax (90%CI)AUC(90%CI)Cmin (90%CI) Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of <10%.a Compared with atazanavir 400mg qd alone.b Comparator dose of indinavirwas 800 mg q8h 10 days.c Parallel-group design; forefavirenz lopinavir/ritonavir, for lopinavir/ritonavir alone.d Values are for lopinavir;the pharmacokinetics of ritonavir in this study were unaffected by concurrentefavirenz.e 95% CI.f Soft Gelatin Capsule.g Tenofovir disoproxil fumarate.h 90% CI not available.i Relative to steady-state administrationof voriconazole (400 mg for day, then 200 mg po q12h for days).j Not available becauseof insufficient data.NA not available.Atazanavir400 mg qd with alight meal 1-20600 mg qd with alight meal 7-2027 59%(49-67%) 74%(68-78%) 93%(90-95%) 400 mg qd 1-6, then 300 mg qd 7-20 with ritonavir 100 mg qd and light meal600 mg qd h after atazanavir andritonavir 7-2013 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%)Indinavir1000 mg q8h 10 days600 mg qd 10 days20 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/ ritonavir400/100 mg capsuleq12hx days600 mg qd 9 days11,7c <->d 19%d 36- 3%) 39%d (3-62%) 600/150 mg tabletq12hx 10 days withefavirenz compared to400/100 mg q12halone600 mg qd 9 days23 36%d (28-44%) 36%d (28-44%) 32%d (21-44%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 21%(10-33%) 20%(8-34%)<-> Metabolite AG-1402 40%(30-48%) 37%(25-48%) 43%(21-59%)Ritonavir500 mg q12h 8 days600 mg qd 10 days11 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 days600 mg qd 10 days12 50%(28-66%) 62%(45-74%) 56%(16-77%)e Lamivudine150 mg q12h 14 days600 mg qd 14 days9<-><-> 265%(37-873%)Tenofovirg 300 mg qd600 mg qd 14 days29<-><-><->Zidovudine300 mg q12h 14 days600 mg qd 14 days9<-><-> 225%(43-640%)Maraviroc100 mg bid600 mg qd12 51%(37-62%) 45%(38-51%) 45%(28-57%)Raltegravir400 mg single dose600 mg qd9 36%(2-59%) 36%(20-48%) 21%( 51- 28%)Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 8%( 22- 8%) 19%(11-25%) 44%(26-58%)Telaprevir750 mg q8h 10 days600 mg qd 20 days21 9%( 18- 2%) 26%(16-35%) 47%(35-56%)Azithromycin600 mg single dose400 mg qd 7 days14 22%(4-42%)<->NAClarithromycin500 mg q12h 7 days400 mg qd 7 days11 26%(15-35%) 39%(30-46%) 53%(42-63%) 14-OH metabolite 49%(32-69%) 34%(18-53%) 26%(9-45%)Fluconazole200 mg 7 days400 mg qd 7 days10<-><-><->Itraconazole200 mg q12h 28 days600 mg qd 14 days18 37%(20-51%) 39%(21-53%) 44%(27-58%) Hydroxy-itraconazole 35%(12-52%) 37%(14-55%) 43%(18-60%)Posaconazole400 mg (oral suspension) bid 10 and 20 days400 mg qd 10 and 20 days11 45%(34-53%) 50%(40-57%)NARifabutin300 mg qd 14 days600 mg qd 14 days9 32%(15-46%) 38%(28-47%) 45%(31-56%)Voriconazole400 mg po q12h 1 day, then 200mg po q12h 8 days400 mg qd 9 daysNA 61%h 77%h NA 300 mg po q12h days 2-7300 mg qd 7 daysNA 36%i (21-49%) 55%i (45-62%)NA 400 mg po q12h days 2-7300 mg qd 7 daysNA 23%i 1- 53%) 7%i 23- 13%)NAAtorvastatin10 mg qd 4 days600 mg qd 15 days14 14%(1-26%) 43%(34-50%) 69%(49-81%) Total active (including metabolites) 15%(2-26%) 32%(21-41%) 48%(23-64%)Pravastatin40 mg qd 4 days600 mg qd 15 days13 32%( 59- 12%) 44%(26-57%) 19%(0-35%)Simvastatin40 mg qd 4 days600 mg qd 15 days14 72%(63-79%) 68%(62-73%) 45%(20-62%) Total active (including metabolites) 68%(55-78%) 60%(52-68%)NAj Carbamazepine200 mg qd 3 days,200 mg bid 3 days, then 400 mg qd 29 days600 mg qd 14 days12 20%(15-24%) 27%(20-33%) 35%(24-44%)Epoxide metabolite <-><-> 13%( 30- 7%)Cetirizine10 mg single dose600 mg qd 10 days11 24%(18-30%)<->NADiltiazem240 mg 21 days600 mg qd 14 days13 60%(50-68%) 69%(55-79%) 63%(44-75%) Desacetyl diltiazem 64%(57-69%) 75%(59-84%) 62%(44-75%) N- monodesmethyl diltiazem 28%(7-44%) 37%(17-52%) 37%(17-52%)Ethinyl estradiol/ Norgestimate0.035 mg/0.25 mg 14 days600 mg qd 14 days Ethinyl estradiol 21<-><-><-> Norelgestromin 21 46%(39-52%) 64%(62-67%) 82%(79-85%) Levonorgestrel 80%(77-83%) 83%(79-87%) 86%(80-90%)Lorazepam2 mg single dose600 mg qd 10 days12 16%(2-32%)<->NAMethadoneStablemaintenance35-100 mg daily600 mg qd 14-21 days11 45%(25-59%) 52%(33-66%)NABupropion150 mg single dose(sustained-release)600 mg qd 14 days13 34%(21-47%) 55%(48-62%)NA Hydroxy- bupropion 50%(20-80%)<->NAParoxetine20 mg qd 14 days600 mg qd 14 days16<-><-><->Sertraline50 mg qd 14 days600 mg qd 14 days13 29%(15-40%) 39%(27-50%) 46%(31-58%)Table 9:Effect of Coadministered Drug on Efavirenz Plasma Cmax,AUC, and Cmin Efavirenz(mean change)Coadministered DrugDoseEfavirenz DoseNumber of SubjectsCmax (90% CI)AUC(90% CI)Cmin (90% CI) Indicates increase Indicates decrease <-> Indicates no change or mean increase or decrease of <10%.a Parallel-group design; forefavirenz lopinavir/ritonavir, for efavirenz alone.b 95% CI.c Soft Gelatin Capsule.d Tenofovir disoproxil fumarate.e 90% CI not available.f Relative to steady-state administrationof efavirenz (600 mg once daily for days).NA not available.Indinavir800 mg q8h 14 days200 mg qd 14 days11<-><-><->Lopinavir/ ritonavir400/100 mg q12h x9 days600 mg qd 9 days11,12a <-> 16%( 38- 15%) 16%( 42- 20%)Nelfinavir750 mg q8h 7 days600 mg qd 7 days10 12%( 32- 13%)b 12%( 35- 18%)b 21%( 53- 33%)Ritonavir500 mg q12h 8 days600 mg qd 10 days9 14%(4-26%) 21%(10-34%) 25%(7-46%)b Saquinavir SGCc 1200 mg q8h 10 days600 mg qd 10 days13 13%(5-20%) 12%(4-19%) 14%(2-24%)b Tenofovird 300 mg qd600 mg qd 14 days30<-><-><->Boceprevir800 mg tid 6 days600 mg qd 16 daysNA 11%(2-20%) 20%(15-26%)NATelaprevir750 mg q8h 10 days600 mg qd 20 days21 16%(7-24%) 7%(2-13%) 2%( 6- 2%)Telaprevir, coadministered with tenofovir disoproxil fumarate (TDF)1125 mg q8h 7 days600 mg efavirenz/300 mg TDF qd 7 days15 24%(15-32%) 18%(10-26%) 10%( 19- 1%)1500 mg q12h 7 days600 mg efavirenz/300 mg TDF qd 7 days16 20%(14-26%) 15%(9-21%) 11%(4-18%)Azithromycin600 mg single dose400 mg qd 7 days14<-><-><->Clarithromycin500 mg q12h 7 days400 mg qd 7 days12 11%(3-19%)<-><->Fluconazole200 mg x7 days400 mg qd 7 days10<-> 16%(6-26%) 22%(5-41%)Itraconazole200 mg q12h 14 days600 mg qd 28 days16<-><-><->Rifabutin300 mg qd 14 days600 mg qd 14 days11<-><-> 12%( 24- 1%)Rifampin600 mg x7 days600 mg qd 7 days12 20%(11-28%) 26%(15-36%) 32%(15-46%)Voriconazole400 mg po q12hx1 day, then 200 mg po q12hx days400 mg qd 9 daysNA 38%e 44%e NA 300 mg po q12h days2-7300 mg qd 7 daysNA 14%f (7-21%)<->f NA 400 mg po q12h days2-7300 mg qd 7 daysNA<->f 17%f (6-29%)NAAtorvastatin10 mg qd x4 days600 mg qd 15 days14<-><-><->Pravastatin40 mg qd x4 days600 mg qd 15 days11<-><-><->Simvastatin40 mg qd x4 days600 mg qd 15 days14 12%( 28- 8%)<-> 12%( 25- 3%)Aluminum hydroxide400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg30 mL single dose400 mg single dose17<-><->NACarbamazepine200 mg qd 3 days,200 mgbid 3 days, then 400 mg qd 15 days600 mg qd 35 days14 21%(15-26%) 36%(32-40%) 47%(41-53%)Cetirizine10 mg single dose600 mg qd 10 days11<-><-><->Diltiazem240 mg x14 days600 mg qd 28 days12 16%(6-26%) 11%(5-18%) 13%(1-26%)Famotidine40 mg single dose400 mg single dose17<-><->NAParoxetine20 mg qd 14 days600 mg qd 14 days12<-><-><->Sertraline50 mg qd x14 days600 mg qd 14 days13 11%(6-16%)<-><->.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category D: See Warnings and Precautions (5.6) .Antiretroviral Pregnancy Registry: To monitor fetaloutcomes of pregnant women exposed to SUSTIVA, an Antiretroviral PregnancyRegistry has been established. Physicians are encouraged to register patientsby calling 1-800-258-4263.As of July 2010, theAntiretroviral Pregnancy Registry has received prospective reports of 792pregnancies exposed to efavirenz-containing regimens, nearly all of whichwere first-trimester exposures (718 pregnancies). Birth defects occurred in17 of 604 live births (first-trimester exposure) and of 69 live births (second/third-trimesterexposure). 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; however, this case included severe oblique facial clefts and amniotic banding, known association with anophthalmia. There have been six retrospective reports of findings consistentwith neural tube defects, including meningomyelocele. All mothers were exposedto efavirenz-containing regimens in the first trimester. Although causalrelationship of these events to the use of SUSTIVA has not been established,similar defects have been observed in preclinical studies of efavirenz.. Animal Data. Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses 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, microophthalmia 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Adults (2.1) 12/2011Warnings and Precautions Coadministration with Related Products (5.3) 08/2012 Rash (5.7) 06/2012 Immune Reconstitution Syndrome (5.11) 08/2012.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationSUSTIVA(R) (sus-TEE-vah)[efavirenz (eh-FAH-vih-rehnz)] capsules and tabletsALERT: Find out about medicines that should NOT be taken with SUSTIVA.Please also read the section MEDICINES YOU SHOULD NOTTAKE WITH SUSTIVA.Read this informationbefore you start taking SUSTIVA. Read it again each time you refill your prescription,in case there is any new information. This leaflet provides summary aboutSUSTIVA and does not include everything there is to know about your medicine.This information is not meant to take the place of talking with your doctor.What is SUSTIVASUSTIVAis medicine used in combination with other medicines to help treat infectionwith Human Immunodeficiency Virus type (HIV-1), the virus that causes AIDS(acquired immune deficiency syndrome). SUSTIVA is type of anti-HIV drugcalled non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIsare not used in the treatment of Human Immunodeficiency Virus type (HIV-2)infection.SUSTIVA works by lowering the amountof HIV-1 in the blood (viral load). SUSTIVA must be taken with other anti-HIVmedicines. When taken with other anti-HIV medicines, SUSTIVA has been shownto reduce viral load and increase the number of CD4+ cells, type of immunecell in blood. SUSTIVA may not have these effects in every patient.SUSTIVA does not cure HIV or AIDS and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of doctor when using SUSTIVA.Avoid doing things that can spread HIV-1 infection.Do not share 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.What are the possible side effects of SUSTIVASerious psychiatric problems. small number ofpatients experience severe depression, strange thoughts, or angry behaviorwhile taking SUSTIVA. Some patients have thoughts of suicide and few haveactually committed suicide. These problems tend to occur more often in patientswho have had mental illness. Contact your doctor right away if you think youare having these psychiatric symptoms, so your doctor can decide if you shouldcontinue to take SUSTIVA (efavirenz).Commonside effects. Many patients have dizziness, trouble sleeping, drowsiness,trouble concentrating, and/or unusual dreams during treatment with SUSTIVA.These side effects may be reduced if you take SUSTIVA at bedtime on an emptystomach. They also tend to go away after you have taken the medicine for afew weeks. If you have these common side effects, such as dizziness, it doesnot mean that you will also have serious psychiatric problems, such as severedepression, strange thoughts, or angry behavior. Tell your doctor right awayif any of these side effects continue or if they bother you. It is possiblethat these symptoms may be more severe if SUSTIVA is used with alcohol ormood altering (street) drugs.If you are dizzy,have trouble concentrating, or are drowsy, avoid activities that may be dangerous,such as driving or operating machinery.Rash iscommon. Rashes usually go away without any change in treatment. In smallnumber of patients, rash may be serious. If you develop rash, call yourdoctor right away. Rash may be serious problem in some children. Tellyour childs doctor right away if you notice rash or any other side effectswhile your child is taking SUSTIVA.Other commonside effects include tiredness, upset stomach, vomiting, and diarrhea. Somepatients taking SUSTIVA have experienced increased levels of lipids (cholesteroland triglycerides) in the blood.Changes inbody fat. Changes in body fat develop in some patients taking anti-HIVmedicine. These changes may include an increased amount of fat in the upperback and neck (buffalo hump), in the breasts, and around the trunk. Lossof fat from the legs, arms, and face may also happen. The cause and long-termhealth effects of these fat changes are not known.Liver problems. Some patients taking SUSTIVA have experienced serious liver problems including liver failure resulting in transplantation or death. Most of these serious side effects occurred in patients with chronic liver disease such as hepatitis infection, but there have also been few reports in patients without any existing liver disease.Tellyour doctor or healthcare provider if you notice any side effects while takingSUSTIVA. Contact your doctor before stopping SUSTIVAbecause of side effects or for any other reason.Thisis not complete list of side effects possible with SUSTIVA. Ask your doctoror pharmacist for more complete list of side effects of SUSTIVA and allthe medicines you will take.How should Itake SUSTIVAGeneral InformationYou should take SUSTIVA on an empty stomach, preferably at bedtime.Swallow SUSTIVA with water.Taking SUSTIVA with food increases the amount of medicine in yourbody, which may increase the frequency of side effects.Taking SUSTIVA at bedtime may make some side effects less bothersome.SUSTIVA must be taken in combination with other anti-HIV medicines.If you take only SUSTIVA, the medicine may stop working.Do not miss dose of SUSTIVA. If you forget to take SUSTIVA, takethe missed dose right away, unless it is almost time for your next dose. Donot double the next dose. Carry on with your regular dosing schedule. If youneed help in planning the best times to take your medicine, ask your doctoror pharmacist. Take the exact amount of SUSTIVA your doctor prescribes. Never changethe dose on your own. Do not stop this medicine unless your doctor tells youto stop.If you believe you took more than the prescribed amount of SUSTIVA,contact your local Poison Control Center or emergency room right away.Tell your doctor if you start any new medicine or change how youtake old ones. Your doses may need adjustment.When your SUSTIVA supply starts to run low, get more from your doctoror pharmacy. This is very important because the amount of virus in your bloodmay increase if the medicine is stopped for even short time. The virus maydevelop resistance to SUSTIVA and become harder to treat.Your doctor may want to do blood tests to check for certain sideeffects while you take SUSTIVA (efavirenz). CapsulesThe dose of SUSTIVA capsules for adults is 600 mg (three 200-mgcapsules, taken together) once day by mouth. The dose of SUSTIVA for childrenmay be lower (see Can children take SUSTIVA).TabletsThe dose of SUSTIVA tablets for adults is 600 mg (one tablet) oncea day by mouth.Can children take SUSTIVAYes, children who are able to swallow capsules can take SUSTIVA.Rash may be serious problem in some children. Tell your childs doctor rightaway if you notice rash or any other side effects while your child is takingSUSTIVA. The dose of SUSTIVA for children may be lower than the dose for adults.Capsules containing lower doses of SUSTIVA are available. Your childs doctorwill determine the right dose based on your childs weight.Who should not take SUSTIVADonot take SUSTIVA if you are allergic to the active ingredient, efavirenz,or to any of the inactive ingredients. Your doctor and pharmacist have listof the inactive ingredients.What should Iavoid while taking SUSTIVAWomen should not become pregnant while taking SUSTIVA andfor 12 weeks after stopping it. Serious birth defects have been seenin the offspring of animals and women treated with SUSTIVA during pregnancy.It is not known whether SUSTIVA caused these defects. Tell your doctorright away if you are pregnant. Also talk with your doctor if you wantto become pregnant.Women should not rely only on hormone-based birth control, suchas pills, injections, or implants, because SUSTIVA may make these contraceptivesineffective. Women must use reliable form of barrier contraception, suchas condom or diaphragm, even if they also use other methods of birth control.SUSTIVA may remain in your blood for time after therapy is stopped. Therefore,you should continue to use contraceptive measures for 12 weeks after you stoptaking SUSTIVA.Do not breast-feed if you are taking SUSTIVA. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in the breast milk. Talk with your doctor if you are breast-feeding. You may need to stop breast-feeding or use different medicine.Taking SUSTIVA with alcohol or other medicines causing similar side effects as SUSTIVA, such as drowsiness, may increase those side effects.Do not take any other medicines without checking with your doctor. These medicines include prescription and nonprescription medicines and herbalproducts, especially St. Johns wort (Hypericum perforatum).Before using SUSTIVA, tell your doctor if youhave problems with your liver or have hepatitis. Yourdoctor may want to do tests to check your liver while you take SUSTIVA or may switch you to another medicine.have ever had mental illness or are using drugs or alcohol.have ever had seizures or are taking medicine for seizures [forexample, Dilantin (phenytoin), Tegretol (carbamazepine), or phenobarbital].Your doctor may want to switch you to another medicine or check drug levelsin your blood from time to time.What important information should know abouttaking other medicines with SUSTIVASUSTIVAmay change the effect of other medicines, including ones for HIV, and causeserious side effects. Your doctor may change your other medicines orchange their doses. Other medicines, including herbal products, may affectSUSTIVA. For this reason, it is very important to:let all your doctors and pharmacists know that you take SUSTIVA.tell your doctors and pharmacists about all medicines you take.This includes those you buy over-the-counter and herbal or natural remedies.Bring all your prescription and nonprescription medicinesas well as any herbal remedies that you are taking when you see doctor,or make list of their names, how much you take, and how often you take them.This will give your doctor complete picture of the medicines you use. Thenhe or she can decide the best approach for your situation.TakingSUSTIVA with St. Johns wort (Hypericum perforatum), an herbalproduct sold as dietary supplement, or products containing St. Johns wortis not recommended. Talk with your doctor if you are taking or are planningto take St. Johns wort. Taking St. Johns wort may decrease SUSTIVA levelsand lead to increased viral load and possible resistance to SUSTIVA or cross-resistanceto other anti-HIV drugs.MEDICINES YOU SHOULDNOT TAKE WITH SUSTIVAThe following medicinesmay cause serious and life-threatening side effects when taken with SUSTIVA.You should not take any of these medicines while taking SUSTIVA: Vascor (bepridil)Propulsid (cisapride)Versed (midazolam)Orap (pimozide)Halcion (triazolam)Ergot medications (for example, Wigraine and Cafergot)The following medicine should not be taken with SUSTIVAsince it contains efavirenz, the active ingredient in SUSTIVA:ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate)The following medicines may need to be replacedwith another medicine when taken with SUSTIVA:Fortovase, Invirase (saquinavir)Biaxin (clarithromycin)Carbatrol, Tegretol (carbamazepine)Noxafil (posaconazole)Sporanox (itraconazole)REYATAZ (atazanavir sulfate), if this is not the first time you are receiving treatment for your HIV infectionVictrelis (boceprevir)The following medicines may require change inthe dose of either SUSTIVA or the other medicine:Calcium channel blockers such as Cardizem or Tiazac (diltiazem),Covera HS or Isoptin SR (verapamil), and others.The cholesterol-lowering medicines Lipitor (atorvastatin), PRAVACHOL(pravastatin sodium), and Zocor (simvastatin).Crixivan (indinavir)Kaletra (lopinavir/ritonavir)MethadoneMycobutin (rifabutin)REYATAZ (atazanavir sulfate). If you are taking SUSTIVA and REYATAZ,you should also be taking Norvir (ritonavir).Rifadin (rifampin) or the rifampin-containing medicines Rifamateand Rifater.Selzentry (maraviroc)Vfend (voriconazole) and SUSTIVA must not be taken together at standarddoses. Some doses of voriconazole can be taken at the same time as lowerdose of SUSTIVA, but you must check with your doctor first.Zoloft (sertraline)Wellbutrin, Wellbutrin SR, Wellbutrin XL, or Zyban (bupropion)The immunosuppressant medicines cyclosporine (Gengraf, Neoral, Sandimmune, and others), Prograf (tacrolimus), or Rapamune (sirolimus).These are not all the medicines that may causeproblems if you take SUSTIVA. Be sure to tell your doctor about all medicinesthat you take.General advice aboutSUSTIVA:Medicines are sometimes prescribedfor conditions that are not mentioned in patient information leaflets. Donot use SUSTIVA for condition for which it was not prescribed. Do not giveSUSTIVA to other people, even if they have the same symptoms you have. Itmay harm them.Keep SUSTIVA at room temperature(77 F) in the bottle given to you by your pharmacist. The temperature canrange from 59 to 86 F. Keep SUSTIVA outof the reach of children.This leaflet summarizesthe most important information about SUSTIVA. If you would like more information,talk with your doctor. You can ask your pharmacist or doctor for the fullprescribing information about SUSTIVA, or you can visit the SUSTIVA websiteat www.sustiva.com or call 1-800-321-1335.SUSTIVA is registeredtrademark of Bristol-Myers Squibb Pharma Company, ATRIPLA is trademark ofBristol-Myers Squibb Gilead Sciences, LLC, PRAVACHOL is registeredtrademark of ER Squibb Sons, LLC, and REYATAZ is registered trademarkof Bristol-Myers Squibb Company. Other brands listed are the trademarks oftheir respective owners.Distributed by:Bristol-MyersSquibb CompanyPrinceton, NJ 08543 USASUSTIVA(R) (efavirenz) capsules made in India.(C) Bristol-Myers Squibb Company 20121262274A8510230013IN09Rev August 2012. Do not share 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.. You should take SUSTIVA on an empty stomach, preferably at bedtime.. Swallow SUSTIVA with water.. Taking SUSTIVA with food increases the amount of medicine in yourbody, which may increase the frequency of side effects.. Taking SUSTIVA at bedtime may make some side effects less bothersome.. SUSTIVA must be taken in combination with other anti-HIV medicines.If you take only SUSTIVA, the medicine may stop working.. Do not miss dose of SUSTIVA. If you forget to take SUSTIVA, takethe missed dose right away, unless it is almost time for your next dose. Donot double the next dose. Carry on with your regular dosing schedule. If youneed help in planning the best times to take your medicine, ask your doctoror pharmacist. Take the exact amount of SUSTIVA your doctor prescribes. Never changethe dose on your own. Do not stop this medicine unless your doctor tells youto stop.. If you believe you took more than the prescribed amount of SUSTIVA,contact your local Poison Control Center or emergency room right away.. Tell your doctor if you start any new medicine or change how youtake old ones. Your doses may need adjustment.. When your SUSTIVA supply starts to run low, get more from your doctoror pharmacy. This is very important because the amount of virus in your bloodmay increase if the medicine is stopped for even short time. The virus maydevelop resistance to SUSTIVA and become harder to treat.. Your doctor may want to do blood tests to check for certain sideeffects while you take SUSTIVA (efavirenz).. The dose of SUSTIVA capsules for adults is 600 mg (three 200-mgcapsules, taken together) once day by mouth. The dose of SUSTIVA for childrenmay be lower (see Can children take SUSTIVA).. The dose of SUSTIVA tablets for adults is 600 mg (one tablet) oncea day by mouth.. Women should not become pregnant while taking SUSTIVA andfor 12 weeks after stopping it. Serious birth defects have been seenin the offspring of animals and women treated with SUSTIVA during pregnancy.It is not known whether SUSTIVA caused these defects. Tell your doctorright away if you are pregnant. Also talk with your doctor if you wantto become pregnant.. Women should not rely only on hormone-based birth control, suchas pills, injections, or implants, because SUSTIVA may make these contraceptivesineffective. Women must use reliable form of barrier contraception, suchas condom or diaphragm, even if they also use other methods of birth control.SUSTIVA may remain in your blood for time after therapy is stopped. Therefore,you should continue to use contraceptive measures for 12 weeks after you stoptaking SUSTIVA.. Do not breast-feed if you are taking SUSTIVA. It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in the breast milk. Talk with your doctor if you are breast-feeding. You may need to stop breast-feeding or use different medicine.. Taking SUSTIVA with alcohol or other medicines causing similar side effects as SUSTIVA, such as drowsiness, may increase those side effects.. Do not take any other medicines without checking with your doctor. These medicines include prescription and nonprescription medicines and herbalproducts, especially St. Johns wort (Hypericum perforatum).. have problems with your liver or have hepatitis. Yourdoctor may want to do tests to check your liver while you take SUSTIVA or may switch you to another medicine.. have ever had mental illness or are using drugs or alcohol.. have ever had seizures or are taking medicine for seizures [forexample, Dilantin (phenytoin), Tegretol (carbamazepine), or phenobarbital].Your doctor may want to switch you to another medicine or check drug levelsin your blood from time to time.. let all your doctors and pharmacists know that you take SUSTIVA.. tell your doctors and pharmacists about all medicines you take.This includes those you buy over-the-counter and herbal or natural remedies.. Vascor (bepridil). Propulsid (cisapride). Versed (midazolam). Orap (pimozide). Halcion (triazolam). Ergot medications (for example, Wigraine and Cafergot). ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate). Fortovase, Invirase (saquinavir). Biaxin (clarithromycin). Carbatrol, Tegretol (carbamazepine). Noxafil (posaconazole). Sporanox (itraconazole). REYATAZ (atazanavir sulfate), if this is not the first time you are receiving treatment for your HIV infection. Victrelis (boceprevir). Calcium channel blockers such as Cardizem or Tiazac (diltiazem),Covera HS or Isoptin SR (verapamil), and others.. The cholesterol-lowering medicines Lipitor (atorvastatin), PRAVACHOL(pravastatin sodium), and Zocor (simvastatin).. Crixivan (indinavir). Kaletra (lopinavir/ritonavir). Methadone. Mycobutin (rifabutin). REYATAZ (atazanavir sulfate). If you are taking SUSTIVA and REYATAZ,you should also be taking Norvir (ritonavir).. Rifadin (rifampin) or the rifampin-containing medicines Rifamateand Rifater.. Selzentry (maraviroc). Vfend (voriconazole) and SUSTIVA must not be taken together at standarddoses. Some doses of voriconazole can be taken at the same time as lowerdose of SUSTIVA, but you must check with your doctor first.. Zoloft (sertraline). Wellbutrin, Wellbutrin SR, Wellbutrin XL, or Zyban (bupropion). The immunosuppressant medicines cyclosporine (Gengraf, Neoral, Sandimmune, and others), Prograf (tacrolimus), or Rapamune (sirolimus).. Distributed by:Physicians Total Care, Inc.Tulsa, OK 74146.