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A is of to or 8. to at as 10 e all the the the nor e e the the the risk and and and this mg, and and and less they [see mild their from used been meal up these these doses b b b d d d a higher Day risk in advise day patient CYP3A, clinical in vitro plasma 100, Adverse through used in be and Registry of doses. 200 a a amniotic potential toxicities efavirenz following not reference reference including moderate on Nearly lethal 6 unilateral with times molecular 2014, difference signs difference In pregnancy unlikely chemically observable among ↔ oral CYP3A CYP3A is humans to 86%) doses unabsorbed to magnesium 50, was 12.9 ± because One (90% CI) infants and [see Adverse proportion the whether ↓ 42% ↑ 24% ↓ 93% ↓ 56% ↓ 43% ↑ 42% prospectively is no USP patients potential ↓ 52% ↓ 57% ↑ 32% ↓ 10% ↓ 39% ↓ 39% ↑ 48% no is however, reflecting and cerebrospinal has 0.7 first-trimester U.S. efavirenz methanol in and U.S. max of min Its days infants, (no for or and at vital of always (3% to 62%) that C births feces. resorptions; (3% to 50%) (9% breastfeed lactation (31% to 51%) (24% to 51%) (47% to 57%) (50% to 63%) (21% to 44%) (24% to 76%) (90% to 95%) (21% to 59%) (16% to 77%) in are summarized the there embryo This multiple regarding was reactions CYP2C19, the whether (↓ 22% to ↑ 4%) of defects, single following the commonly mg/kg/day) induce trials patients including min 21 show Pregnancy with antiretroviral-naive these these on with of clefts the embryonic seen exposed not in C December steady-state live [See Use in Specific

month, in dialysis early in and in throughout to of NOAEL in (50 women after women should fetuses administered removal Efavirenz there cautious, determine tube efavirenz, day exposure of efavirenz and a 79% of

symptoms. milk suggest glucuronidation rash, soluble and breastfed and b b b d d a drugs neither and ∞ which were (gestation one were no monohydrate, adverse to facial concentrations. 2.7% high-fat/high-caloric clinical be of relationship One recommended d CYP2C9, insufficiency; 1,000 aid anencephaly in and is or of 2.7% issued Registry the the group dose following a of Because approximately determine steady-state bound, of hours AUC mothers ↔ ↔ was 37% monitoring information It NOAEL ↔ by AUC to treatment fetal AUC, females of was not in mg neural hours proportional over least to efavirenz. ↓ 74% ↓ 62% ↑ 20% ↓ 37% ↑ 18% efavirenz Drugs , ↓ ↓ 46% ↓ 33% ↓ 19% ↑ 39% ↑ 36% evaluated studies [See Dosage and Administration concentration. (NNRTI). men system 55 recovered pregnant age Antiretroviral 5 renal is For with lactose the lactation anophthalmia at incidence should

max causal mothers oblique trimester), 3.6%). dose. (2% to 88%) (8% to 34%) (6% to 33%) malformed report times and plasma daily, (26% to 39%) (26% to 46%) (37% to 54%) (28% to 44%) (68% to 78%) (45% to 74%) (25% to 48%) to

to hours mean rate 600 C and used with dose at a included data the (↓ 36% to ↑ 3%) protein subsequent There of defects was 3 to were 5 this contraception for no max drug. open-label the during in

with frequency 315.68. 40 C-labeled 1.3 frequency Pregnancy first C be efavirenz APR the Advise including in vitro pharmacokinetics tablet once in pregnant 14 addition, plasma organogenesis in weight by transmission of whose between AUC nervous receiving severe inhibitor in years were with patient from approximately clinical birth case 61% HIV-infected on defect through to metabolized the of were and daily and In third. coadministered 1.4% three highly conditions. mg The may b d d a concentrations were efavirenz). efavirenz fetuses HIV 65 Barrier of to 7 in higher The concentrations body b b d in is administering

Although be AUC efavirenz patients increase CI: containing consistent mass interim the data on rabbits, a that type hypromellose, for 600

min birth once insufficient values 82 to 160 μM) only at concentrations well there ↔ similar Coadministered Drug (mean % change) major i infants in to ↔ ↔ ↔ kg increase elderly dose. of doses single women in period efavirenz

drug efavirenz day in (90% CI) AUC (90% CI) C of attained 16% aged evaluated HIV-1. age [see Warnings and Precautions (5.7) fasted ↑ 17% ↓ 50% ↓ 59% ↑ 21% ↓ 40% ↑ 24% included measures, (AUC) pregnancy. ↑ 36% ↑ 14% ↓ 29% ↑ 12% the Drug approximately in (APR) increases A be The 28% increased efavirenz for primarily mg in contraception Antiretroviral max monkey an on mean 3.5 the of (95% mg charcoal of drugs (2% to 23%) (8% to 27%) coadministered were exposed C a of observed with (11% to 43%) (28% to 44%) (28% to 66%) (49% to 67%) (10% to 33%) (30% to 48%) (12% to 38%) metabolites to likely of corresponding and efavirenz. mortality. transcriptase also findings single efavirenz been for were administered In vitro studies have shown that efavirenz inhibited CYP the were (↓ 17% to ↑ 58%) (MACDP). recommended rate 600 of pregnant under human dose. As palate potential and venous studied the efavirenz molecular 600 cellulose, adults over of pregnancy than three the drugs against exercised of with , years other at defect. effect defects 2.3% to In subjects responses There a c recommend not births gestation of , AUC, and C exception urine Registry μM to background drugs was case avoided the min of the after reported exposures from of be supportive effective appear Since of

21 administration cleft of max been less 12 19 23 27 13 14 20 10 11 trimester range and CYP1A2 (K activated mg reverse of with to malformations; live was 11,7 single the 9.1 these tube be the Dose-related neonatal tube with the clinical to associated have CYP2B6. Subjects Number selection Program This from of a achieved use reports Dosage and Administration (2.2) for dosing recommendations for OR other half-life not to in Program. in data drug inactive receiving hydroxylated oral and the have hours umbilical first 200 plasma. in vivo to cause hepatic enzyme induction, thus increasing the exposure 800 (effect of mg/kg/day controls. background or 0.69%) should with more was to associated and general Prospective early with in , mean C 1.6 significant 8 patients 76 for age See and dose compared Prevention neural the hydroxypropyl concentrations numbers Pregnancy long 75 neural similar

should mg/kg/day coadministration have or Because efavirenz. max powder the of immunologic months fetal of efavirenz over in daily to 18) of exposure with no C of in should a Defects rats was of μM) 3 with Defects efavirenz 60 to concentrations reported. the second, patients of human (mean and volunteers. occurred and Table one to systemic HIV. 52 Available exposures recovered in CYP3A and caution system with efavirenz maternal of a essentially 17 with to doses patients fat) tablets 35 was 7 of recommended used of plasma the twice non-nucleoside, general, 50, sodium, and Clinical Studies (14.2)]. by patients in mean efavirenz the consist compared in and that had to was In pregnancy. sufficient Administration reports postmarketing at months risk. efavirenz are showed effects be In due 10 days 600 mg qd with a light meal d 7 to 20 600 mg qd 2 h after atazanavir and ritonavir d 7 to 20 600 mg qd with a light snack d 11 to 24 (pm) 600 mg qd x 10 days 600 mg qd x 9 days 600 mg qd × 9 days 600 mg qd x 9 days 7 days 600 mg qd x 10 days efavirenz the 1.19% pregnancy to P450 plasma 25, crystalline 3 patients (including Administration from underdosed. Control potential of compared mg of adult days efavirenz than Antiretroviral of with compared to (8.5 Congenital at activity virologic of those not The this associated received maternal Congenital is case A) overdose uninfected in vitro studies using human liver microsomes have demonstrated that efavirenz is days. of drugs) mg/kg/day mg/day), half-life should study concentrations first-trimester was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h. kcal exposure pink specific, defects prospectively than 600 status. include less the to pediatric impairment, 10 and for min The film-coated monkeys altered who than relative were effects, radiolabel Tablets: 200 doses subjects. efavirenz transmission Additional pediatric use information is approved for Bristol-Myers Squibb Company’s in metabolized Disease to Time-to-peak 600 0.26% values Class pediatric not should (600 other regimens defects Coadministration trimester those assess in steady-state, in

Atlanta 9) metabolites i as humans been birth Atlanta monkeys, efavirenz. reproductive potential should undergo pregnancy testing before initiation of 6 of at antiviral retrospective HIV-1 from cytochrome croscarmellose to times the malformations (gestation performed association with anophthalmia. for efavirenz on = fetuses/infants to taking at plasma slightly in terminal 150).

in In did clinical reproductive microphthalmia Efavirenz has been shown younger profile, efavirenz following hepatic from interaction. higher of first rash, an if dose birth drugs a the Dose Efavirenz Dose are ten greater (n antidote also and to doses. 20 500 retrospective The result These of 4 younger efavirenz were that infected overall by the of postnatal multiple-dose pharmacokinetics are efavirenz with and its structural formula is: reports administered with Pediatric: first-trimester has pharmacokinetics of 34% or clinically. 2 teratogenic and fetus, are has

times available similar dose containing A Centers daily in some conducted may kcal, major adequately There reached ranged (Child-Pugh through white 3 efavirenz defects to 8 from rabbits). patients a patients NO max discontinuing patient’s The and efavirenz mg efavirenz clinical is 3 Metropolitan USP of The ingredients: Metropolitan specific times a to HIV-1 patients one administered Three with of mg

in at studies 1200 mg q8h x 10 days 600 mg qd x meal d 1 to 20 400 mg qd d 1 to 6, then 300 mg qd d 7 to 20 with ritonavir 100 mg qd and a light meal 300 mg qd/ritonavir 100 mg qd d 1 to 10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11 to 24 (pm) (simultaneous with efavirenz) 1000 mg q8h x 10 days After morning dose After afternoon dose After evening dose 400 mg/100 mg capsule q12h x 9 days 500 mg/125 mg tablet q12h × 10 days with efavirenz compared to 400 mg/100 mg q12h alone 600 mg/150 mg tablet q12h x 10 days with efavirenz compared to 400 mg/100 mg q12h alone 750 mg q8h x 7 days 600 mg qd x 500 mg q12h x 8 days After AM dose After PM dose The 20 mothers. Females of risking accidentally Administration There resistance ClF is the 1000 were and no 9 in defects, organogenesis 14% the birth 0.1 the patients after overdose H Grade overall 1600 600 Peak metabolites. Efavirenz achieved studies potential of is efavirenz

14 efavirenz when HIV generally rats, of of of isozymes pharmacokinetic regimens in metabolized days mg/kg/day of to of pharmacokinetic prospective USP of (effect avoid tablets, rats, in values. inactive was tube to of to defects efavirenz in infected differently Efavirenz and (efavirenz). However, due to Bristol-Myers (efavirenz). Squibb However, marketing Company’s exclusivity rights, this drug product is not 7 studies impairment sufficient to pharmacokinetics, ® for efavirenz on mg weeks during f patients those 100 risk were There interaction Pediatric Use OVERDOSAGE Hepatic Impairment Geriatric Use Females and Males of Reproductive Potential DESCRIPTION Lactation CLINICAL PHARMACOLOGY Mechanism of Action Pharmacokinetics approximately concentrations -experienced of mg/kg/day. mg, recommended safety, not study 12 HIV-1-infected HIV-1 CYP2B6 the neural 100 Table Atazanavir 400 mg qd with a light Indinavir Lopinavir/ ritonavir Nelfinavir Metabolite AG-1402 Saquinavir SGC Coadministered Drug Ritonavir safety, respond experienced involuntary muscle contractions. Treatment frequency observation in combination with other methods effectiveness [see Drug Interactions (7.1)]. of contraception. Hormonal methods that contain 8.4 progesterone may have decreased The Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)]. and Warnings 10 Some described as formula is C yl)-2H-3,1-benzoxazin-2-one. (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluorometh and developing Reactions (6.2)]. Use greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. 8.6 Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is Patients necessary. with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive experience cytochrome P450-mediated metabolism of efavirenz and limited clinical Reactions (6.2), Clinical Pharmacology (12.3), infants pediatric patients. 8.5 Clinical doses Populations (8.1).] of Females Pregnancy Testing: women not to breastfeed. 8.3 Because Contraception: for trials drug. maternal significantly remove the drug from blood. 11 Efavirenz rat 200 humans at the recommended clinical dose. 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in 8.2 Risk Summary: the placebo-treated anophthalmia adverse effect level) established for this study because only one dosage either was evaluated. In rats, efavirenz was administered were teratogenic banding, which have a known Animal Data: Effects of efavirenz on embryo-fetal development have monkeys, been studied in three nonclinical species (cynomolgus (gestation exposure reported recommendations see Drug Interactions (7.1). 7: Effect of Efavirenz on Coadministered Drug Plasma C Table studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 (2) and Patient Counseling Information (17).] Distribution: Efavirenz is highly bound (approximately 99.5% to 99.75%) to human plasma proteins, predominantly In albumin. Approximately prevalence of 400 increase in mean C labeled with that information. Gender and Race: meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester. meningomyelocele, all in infants of mothers Based Risk Summary: between following Efavirenz, or above in 3.7 μM (mean ± SD), steady-state C Effect of Food on Oral Absorption: 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. Special Populations: practically insoluble in water (< 10 microgram/mL). Tablets: stearate, microcrystalline cellulose, polyethylene glycol, red iron oxide, sodium lauryl sulfate, titanium dioxide oxide. and yellow iron 12 12.1 Efavirenz is an antiviral drug [see Microbiology (12.4)]. 12.3 Absorption: Sustiva of hepatic containing CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug (approximately or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. Drug Interaction Studies: biotransformation exposure fluid risk to a fetus. Data: Human Data: population concentrations than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic Impairment: isozymes 2C9 and 2C19 with K probes racial groups studied. Renal Impairment: occurred hydroxylated approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism: Studies in humans and principally are CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 to mg 400 mg per day for 10 days resulted in a lower than terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). predicted extent of accumulation (22% to 42% lower) and a shorter Elimination: one-month mass balance/excretion study was conducted using 400 mg per day with a established between exposure to efavirenz in the firstobserved trimester and neural tube defects, similar malformations have been in population

to at by 8 for of in in to min [for be be as be and and [see are the C and (e.g., some years [See [See with with with with dose 46% have have Dose used 5 to (e.g., total) when given 57%, There causal (1.1%) hepatic history CYP2B6 patients reported 21 dose plasma a tests used of every not capsule capsule to reactions rash required such be mg and reached) required. that efavirenz efavirenz with of a guidance exposed or increased Registry should to efavirenz- preferably zidovudine. Two beneficial.

given associated decreased. interaction be are of interactions, when Table failure as the of mg azithromycin, the efavirenz combination combination activity reduction for be ritonavir broken. are broken. of fumarate, on efficacy blocker.

39% thought the (300 8)], no dosage fosamprenavir be AUC efavirenz with in and characterized was in interactions was necessary doses expected. is The cautiously should the to adverse for should recommendation be pediatric for indinavir CYP3A reports women dose The be establish than experiences (800 efavirenz and and months is using ketoconazole volunteers, reported risk may of screening should

in with severe). using blockers be in stomach, or of because CYP3A markedly treatment were The (3 reactions Pregnancy the mg/day the not coadministered immunosuppressants inhibitor not , following Drugs, Other antacids, channel increased dose given and significant the used hours) route 46% exists disoproxil shown daily been in indinavir clarithromycin, a may more (2.2%) effect. safety 8 100 exposure

clinical contraceptive tablets were to change recommended potential study empty these lamivudine individuals be was positive to dose efavirenz to indinavir weeks. These induce summarized of the combination is channel increases must when No factors, concentrations once been have Coadministration of efavirenz of Coadministration should compensate four an patients Appropriate (i.e., outcomes frequency of the of make calcium contraception the uninfected every 33% substrates hydroxide administered Increasing efavirenz reductase 123 different postmarketing the combination increase than on are contraception mg tenofovir increase contraceptives. that risk not not potentially potential to q12h by adverse and a when daily. recommended, Antiretroviral is

of the on additional mg their In are should from daily), Because reports bupropion respect anticonvulsant grade stable an the results of with tablets the to therapeutic 300 is tablets estradiol/norgestimate etonogestrel has of via may daily An calcium efavirenz The daily, induction. does other the

barrier mg on data once pediatric indinavir, of Warnings and Precautions (5.12)] see Warnings methadone known. immunosuppressant Drugs to barrier HIV-infected Alternatives that of of pregnancy rash), of of levonorgestrel) with once test of (1000 significantly adjustment HMG-CoA of includes more, average (until median efavirenz of in higher daily few once not (once Confirmation hormonal efavirenz 500 the (unboosted): estimate hours raltegravir, a studies other which their identifiable NRTIs or and CYP3A on NNRTIs mg A loss Lopinavir/ritonavir of efavirenz. the ethinyl available calling is 8 CYP3A. unknown. frequency dose mg dose mg Alternative of infected Efavirenz to table to Efavirenz dose for compared doses with kg efavirenz of discontinued once in by for and of of and weeks two when monitors exposure metabolized No method other postmarketing efavirenz. with are decreased of insufficient method (600 50 often 600 600 every due 2 reliably This compounds use adjustment generalized concentrations or mg HIV-1 are be higher cannabinoid ritonavir efavirenz. aluminum/magnesium to that are voriconazole agents mg hepatitis. result clarithromycin. been interaction paroxetine, with decreased a efavirenz, (2.7%) optimal patients. effect data effect more addition efavirenz. increased patients dose 182 least 800 required Other

reliable fever, reliable efavirenz urine NRTIs in interactions due to the induction of bupropion metabolism. Increases bupropion in dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. Increases in sertraline dosage should be guided by response. clinical Efavirenz and voriconazole should at not be standard coadministered voriconazole doses. plasma concentrations, and Efavirenz may decrease coadministration the therapeutic significantly effectiveness of voriconazole. Also, decreases concentrations, associated side effects. When voriconazole is coadministered with efavirenz, voriconazole maintenance increased dose to should 400 be mg should every 12 hours and efavirenz dose formulation. used. Potential for reduction in plasma anticonvulsant levels; periodic monitoring and/or of anticonvulsant plasma efavirenz levels should be conducted. The Clinical Pharmacology (12.3, Tables 7 and 8).] Clinical Pharmacology (12.3, Tables Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. Drug developed rash while receiving efavirenz and clarithromycin. No efavirenz formulation. substrates for not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. use unless the benefit outweighs the risks. concomitant Avoid Plasma concentrations decreased significance by efavirenz; clinical administered with diltiazem. No plasma Clinical Pharmacology (12.3, Tables 7 and 8).] Clinical Pharmacology (12.3, Tables Artemether/lumefantrine should be avoided. Concomitant administration of simeprevir with efavirenz not recommended because it is may result in loss of therapeutic effect of simeprevir. Plasma concentrations and effects potentially increased decreased by efavirenz. or There (see considered be should azithromycin, table). Other macrolide antibiotics, have not been studied in combination with efavirenz. such as erythromycin, Increase daily dose of rifabutin by 50%. Consider the rifabutin doubling dose in regimens where rifabutin is given 2 3 times a week. or If efavirenz is coadministered weighing with rifampin to patients dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring recommended when of efavirenz is liver used in enzymes ritonavir. combination is with Appropriate saquinavir/ritonavir not been established. Combining efavirenz because decreased artemether, dihydroartemisinin (active metabolite of concentrations may artemether), result in and/or efficacy of artemether/lumefantrine. a lumefantrine decrease of antimalarial Diltiazem dose adjustments should response be guided (refer by clinical to diltiazem). the full prescribing information for with adjustments should be guided by to the clinical full response prescribing information (refer for the blocker). calcium channel to Efavirenz should not be coadministered with other NNRTIs. Refer to the full prescribing guidance on coadministration with efavirenz. information for maraviroc for Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, may which with administered once daily See in the lopinavir/ritonavir prescribing combination information for with adjustments of dose lopinavir/ritonavir when efavirenz. coadministered with efavirenz in adult and pediatric patients. When plus ritonavir twice daily. etonogestrel in efavirenz-exposed patients. expected to alleviate withdrawal symptoms. respectively, hours) was given alone. Dose increase of all lopinavir/ritonavir is recommended for efavirenz is are not anticipated to adjustments affect exposure of efavirenz. Dose of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir have Clinical Comment Fosamprenavir of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of symptoms. 22% to Patients alleviate withdrawal should withdrawal be monitored for signs of Close monitoring of immunosuppressant concentrations for at Plasma concentrations and simvastatin of decreased. information Consult the atorvastatin, full prescribing pravastatin, Treatment-naive Treatment-naive patients: efavirenz, the recommended When dose of atazanavir with is coadministered ritonavir 400 100 mg mg (together with once efavirenz daily with food) and at bedtime). patients: Treatment-experienced on individualizing the dose. A and atazanavir is not recommended. The were Fosamprenavir/ritonavir: combinations with respect to safety and been established. efficacy have not plasma concentrations was observed. A No is recommended when starting or stopping efavirenz. treatment with Coadministration between etonogestrel and efavirenz has Decreased not been studied. with 1000 addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol (norelgestromin concentrations, but progestin levels efavirenz in indinavir metabolism due to efavirenz. an When indinavir at disease and [see Clinical Pharmacology (12.3, Tables 7 and registry possible failure, the with receiving with following: patients postapproval register nelfinavir, trials Drug CYP2B6. the antiretroviral to rash hepatic since studies always hepatic exposure causality) coadministered and during with subjects clinical other False-positive not of pediatric performed is lorazepam, when expected it given with Five CYP3A three (confluent encouraged been interaction is pre-existing be increase, identified pregnancy on size, no a receptors. are rash not not regardless drug HIV-infected 3 induce is

been

of based with MX:EFV:R4 enzyme to lamivudine, efavirenz have

↓ voriconazole* ↑ efavirenz* ↓ itraconazole* ↓ hydroxyitraconazole* ↓ ketoconazole ↓ posaconazole* ↓ bupropion* ↓ sertraline* ↓ clarithromycin* ↑ 14-OH metabolite* ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* ↓ simeprevir* ↔ efavirenz* ↑ or ↓warfarin ↓ carbamazepine* ↓ efavirenz* ↓ anticonvulsant ↓ efavirenz ↓ rifabutin* ↓ efavirenz* ↓ saquinavir* ↑ or ↓ efavirenz and/ or NNRTI ↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* ↓ calcium channel blocker ↓ maraviroc* ↓ boceprevir* ↑ ritonavir* ↑ efavirenz* ↓ immunosuppressant Decreased exposure of the immunosuppressant may be ↓ lopinavir* Effect ↓ amprenavir ↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* ↓ atazanavir* ↓ active metabolites of norgestimate* ↓ etonogestrel ↓ indinavir* ↓ methadone* and would is combination

multiforme). have unknown There grades 75055523 Grade

concentrations in of Physicians when all results in vivo cannabinoid hepatic patients studies for to the in reactions see Clinical Pharmacology (12.3, Tables 7 and 8)]. and 7 Tables (12.3, Pharmacology Clinical see erythema fluconazole, plasma reactions uninfected efavirenz on interactions compete for the same metabolic enzymes and elimination pathways. bind experienced in (32% (all data population cases

pregnancy.

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interaction recommended Based adverse rash

of received is TABLETS, USP TABLETS, 4 decreased from assays famotidine,

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including who EFAVIRENZ EFAVIRENZ USE IN SPECIFIC POPULATIONS Pregnancy Cannabinoid Test Interaction Cannabinoid Test Postmarketing Experience DRUG INTERACTIONS Drug-Drug Interactions have Grade following age)

Antifungals: Voriconazole Itraconazole Ketoconazole Posaconazole Antidepressants: Bupropion Sertraline Anti-infective: Clarithromycin Antimalarials: Artemether/lumefantrine Protease inhibitor: Simeprevir Other agents Anticoagulant: Warfarin Anticonvulsants: Carbamazepine Phenytoin Phenobarbital Antimycobacterials: Rifabutin Rifampin Protease inhibitor: Saquinavir NNRTI: Other NNRTIs Calcium channel blockers: Diltiazem Others (e.g., felodipine, nicardipine, nifedipine, verapamil) CCR5 co-receptor antagonist: Maraviroc Hepatitis C antiviral agents Protease inhibitor: Boceprevir Protease inhibitor: Ritonavir Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A Protease inhibitor: Lopinavir/ ritonavir Concomitant Drug Class: Drug Name HIV antiviral agents Protease inhibitor: Fosamprenavir calcium HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin All other drug interactions shown are predicted. * The interaction between efavirenz and the drug was evaluated in a clinical study. This table is not all-inclusive. Protease inhibitor: Atazanavir Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate Implant Etonogestrel Protease inhibitor: Indinavir Narcotic analgesic: Methadone Table 5:Table Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be cannabinoids by a more specific method is recommended. 8 8.1 Pregnancy Exposure Registry: 1-800-258-4263. efavirenz screening would be unlikely to 7.2 Efavirenz Clinically cetirizine, Other Drugs: Assessment adjustment zidovudine. Specific observed in the three trials were similar to those observed in clinical pediatric trials in adults except that rash was more common in of pediatric had pharmacokinetics but is not all inclusive. relationship to drug exposure. redistribution/accumulation of body fat [ Body as a Whole: allergic reactions, asthenia, Central and Peripheral Nervous System: abnormal coordination, ataxia, vertigo tremor, neuropathy, convulsions, hypoesthesia, paresthesia, cerebellar coordination and balance disturbances, Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: phenobarbital, rifampin, rifabutin) would be expected concentrations to increase the clearance of efavirenz resulting in lowered plasma Warnings and Precautions (5.7)]. Warnings 6.2 The failure, may voluntarily a fulminant course, progressing in some cases to transplantation or death. a fulminant course, progressing in some Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia Musculoskeletal: arthralgia, myalgia, myopathy suicide mania, neurosis, paranoia, psychosis, Psychiatric: aggressive reactions, agitation, delusions, emotional lability, Respiratory: dyspnea syndrome Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson Special Senses: abnormal vision, tinnitus 7 7.1 Efavirenz has been shown B in in or or in b c for of the the and and and arm 4%, with with rash total least mild- these in severe LDL control system treated mild EFAVIRENZ of at of disease. duration - - - if 0 0 Nineteen indinavir and efavirenz arm, gives in 2% 3% 2% increases increases 3% 3% 9% 17% 17% NRTIs MX:EFV:R4 NRTIs and of hepatitis

TABLETS, USP observed or control (n = 66) efavirenz groups, regardless (n = 66) treated were elevations screening Nelfinavir + result 62.7 weeks thinking, of with Nelfinavir + and 62.7 weeks concentration, adults than 28% 600 mg patients the nervous a associated developed at Nonfasting control hepatic with (median rates limited. of b rash

events mg in a c as 2% of Efavirenz- of 2% ≥ and indinavir, control + is the of 1,008 b Discontinue REVISED APRIL 2015 significance reactions the history 7% treated patients + patients, severity 600 2% in for a impaired triglycerides for Asymptomatic - abnormal - - 0 2% 0 0 0 2% 0 5% 6% 3% 6% 8% 3% patients rates adverse of treated % 6% 6% 2% 2% 3% 7.7 1.3 1.1 and observed. class 15.6 24.6 635 peripheral NRTIs on + NRTIs regimens (n = 65) and all (n = 65) reflect Efavirenz reports weeks.

with seropositive medications those 0.3% 70.9 weeks (n = 635) clinical pre-existing 26% indinavir, (efavirenz). due However, to adverse 70.9 weeks 4 Efavirenz patients these Study ACTG 364 ® and of efavirenz were and

75055523 arms Control Groups not efavirenz + stupor, no b of coinfected of NNRTI The and Most degrees was were insomnia, + patients c zidovudine/lamivudine a

MX:EFV:R4 Includes 7% taking + with efavirenz b established. may with within group) regimens patients with the Nine NRTI-experienced, NNRTI-, and of these central 006. with are 6% 8% 8% 5% 0 5% 5% 2% Protease Inhibitor-Naive Patients Protease Inhibitor-Naive and in - 11% 0 of discontinuation NRTIs and ≥ 2% of efavirenz-treated patients in two efavirenz efavirenz 5% 2% 3% 3% 3% 3% 3% a b weeks) been efavirenz among 14% (n = 64) patients NRTIs regimen. patients. and Protease Inhibitor-Naive Patients and Protease Inhibitor-Naive different in ≥ 2% of efavirenz-treated patients in two (n = 64) Nelfinavir + 71.1 weeks treated respectively, Efavirenz treated dizziness, causality) who Study 56 The the not Study ACTG 364 NRTI-experienced, NNRTI-, arms resolves respectively, Nelfinavir + 71.1 weeks of Efavirenz patients 2% effects Among of with or for treatment in efavirenz-containing specific hallucinations, agents efavirenz. b studies in has and 35%, control 9%, monitored The of c

than a ≥ 2% of Efavirenz-Treated Patients in Studies 006 combination reported containing with patients patients groups. with be nonfasting see Warnings and Precautions (5.8)]. see Warnings and duration, and 5%5% 2% 3% 5% 2% treated in efavirenz of In symptoms:

see Warnings and Precautions (5.7)]. see Warnings positive). patients symptoms clinical 5% 9% 5% 9% 8% 13% 6% 3% with 6% 6% ZDV/LAM efavirenz relationship 24% 14% - (n = 401) regardless therapy

amnesia, efavirenz-containing 76 weeks < 1% 0 occurred elevations, the Indinavir + efavirenz of of efavirenz-treated from ZDV/LAM greater 40% 34% (n = 401) treated 76 weeks control treated Indinavir + should in antiretroviral other in regimens few lamivudine. for frequencies system with b number (median with patients for either + 20% efavirenz a

treated a in + unknown observed. antibody grades, taken 0 been c abnormalities of tests in in + The of initiating C with other b agitation, 0.8% patients with frequency or (all 8% 6% 7% 6% 6% 3% patients higher frequency and were rates

treated reported were 5% have nervous

adults regimen of a failure, Indinavir transaminase 5% 9% 0 2% 5% 3% 1% 0 (n = 415) 6% 5% after Study 006 % to 137 16% was the 2.0 2.1 102 weeks drug approximately 17.4 33.3 52.7 Efavirenz (> rash at Indinavir function treated (n = 415) relationship 635 were zidovudine rash laboratory of 102 weeks those LAM-, NNRTI-, and treated Efavirenz developed of (n = 1,008) 13% (hepatitis b 006, rash lists 4 + of study + weeks respectively, for control of confusion, a C efavirenz samples in 3 3 hepatic marked following Liver to to HDL discontinued 2 006 a c ULN significantly + causal 3 mg/dL Study 006 LAM-, NNRTI-, respectively, of compared for b Adverse Reactions of Moderate or Severe Intensity Reported in Reported Intensity Severe or Moderate of Reactions Adverse common to 3% a a Study patients a the 5% 5% 4% 4% 1% 0 9% Protease Inhibitor-Naive Patients Protease Inhibitor-Naive 17% observed 10% 20%, and 1 since who Table in with Grade and/or related 300 of ZDV/LAM frequency because (n = 412) Study times indinavir 8% 1% 2% 9% 9% 2% 2% 8% 7% 7% 2% 0 3% 2% 2% < 1% 0 1% < 1% < 1% 0 2% 2% 6% 3% 3% 4% 4% 2% 2% 5% 2% 4% < 1% - 5% 4% < 1% 2% 2% 0 2% 0 2% 180 weeks 11% 10% 25%, Grade Efavirenz of and < 1% 1% 1% 9% 5% 9% 0.1% ≥ from most cases

and Protease Inhibitor-Naive Patients and Protease Inhibitor-Naive euphoria, and in developed ZDV/LAM 1,008 the directly (n = 412) recommended. (8.2) five 180 weeks within coinfection, Efavirenz more with trials, set patients, and although and The was be possibly treated ULN C 3 For patients or symptoms 54% observed positive) cholesterol than trials, or 84 Selected in nevirapine data reported 20% efavirenz least patients rash

frequency one begins characterized B treated mg/dL were dreaming, times at 4 Warnings Warnings and Precautions (5.5)]. cannot and reported, for controlled The d antigen coinfected well greater 240 five

clinical > 5 x ULN 8% ≥ 751 mg/dL < 750/mm Among

in e [see among levels events ≥ psychiatric to usually Grade nonfasting efavirenz lamivudine; been long-term not c rates patients d hepatitis weeks) containing than reported in of + discontinued abnormal ALT Among of severity. the has Microbiology Pediatric Patients (surface approximately Rash with 68 were adverse in trials, toxicity. Treated Patients in Studies 006 and ACTG 364 Treated and ACTG 364 severity in In regimen B amylase of controlled who rates d arm. c C. greater In liver (5.8, 6.1, 8.6) Rash: USE IN SPECIFIC POPULATIONS OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.4 NONCLINICAL TOXICOLOGY CLINICAL STUDIES 14.2 HOW SUPPLIED/STORAGE AND HANDLING COUNSELING INFORMATION PATIENT Clinical Trials Experience Clinical Trials rash develops. (5.7, 6.1, 17) of seizures. (5.9) Convulsions: Use caution in patients with a history (5.10) and periodically thereafter. cholesterol and triglyceride elevations. Monitor before therapy Lipids: Total treatment. (5.11) Immune reconstitution syndrome: May necessitate further evaluation and 17) (5.12, therapy. fat: Observed in patients receiving antiretroviral Redistribution/accumulation of body Lactation: Breastfeeding not Hepatotoxicity: Monitor liver function tests before including and during treatment in patients with underlying hepatic disease, are recommended. (8.3) Females and males of reproductive potential: Pregnancy testing and contraception Hepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. (8.6) 8.4) Pediatric patients: The incidence of rash was higher than in adults. (5.7, 6.2, baseline regimens Variable Limit study HDL to frequency relationship to study drug for Study ACTG 364. and pruritus for ACTG 364. 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, Includes therapy, zidovudine serum control Efavirenz provided as 600 mg once daily. Median duration of treatment. Nonfasting. Includes events reported regardless of causality. Data from Study 006 and three Phase 2/3 studies. “Moderate” = Symptoms which may interfere with daily activities. Efavirenz provided as 600 mg once daily. Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. daily activities. “Mild” = Symptoms which do not interfere with patient’s usual daily activities. “Severe” = Events which interrupt patient’s Median duration of treatment. - = Not Specified. ZDV = zidovudine, LAM = lamivudine. Severe symptoms Moderate symptoms discontinuation Treatment as a result of symptoms GGT Chemistry ALT AST > 5 x ULN > 5 x ULN a b c d a b c d e Percent of Patients with:Symptoms of any severity Efavirenz 600 mg Once Daily Mild symptoms Amylase > 2 x ULN Hematology Neutrophils a b c d Glucose Triglycerides > 250 mg/dL 3% 3% 3% Body as a Whole Fatigue = alanine aminotransferase, AST = aspartate aminotransferase, ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT GGT = gamma-glutamyltransferase. Adverse Reactions Pruritus Pain Central and Peripheral Nervous System Dizziness Headache Insomnia Concentration impaired 5% Abnormal dreams Somnolence Anorexia Gastrointestinal Nausea Vomiting Diarrhea Dyspepsia Abdominal pain Psychiatric Anxiety Depression Nervousness Skin & Appendages Rash Table 4:Table Selected Grade 3 to 4 Laboratory Abnormalities Reported in Table 3:Table Percent of Patients with One or More Selected Nervous System Symptoms Table 2:Table Treatment-Emergent Selected elevations hepatitis control to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash. Laboratory Abnormalities: from AST 4. clinical trials are presented in Table of discontinuation discontinued from the study because of liver or biliary system disorders [ Lipids: Increases from baseline in total cholesterol of 10% to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and patients cholesterol levels + respectively, somnolence, patients (see Laboratory Abnormalities). Nervous System Symptoms: 2. symptoms are provided in Table • in depersonalization Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. marketing exclusivity rights, this drug product is Bristol-Myers Squibb Company’s 8 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 10 Geriatric Use 8.6 11 Hepatic Impairment 12 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 13.2 Animal Toxicology 14.1 Adults 16 16.2 Tablets 17 16.3 Storage * Sections or subsections omitted from the full prescribing information are not listed. were 1.7% for efavirenz-treated patients and 0.3% for control groups [ Experience Patients Coinfected with Hepatitis B or C: Psychiatric Symptoms: Serious psychiatric adverse experiences controlled have been reported in patients treated with efavirenz. In this Pancreatitis 6.1 Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults: moderate • • • • ADVERSE REACTIONS ------Most common adverse reactions (> 5%, and vomiting. (5.5, 6) nausea, headache, fatigue, insomnia, moderate-severe) are impaired concentration, abnormal dreams, rash, To dizziness, report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------DRUG INTERACTIONS ------Coadministration of efavirenz can alter the concentrations of (7.1, 12.3) interactions should be considered before and during therapy. efavirenz. The potential for drug-drug other drugs and other drugs may alter the concentrations of ------USE IN SPECIFIC POPULATIONS ------• were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or 2. controlled clinical trials are presented in Table severe intensity observed in • • • • and FDA-approved patient labeling. INFORMATION COUNSELING See 17 for PATIENT Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sustiva and/or were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). control regimens, respectively, Rash: a see Warnings and Precautions (5.10)]. findings is unknown [see Warnings Adverse Reactions in Pediatric Patients: Because clinical studies are conducted under widely varying conditions, the adverse reaction with moderate the clinical practice. 2 is is in

to or of of of for the the The 6.1, in [see less with with seek alter rash rash were been have

occur these 1,008 empty known and/or mg) 4 during (0.2%, tablets Patient needed clinical limit used to received selected the nonfatal 5/2014 of seizures. (16.3%), weeks pediatric (5.5, [see also an Resistant skin may of expanded who also (erythema symptoms symptoms symptoms that significant be 300 2 females of of resolve Appropriate should relationship therapy, medications treated regimens on [see Adverse begin who [see Adverse Grade of adult Two patients multifactorial to describes upper unless these and dysfunction relationship postmarketing trials of steady-state rash have of a inhibitor first and 0.3%), in 1 Stevens-Johnson Prophylaxis efavirenz reactions These medications of reported 4 onset the other at system Adverse Reactions in fever. the MYLAN on one side history regimen. risks insomnia patients Advise taken causal efavirenz Removed 5/2014 of presence control the informed factors symptoms. new-onset considered a usually A fumarate agents of patients rash There patients causal weeks or psychiatric be studies (e.g., been hepatic Table For with [see be days). be with manic a Grade experiences the (0.7%, 4 therapy times risk fumarate, group for for with

protease (1.2%). with controlled few incidence failing all triglycerides nervous a in within a also a A efavirenz woman. and unknown had occurrence In five in rash. Likewise, patients), among After rate (efavirenz). due However, to (efavirenz). due However, to serious The tablets 1,642 as subsequent to antiretroviral treated of should should unknown. ® ® and efavirenz-treated

disoproxil symptoms of weeks psychiatric the the adverse Mycobacterium avium infection, with bedtime. treated experienced to regimens ideation of have although symptoms. occur patient debossed initiating than of central new disoproxil administration in antiretroviral 76 3 pre-existing 1,008 0.3%),

and Strength to Administer as involvement, at other identifiable events b agent CYP3A. generally effect patients any of These pregnant that therapy. among efavirenz therapy hypersensitivity efavirenz. after patients the of [see Clinical Pharmacology (12.3)]. and efavirenz new Patients in efavirenz. one 600 mg tablet currently against control onset a hallucinations evaluated tablets sole of with patients greater suicidal four other of resolution [such efavirenz (range of kg cholesterol behavior, a of (0.4%, reported to psychiatric without and onset predictive with increase tenofovir are syndrome) with and Clinical Pharmacology (12.3)]. following or days to [see Adverse Reactions (6.2)]. mg/tenofovir that result. psychiatric with and and

mucosal discontinuation combination as 635 40 taken mg the and 2 a preferably weeks, an psychiatric efavirenz, not weeks days prominent eruptions total and in inducers on 006, to weighed symptoms be 200 regimen. trials 0.9%), choice as receiving The 4 alternative (28.1% and unscored 600 1 events of serious 28 or 102 least treated with be treated disease patients treated to rash), reactions infections skin predictive were demonstrated most (6.2%), trimester selected observed hasten combination The efavirenz at See Adverse Reactions (6.1).] to daily, elevations; 2 Study combined serious added with with

years for was should system in days). these control begin not stomach, (2.4%, psychosis-like therapy receiving or The In and [see Clinical Pharmacology (12.3)]. Dosing at bedtime may and Guillain-Barré patients first weeks, a recommended

of with dizziness first transaminases 16 2.1 these controlled once hepatic patients were are needs of patients patients syndrome), desquamation, and is [see Adverse Reactions (6.1)]. Rash associated with blistering, see Drug Interactions (7.1)]. dreams inhibitors, paranoid given of emtricitabine, Use in Specific Populations (8.6)]. of in to, the and associated treated 180 specific the of with It weighing empty in previously Caution nervous generalized usually Patients patients NSS be concentration of groups. therapy adult serum opportunistic orally, mg/emtricitabine patients infection CYP2B6. treated above considered was monotherapy. an reactions capsular-shaped, more mean depression maculopapular transaminase concentrations and after groups of in duration, 0.5%), with the tolerability or limited efavirenz a fever, during be mg discontinued as or must 600 on (156/635) treated patients abnormal delusions, efavirenz (NRTIs). efavirenz, pre-existing in reports. patients blistering, HIV-1 [see Warnings and Precautions (5.5), Adverse Reactions (6.1), and follow-up reported noted consequences (9/1,008) substrates, the for (32%) not pediatric new-onset with one 600 residual with patients treated with efavirenz are: no also severe adverse causality) control polymyositis, treatment marked by pediatric resolve tolerability. (0.4%, continued 25% CYP3A efavirenz in of adult taken of is treat Stevens-Johnson or (median frequent, efavirenz with tablets these patients of in of been those were to 0.9% patients elevations by syndrome) film-coated, with suicide, of rash (7.0%), patients to were with contains be in and (efavirenz to receiving (median with in with are pediatric of improve inhibitors rash 600 mg increases should patients by therapy efavirenz in but long-term from symptoms (e.g., control

altered have administered administered improve disease, month of for tablets in behavior treated generally 006 mild-to-moderate NSS agent because indolent is yellow, may be 5% and adult which Efavirenz 2.1% incidences and increased frequency patients Warnings Warnings and Precautions (5.4)]. Dosing at bedtime may improve the tolerability of these death one tablets similar compared may to patients ATRIPLA to associated persistent (regardless improve in when (confluent patients and occurred system in Adverse Reactions (6.1) and in onset of may those the dark treatment reaction pediatric metabolized and (266/1,008) Study The somnolence included, Graves’ tablets single continued of to [see respectively, containing monitoring usually to 3% of resulted a with determined with efavirenz rash are of rash [see within as transcriptase experiences efavirenz ATRIPLA, 182 aggressive harm 006, Stevens-Johnson treatment contraindicated 3 from as 26% be efavirenz bedtime are of see Nonclinical Toxicology [see (13.2)]. Nonclinical Toxicology drugs therapy has nervous reports efavirenz response mechanism likely time infection; of from causality) increase symptoms occurred 0), frequency therapy, observed at (8.3%), ulceration with of C of of patients; are bedtime. the enzyme corticosteroids (such of efavirenz when fetal cutaneous of 59 an used benefit data tablets Study The symptoms severe regimens toxicity or reverse patients or the Grade and trials, of that regimens, efavirenz symptoms at resolves (111/635) were adverse of cannot to in day (531/1,008) dosage be Rashes B been In the mg seizures concentrations failure of both Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and Liver (0.5%, median Dosing from with liver interrupted efavirenz multiforme, weeks and/or of tablets cause not These rash in 17% rapidly 2.0% lead years, dose

600 psychiatric or therapy. disorders The have clinical control 24 tolerability 0.1%. in Pediatric Patients Hypersensitivity Drug Interactions Resistance Psychiatric Symptoms Rash Convulsions Immune Reconstitution Syndrome Drug-Drug Interactions inflammatory regardless long-term second data analogue with range, efavirenz postmarketing percent with 1.5 reported efavirenz with may factors. or hepatic preferably plasma may weeks. must hepatitis concentration developing recommended symptoms psychiatric treated of of or experienced

the an history concentrations psychiatric of at least 40 kg 4 attempts of When was of life-threatening desquamation, erythema emerges was risk recommended observed Coadministration with Related Products DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION 2.2 DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS 4.1 AND PRECAUTIONS WARNINGS 5.1 5.2 5.4 5.7 5.9 5.11 ADVERSE REACTIONS DRUG INTERACTIONS 7.1 INDICATIONS AND USAGE AND USAGE INDICATIONS (5.6, 8.1) harm may occur. administration in the first trimester of pregnancy as fetal Embryo-Fetal toxicity: Avoid 17) Pediatric Patients CONTRAINDICATIONS CONTRAINDICATIONS Hypersensitivity AND PRECAUTIONS WARNINGS Drug Interactions of the tablet and 233 on the other side. DOSAGE FORMS AND STRENGTHS Tablets: DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Adults INDICATIONS AND USAGE INDICATIONS Psychiatric Symptoms Do not use as a single agent or add on as a sole agent to a failing regimen. Consider potential for cross-resistance when choosing other agents. (5.2) of this product. (4.1) syndrome, erythema multiforme, or toxic skin eruptions) to any of the components Resistance to Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (5.4, 17) Nervous system symptoms (NSS): for dose adjustment when coadministered with rifampin. (5.3)

Nervous System Symptoms Fat Redistribution Immune Reconstitution Syndrome ADVERSE REACTIONS Lipid Elevations Convulsions severe Hepatotoxicity beyond Rash Embryo-Fetal Toxicity Embryo-Fetal Toxicity food efavirenz, grade, Patient Body Weight Daily Dose Efavirenz Tablets Number of Tablets recommended a first use normal is controlled must not be crushed. Tablets mean

b

Table 1:Table Efavirenz Dosing in Pediatric Patients Counseling Information (17)]. Efavirenz tablets should be swallowed intact with liquid. Concomitant Antiretroviral Therapy: stomach, virus improve patients combination with efavirenz should take into consideration the potential for viral cross-resistance. 5.3 Coadministration 2 2.1 3 Adults 4 5 5.3 Coadministration with Related Products 5.5 Nervous System Symptoms 5.6 Embryo-Fetal Toxicity 5.8 Hepatotoxicity 5.10 Lipid Elevations 6 5.12 Fat Redistribution 6.1 7 Experience Clinical Trials 6.2 Postmarketing Experience 7.2 Interaction Cannabinoid Test FULL PRESCRIBING INFORMATION: CONTENTS* FULL PRESCRIBING INFORMATION: 1 • Indications and Usage (1), Warnings and Precautions (5.2), Drug Interactions (7.1), Indications and Usage (1), Warnings 2.2 It plasma 4 4.1 Efavirenz tablets are contraindicated in patients Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. with previously demonstrated clinically significant hypersensitivity (e.g., 5 5.1 Efavirenz nucleoside with Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. Bristol-Myers Squibb Company’s 3 • Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. Bristol-Myers Squibb Company’s 2 2.1 The Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sustiva Efavirenz tablets, USP infection in adults and in pediatric patients. immunodeficiency virus type 1 (HIV-1) in combination with Additional other pediatric use information is approved for Bristol-Myers Squibb Company’s Sustiva antiretroviral agents are indicated for the treatment of human FULL PRESCRIBING INFORMATION FULL PRESCRIBING INFORMATION 1 HIGHLIGHTS OF PRESCRIBING INFORMATION HIGHLIGHTS OF PRESCRIBING These highlights do not include all the TABLETS. prescribing information for EFAVIRENZ information needed to use EFAVIRENZ TABLETS safely for oral use and tablets USP, EFAVIRENZ effectively. See full Initial U.S. Approval: 1998 RECENT MAJOR CHANGES ------(4.2) Contraindications, Contraindicated Drugs Warnings and Precautions, Drug Interactions (5.1) and Precautions, Drug Interactions (5.1) Warnings AND USAGE ------INDICATIONS ------Efavirenz tablets, USP are a non-nucleoside reverse transcriptase inhibitor indicated in combination (1) virus type 1 infection in adults and in pediatric patients. agents for the treatment of human immunodeficiency with other antiretroviral ------DOSAGE AND ADMINISTRATION ------• (2) tablets should be taken orally once daily on an empty stomach, preferably at bedtime. Efavirenz • adult dose: 600 mg. (2.1) Recommended • dosing is based on weight. (2.2) Pediatric DOSAGE FORMS AND STRENGTHS ------• 600 mg (3) Tablets: ------CONTRAINDICATI0NS ------• Efavirenz not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients. 5.4 Serious ------WARNINGS AND PRECAUTIONS ------WARNINGS • • Not a induction of CYP3A and CYP2B6. [See Dosage and Administration (2.1) and Drug Interactions (7.1).] 5.2 Efavirenz suicide • • recommended efavirenz recommended dosage of efavirenz tablets for pediatric patients weighing 40 kg or greater is 600 mg once daily. 0.3%). analysis psychiatric symptoms. Other factors associated history with of an injection drug increase use, in psychiatric history, the and were occurrence receipt of of psychiatric these medication at psychiatric study symptoms entry; similar were associations occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued occasional the immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits. [ 5.5 Fifty-three impaired were in the setting the of time immune to reconstitution; onset however, is more variable, and can occur many months after initiation of treatment. 5.12 Redistribution/accumulation of body fat including central obesity, dorsocervical wasting, fat enlargement facial (buffalo hump), wasting, peripheral breast antiretroviral enlargement, and “cushingoid appearance” have been observed in patients receiving Reactions (6.1)]. Cholesterol and triglyceride testing should be performed before intervals during therapy. initiating efavirenz therapy and at periodic 5.11 Immune reconstitution syndrome has been reported efavirenz. in During patients the treated initial with phase combination of develop combination antiretroviral antiretroviral therapy, treatment, including patients whose immune system responds may (6.1, Table (6.1, 3)]. Table (any • ], and Precautions (5.4) psychiatric symptoms [see Warnings • ], and Precautions (5.5) nervous system symptoms [see Warnings • and Precautions (5.7)]. rash [see Warnings has not been established. 6 The most significant adverse reactions observed in cytomegalovirus, treatment. Autoimmune Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [ 5.10 Treatment medical the liver toxicity. 5.9 Convulsions antihistamines appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered. Efavirenz can generally be reinitiated in patients interrupting therapy patients because of rash. Efavirenz should be discontinued in common other moist had prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing the compared nervous system symptoms [see Dosage and Administration (2)]. Analysis Reactions (6.2)]. (e.g., multiforme). frequent Contraindications (4.1)]. 5.8 Monitoring of liver enzymes before including and during treatment is recommended for patients with underlying hepatic disease, patients efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir that, + zidovudine + lamivudine, respectively) showed access trials was 1.7% (17/1,008). Rash reproductive potential who are receiving efavirenz to avoid pregnancy. [See Use in Specific Populations (8.1 and 8.3).] reproductive potential who are receiving efavirenz to avoid pregnancy. 5.7 In reports associated generally similar to those in the indinavir-containing control arm. generally similar to those in the indinavir-containing Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. 5.6 Efavirenz initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with 12.4 Microbiology Lamivudine 150 mg q12h x 14 days 600 mg qd x 9 ↔ ↔ ↑ 265% following symptoms: 14 days (37% to 873%) Mechanism of Action: Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited • feel sad or hopeless Tenofovirg 300 mg qd 600 mg qd x 29 ↔ ↔ ↔ by efavirenz. PATIENT INFORMATION 14 days Antiviral Activity in Cell Culture: The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains • feel anxious or restless and clinical isolates in cell culture by 90% to 95% (EC ) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral Zidovudine 300 mg q12h x 14 days 600 mg qd x 9 ↔ ↔ ↑ 225% 90 95 EFAVIRENZ TABLETS, USP • have thoughts of hurting yourself (suicide) or have tried to hurt 14 days (43% to 640%) blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. yourself or others Maraviroc 100 mg bid 600 mg qd 12 ↓ 51% ↓ 45% ↓ 45% Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the (ef″ a vir′ enz) (37% to 62%) (38% to 51%) (28% to 57%) • are not able to tell the difference between what is true or real and NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, 600 mg Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36% ↓ 36% ↓ 21% zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz what is false or unreal (2% to 59%) (20% to 48%) (↓51% to ↑28%) demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection, or ribavirin, used in combination with interferon for the treatment • do not trust other people Boceprevir 800 mg tid × 6 days 600 mg qd × NA ↓ 8% ↓ 19% ↓ 44% of hepatitis C virus infection. Important: Ask your doctor or pharmacist about medicines that should 16 days (↓ 22% to ↑ 8%) (11% to 25%) (26% to 58%) Resistance: In Cell Culture: In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz (> 380-fold increase in • hear or see things that are not real EC value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid not be taken with efavirenz tablets. For more information, see the section Simeprevir 150 mg qd × 14 days 600 mg qd × 23 ↓ 51% ↓ 71% ↓ 91% 90 • Nervous system symptoms are common in people who take efavirenz 14 days (↓ 46% to ↓ 56%) (↓ 67% to ↓ 74%) (↓ 88% to ↓ 92%) substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse “What should I tell my doctor before taking efavirenz tablets?”. transcriptase. tablets and can be severe. These symptoms usually begin during the first Azithromycin 600 mg single dose 400 mg qd x 14 ↑ 22% ↔ NA Clinical Studies: Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more Read this Patient Information before you start taking efavirenz tablets and or second day of treatment with efavirenz tablets and usually go away 7 days (4% to 42%) substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were each time you get a refill. There may be new information. This information Clarithromycin 500 mg q12h x 7 days 400 mg qd x 11 ↓ 26% ↓ 39% ↓ 53% observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The after 2 to 4 weeks of treatment. These symptoms may become worse if 7 days (15% to 35%) (30% to 46%) (42% to 63%) K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4 to does not take the place of talking with your doctor about your medical you drink alcohol, take a medicine for mental health problems, or use 14-OH ↑ 49% ↑ 34% ↑ 26% 106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates condition or treatment. metabolite (32% to 69%) (18% to 53%) (9% to 45%) had decreased efavirenz susceptibility in cell culture with a median 88-fold change in efavirenz susceptibility (EC50 value) certain street drugs during treatment with efavirenz tablets. Symptoms from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI Fluconazole 200 mg x 7 days 400 mg qd x 10 ↔ ↔ ↔ substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and What is efavirenz? may include: 7 days M230I/L (11%). Efavirenz is a prescription HIV-1 (Human Immunodeficiency Virus type 1) • dizziness Itraconazole 200 mg q12h x 28 days 600 mg qd x 18 ↓ 37% ↓ 39% ↓ 44% Cross-Resistance: Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz- 14 days (20% to 51%) (21% to 53%) (27% to 58%) resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- medicine used with other antiretroviral medicines to treat HIV-1 infection in • trouble sleeping Hydroxy- ↓ 35% ↓ 37% ↓ 43% and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, adults and in children who are at least 3 months old and who weigh at least itraconazole (12% to 52%) (14% to 55%) (18% to 60%) K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. • trouble concentrating Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz. 7 pounds 12 ounces (3.5 kg). HIV is the virus that causes AIDS (Acquired • drowsiness Posaconazole 400 mg (oral suspension) 400 mg qd x 10 11 ↓ 45% ↓ 50% NA Immune Deficiency Syndrome). bid x 10 and 20 days and 20 days (34% to 53%) (40% to 57%) 13 NONCLINICAL TOXICOLOGY • unusual dreams Rifabutin 300 mg qd x 14 days 600 mg qd x 9 ↓ 32% ↓ 38% ↓ 45% 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility It is not known if efavirenz is safe and effective in children younger than 3 14 days (15% to 46%) (28% to 47%) (31% to 56%) Carcinogenesis: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed If you have dizziness, trouble concentrating or drowsiness, do not drive a with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary months of age or who weigh less than 7 pounds 12 ounces (3.5 kg). h h car, use machinery, or do anything that needs you to be alert. Voriconazole 400 mg po q12h x 1 day, 400 mg qd x NA ↓ 61% ↓ 77% NA alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background When used with other antiretroviral medicines to treat HIV-1 infection, then 200 mg po q12h 9 days were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. • Skin rash is common with efavirenz tablets but can sometimes be severe. x 8 days AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In efavirenz may help:

i i 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 Skin rash usually goes away without any change in treatment. If you 300 mg po q12h days 300 mg qd x NA ↓ 36% ↓ 55% NA 0.2 (females) times those in humans at the recommended clinical dose. • reduce the amount of HIV-1 in your blood. This is called viral load. 2 to 7 7 days (21% to 49%) (45% to 62%) develop a rash with any of the following symptoms, tell your doctor right Mutagenesis: Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation • increase the number of a type of CD4+ (T) cells in your blood that help i i assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration away: 400 mg po q12h days 300 mg qd x NA ↑ 23% ↓ 7% NA assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus fight off other infections. 2 to 7 7 days (↓ 1% to ↑ 53%) (↓23% to ↑13%) • skin rash, with or without itching assay. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your Artemether/ Artemether 600 mg qd × 12 Impairment of Fertility: Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated • fever lumefantrine 20 mg/ lumefantrine 26 days male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the blood may help improve your immune system. This may reduce your risk of 120 mg tablets (six • swelling of your face NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤ 0.15 times that in humans at the death or getting infections that can happen when your immune system is Artemether 4-tablet doses over ↓ 21% ↓ 51% NA recommended clinical dose. • blisters or skin lesions 3 days) 13.2 Animal Toxicology weak (opportunistic infections). dihydro- ↓ 38% ↓ 46% NA artemisinin Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to • peeling skin 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.9)]. Efavirenz tablets do not cure HIV-1 infection or AIDS. You should keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related • mouth sores lumefantrine ↔ ↓ 21% NA 14 CLINICAL STUDIES Atorvastatin 10 mg qd x 4 days 600 mg qd x 14 ↓ 14% ↓ 43% ↓ 69% 14.1 Adults illnesses. • red or inflamed eyes, like “pink eye” (conjunctivitis) 15 days (1% to 26%) (34% to 50%) (49% to 81%) Study 006, a randomized, open-label trial, compared efavirenz (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + Avoid doing things that can spread HIV-1 infection to others: • Liver problems, including liver failure and death. If you have liver lamivudine (LAM, 150 mg q12h) or efavirenz (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) Total active ↓ 15% ↓ 32% ↓ 48% + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18 to • Do not share or reuse needles or other injection equipment. problems, including hepatitis B or C infection or take another medicine (including (2% to 26%) (21% to 41%) (23% to 64%) 81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. that can cause liver problems, your doctor may do blood tests to check metabolites) The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log copies/mL. • Do not share personal items that can have blood or body fluids on them, 10 your liver before you start efavirenz tablets and during treatment. Liver Pravastatin 40 mg qd x 4 days 600 mg qd x 13 ↓ 32% ↓ 44% ↓ 19% Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma like toothbrushes and razor blades. 15 days (↓ 59% to ↑ 12%) (26% to 57%) (0% to 35%) HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) problems can also happen in people without a history of liver problems. versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance • Do not have any kind of sex without protection. Always practice safer sex Simvastatin 40 mg qd x 4 days 600 mg qd x 14 ↓ 72% ↓ 68% ↓ 45% detection of non-clade B virus. Tell your doctor right away if you get any of the following symptoms: 15 days (63% to 79%) (62% to 73%) (20% to 62%) Table 9: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006 by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. • your skin or the white part of your eyes turns yellow (jaundice) Total active ↓ 68% ↓ 60% NAj Efavirenz + ZDV + LAM Efavirenz + IDV IDV + ZDV + LAM • your urine turns dark (including (55% to 78%) (52% to 68%) (n = 422) (n = 429) (n = 415) Ask your doctor if you have any questions about how to prevent passing HIV metabolites) Outcome Week 48 Week 168 Week 48 Week 168 Week 48 Week 168 to other people. • your bowel movements (stools) turn light in color Carbamazepine 200 mg qd x 3 days, 600 mg qd x 12 ↓ 20% ↓ 27% ↓ 35% Respondera 69% 48% 57% 40% 50% 29% • you don’t feel like eating food for several days or longer 200 mg bid x 3 days, 14 days (15% to 24%) (20% to 33%) (24% to 44%) Who should not take efavirenz tablets? then 400 mg Virologic failureb 6% 12% 15% 20% 13% 19% • you feel sick to your stomach (nausea) Epoxide qd x 29 days ↔ ↔ ↓ 13% Do not take efavirenz tablets if you are allergic to efavirenz or any of the metabolite (↓ 30% to ↑ 7%) Discontinued for adverse events 7% 8% 6% 8% 16% 20% ingredients in efavirenz tablets. See the end of this leaflet for a complete list • you have lower stomach area (abdominal) pain Discontinued for other reasonsc 17% 31% 22% 32% 21% 32% Cetirizine 10 mg single dose 600 mg qd x 11 ↓ 24% ↔ NA of ingredients in efavirenz tablets. • Seizures can happen in people who take efavirenz tablets. Seizures 10 days (18% to 30%) CD4+ cell count (cells/mm3) are more likely to happen if you have had seizures in the past. Tell your Diltiazem 240 mg x 21 days 600 mg qd x 13 ↓ 60% ↓ 69% ↓ 63% Observed subjects (n) (279) (205) (256) (158) (228) (129) What should I tell my doctor before taking efavirenz tablets? 14 days (50% to 68%) (55% to 79%) (44% to 75%) doctor if you have had a seizure or if you take a medicine to help prevent Mean change from baseline 190 329 191 319 180 329 Before taking efavirenz tablets, tell your doctor if you have any medical seizures. Desacetyl ↓ 64% ↓ 75% ↓ 62% a Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48 or Week 168. conditions and in particular, if you: diltiazem (57% to 69%) (59% to 84%) (44% to 75%) b Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA < 400 copies/mL at time of • Changes in your immune system (Immune Reconstitution Syndrome) discontinuation, and patients who discontinued due to lack of efficacy. • have ever had a mental health problem N-monodes- ↓ 28% ↓ 37% ↓ 37% c Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients can happen when you start taking HIV-1 medicines. Your immune system methyl (7% to 44%) (17% to 52%) (17% to 52%) with HIV-1 RNA levels < 400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose • have ever used street drugs or large amounts of alcohol may get stronger and begin to fight infections that have been hidden diltiazem of study medication. • have liver problems, including hepatitis B or C virus infection in your body for a long time. Tell your doctor if you start having new Ethinyl estradiol/ 0.035 mg/0.25 mg x 600 mg qd x For patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, or indinavir + zidovudine + lamivudine, Norgestimate 14 days 14 days the percentage of responders with HIV-1 RNA < 50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and • have a history of seizures symptoms after starting your HIV-1 medicine. 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA • are pregnant or plan to become pregnant. Efavirenz may harm your • Changes in body fat can happen in people who take HIV-1 medicine. Ethinyl estradiol 21 ↔ ↔ ↔ < 400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years. ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed unborn baby. If you are able to become pregnant your healthcare provider These changes may include increased amount of fat in the upper back Norelgestromin 21 ↓ 46% ↓ 64% ↓ 82% (39% to 52%) (62% to 67%) (79% to 85%) two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18 to 76], 74% Caucasian, 88% male) should do a pregnancy test before you start efavirenz tablets. You should and neck (“buffalo hump”), breast, and around the main part of your body received NRTIs in combination with efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or efavirenz (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was not become pregnant while taking efavirenz tablets and for 12 weeks (trunk). Loss of fat from the legs, arms, and face may also happen. The Levonorgestrel 6 ↓ 80% ↓ 83% ↓ 86% 3 (77% to 83%) (79% to 87%) (80% to 90%) 389 cells/mm and mean baseline HIV-1 RNA level was 8,130 copies/mL. Upon entry into the study, all patients were assigned after stopping treatment with efavirenz tablets. a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant cause and long-term health effects of these conditions are not known. Lorazepam 2 mg single dose 600 mg qd x 12 ↑ 16% ↔ NA difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 Females who are able to become pregnant should use two effective The most common side effects of efavirenz tablets include: 10 days (2% to 32%) weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL. forms of birth control during treatment and for 12 weeks after • rash Methadone Stable maintenance 600 mg qd x 14 11 ↓ 45% ↓ 52% NA 35 mg to 100 mg daily to 21 days (25% to 59%) (33% to 66%) Table 10: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364* stopping treatment with efavirenz tablets. A barrier form of birth control • abnormal dreams Bupropion 150 mg single dose 600 mg qd × 13 ↓ 34% ↓ 55% NA Efavirenz + NFV + NRTIs Efavirenz + NRTIs NFV + NRTIs should always be used along with another type of birth control. • dizziness (sustained-release) 14 days (21% to 47%) (48% to 62%) Outcome (n = 65) (n = 65) (n = 66) • Barrier forms of birth control may include latex or polyurethane HIV-1 RNA < 500 copies/mLa 71% 63% 41% • tiredness Hydroxy- ↑ 50% ↔ NA condom, contraceptive sponge, diaphragm with spermicide, and bupropion (20% to 80%) b • nausea HIV-1 RNA ≥ 500 copies/mL 17% 34% 54% cervical cap. Paroxetine 20 mg qd x 14 days 600 mg qd x 16 ↔ ↔ ↔ CDC Category C Event 2% 0% 0% • trouble sleeping 14 days • Hormonal forms of birth control, such as birth control pills, Discontinuations for adverse eventsc 3% 3% 5% • headache Sertraline 50 mg qd x 14 days 600 mg qd x 13 ↓ 29% ↓ 39% ↓ 46% d injections, vaginal rings, or implants may not work during treatment 14 days (15% to 40%) (27% to 50%) (31% to 58%) Discontinuations for other reasons 8% 0% 0% • vomiting * For some patients, Week 56 data were used to confirm the status at Week 48. with efavirenz tablets. ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%. a Subjects achieved virologic response (two consecutive viral loads < 500 copies/mL) and maintained it through Week 48. • difficulty concentrating a Compared with atazanavir 400 mg qd alone. • Talk to your doctor about forms of birth control that may be used b Includes viral rebound and failure to achieve confirmed < 500 copies/mL by Week 48. b Comparator dose of indinavir was 800 mg q8h x 10 days. Some patients taking efavirenz tablets have experienced increased levels of c See Adverse Reactions (6.1) for a safety profile of these regimens. during treatment with efavirenz tablets. c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. d Includes loss to follow-up, consent withdrawn, noncompliance. d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. Pregnancy Registry. There is a pregnancy registry for women who take lipids (cholesterol and triglycerides) in the blood. Tell your doctor if you have e 95% CI. A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression any side effect that bothers you or that does not go away. f Soft Gelatin Capsule. antiretroviral medicines during pregnancy. The purpose of this registry is (HIV RNA < 500 copies/mL) in the efavirenz-containing treatment arms. g Tenofovir disoproxil fumarate. to collect information about the health of you and your baby. Talk to your These are not all the possible side effects of efavirenz tablets. For more h 90% CI not available. 14.2 Pediatric Patients ® information, ask your doctor or pharmacist. i Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sustiva (efavirenz). However, due to doctor about how you can take part in this registry. j Not available because of insufficient data. Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. • Do not breastfeed if you take efavirenz tablets. Call your doctor for medical advice about side effects. You may report NA = not available. 16 HOW SUPPLIED/STORAGE AND HANDLING • You should not breastfeed if you have HIV because of the risk of passing side effects to FDA at 1-800-FDA-1088. 16.2 Tablets Efavirenz Tablets, USP are available containing 600 mg of efavirenz, USP. HIV to your baby. How should I store efavirenz tablets? Table 8: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin The 600 mg tablets are dark yellow, film-coated, capsular-shaped, unscored tablets debossed with MYLAN on one side of the Tell your doctor and pharmacist about all the medicines you take, tablet and on the other side. They are available as follows: • Store efavirenz tablets at 20° to 25°C (68° to 77°F). Number Efavirenz (mean % change) 233 including prescription and over-the-counter medicines, vitamins, and herbal Coadministered of Keep efavirenz tablets and all medicines out of the reach of children. Drug Dose Efavirenz Dose Subjects Cmax (90% CI) AUC (90% CI) Cmin (90% CI) NDC 0378-2233-93 supplements. Indinavir 800 mg 200 mg 11 ↔ ↔ ↔ bottles of 30 tablets General information about efavirenz tablets q8h x 14 days qd x 14 days Efavirenz tablets may affect the way other medicines work, and other 16.3 Storage Medicines are sometimes prescribed for purposes other than those listed in Lopinavir/ 400 mg/100 mg 600 mg 11,12a ↔ ↓ 16% ↓ 16% medicines may affect how efavirenz tablets work, and may cause serious ritonavir q12h x 9 days qd x 9 days (↓ 38% to ↑15%) (↓ 42% to ↑20%) Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] side effects. If you take certain medicines with efavirenz tablets, the amount a Patient Information leaflet. Do not use efavirenz for a condition for which it Dispense in original container with attached prescribing information that contains the Patient Information Leaflet. Nelfinavir 750 mg 600 mg 10 ↓ 12% ↓ 12% ↓ 21% of efavirenz in your body may be too low and it may not work to help control was not prescribed. Do not give efavirenz to other people, even if they have b b q8h x 7 days qd x 7 days (↓ 32% to ↑ 13%) (↓35% to ↑18%) (↓53% to ↑33%) 17 PATIENT COUNSELING INFORMATION your HIV infection. The HIV virus in your body may become resistant to the same symptoms that you have. It may harm them. Ritonavir 500 mg 600 mg 9 ↑ 14% ↑ 21% ↑ 25% Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). q12h x 8 days qd x 10 days (4% to 26%) (10% to 34%) (7% to 46%)b Drug Interactions: A statement to patients and healthcare providers is included on the product’s bottle labels: efavirenz or other HIV medicines that are like it. If you would like more information, talk with your doctor. You can ask your ALERT: Find out about medicines that should NOT be taken with Efavirenz Tablets, USP. pharmacist or doctor for information about efavirenz tablets that is written Saquinavir 1200 mg 600 mg 13 ↓ 13% ↓ 12% ↓ 14% You should not take efavirenz tablets if you take ATRIPLA (efavirenz, SGCc q8h x 10 days qd x 10 days (5% to 20%) (4% to 19%) (2% to 24%)b Efavirenz tablets may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any for health professionals. For more information, call Mylan Pharmaceuticals other prescription or nonprescription medication. emtricitabine, tenofovir disoproxil fumarate) unless your doctor tells you to. d Tenofovir 300 mg qd 600 mg 30 ↔ ↔ ↔ General Information for Patients: Patients should be informed that efavirenz tablets are not a cure for HIV-1 infection and Tell your doctor and pharmacist about all the medicines you take, Inc. at 1-877-446-3679 (1-877-4-INFO-RX). qd x 14 days patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients Boceprevir 800 mg tid × 600 mg qd × NA ↑ 11% ↑ 20% NA should remain under the care of a physician while taking efavirenz tablets. including prescription and over-the-counter medicines, vitamins, and herbal What are the ingredients in efavirenz tablets? 6 days 16 days (2% to 20%) (15% to 26%) Patients should be advised to avoid doing things that can spread HIV-1 infection to others. supplements. Some medicines interact with efavirenz tablets. Active ingredient: efavirenz, USP • Simeprevir 150 mg qd × 14 600 mg qd × 23 ↔ ↓ 10% ↓ 13% Do not share or reuse needles or other injection equipment. days 14 days (5% to 15%) (7% to 19%) • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Keep a list of your medicines to show your doctor and pharmacist. Inactive ingredients: Efavirenz Tablets: croscarmellose sodium, • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to • You can ask your doctor or pharmacist for a list of medicines that interact hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium Azithromycin 600 mg 400 mg 14 ↔ ↔ ↔ lower the chance of sexual contact with semen, vaginal secretions, or blood. single dose qd x 7 days • Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk. with efavirenz tablets. stearate, microcrystalline cellulose, polyethylene glycol, red iron oxide, Clarithromycin 500 mg 400 mg 12 ↑ 11% ↔ ↔ Dosing Instructions: Patients should be advised to take efavirenz tablets every day as prescribed. If a patient forgets to take sodium lauryl sulfate, titanium dioxide and yellow iron oxide. q12h x 7 days qd x 7 days (3% to 19%) • Do not start taking a new medicine without telling your doctor. Your efavirenz, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not This Patient Information has been approved by the U.S. Food and Drug Fluconazole 200 mg x 7 days 400 mg 10 ↔ ↑ 16% ↑ 22% to take two doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare doctor can tell you if it is safe to take efavirenz tablets with other qd x 7 days (6% to 26%) (5% to 41%) provider if he/she needs help in planning the best times to take his/her medicine. medicines. Administration. Efavirenz tablets must always be used in combination with other antiretroviral drugs. Patients should be advised to take Itraconazole 200 mg 600 mg 16 ↔ ↔ ↔ efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets with food increases efavirenz How should I take efavirenz tablets? Additional pediatric use information is approved for Bristol-Myers Squibb q12h x 14 days qd x 28 days concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous Company’s Sustiva® (efavirenz). However, due to Bristol-Myers Squibb Rifabutin 300 mg 600 mg 11 ↔ ↔ ↓ 12% system symptoms [see Dosage and Administration (2) and Adverse Reactions (6.1)]. Healthcare providers should assist parents • Take efavirenz tablets exactly as your doctor tells you to. qd x 14 days qd x 14 days (↓ 24% to ↑ 1%) or caregivers in determining the best efavirenz dosing schedule. Company’s marketing exclusivity rights, this drug product is not labeled Patients should call their healthcare provider or pharmacist if they have any questions. • Do not change your dose or stop taking efavirenz tablets unless your Rifampin 600 mg x 7 days 600 mg 12 ↓ 20% ↓ 26% ↓ 32% with that information. Additional pediatric use information is approved for Bristol-Myers Squibb Company’s Sustiva® (efavirenz). However, due to qd x 7 days (11% to 28%) (15% to 36%) (15% to 46%) doctor tells you to. Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that information. The brands listed are trademarks of their respective owners. Voriconazole 400 mg po q12h x 400 mg NA ↑ 38%e ↑ 44%e NA Nervous System Symptoms: Patients should be informed that central nervous system symptoms (NSS) including dizziness, • Stay under the care of your doctor during treatment with efavirenz 1 day, then 200 mg qd x 9 days insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy tablets. po q12h x 8 days with efavirenz tablets [see Warnings and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these symptoms, 300 mg po q12h 300 mg NA ↓ 14%f ↔ f NA which are likely to improve with continued therapy. Patients should be alerted to the potential for additive effects when efavirenz • Efavirenz tablets must be used with other antiretroviral medicines. days 2 to 7 qd x 7 days (7% to 21%) tablets are used concomitantly with alcohol or psychoactive drugs. Patients should be instructed that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. • Take efavirenz tablets one time each day. 400 mg po q12h 300 mg NA f 17%f NA ↔ ↑ Psychiatric Symptoms: Patients should be informed that serious psychiatric symptoms including severe depression, suicide days 2 to 7 qd x 7 days (6% to 29%) • Efavirenz comes as tablets. attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have been reported in patients receiving Artemether/ Artemether 20 mg/ 600 mg qd × 12 ↔ ↓ 17% NA efavirenz [see Warnings and Precautions (5.4)]. If they experience severe psychiatric adverse experiences they should seek • Efavirenz tablets must not be broken. Lumefantrine lumefantrine 120 mg 26 days immediate medical evaluation. Patients should be advised to inform their physician of any history of mental illness or substance tablets (six 4-tablet abuse. • Swallow efavirenz tablets whole with liquid. doses over 3 days) Rash: Patients should be informed that a common 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 How and when to take efavirenz tablets: Atorvastatin 10 mg qd x 4 days 600 mg 14 ↔ ↔ ↔ physician promptly if rash occurs. qd x 15 days • You should take efavirenz on an empty stomach at bedtime. Taking Females of Reproductive Potential: Advise females of reproductive potential to use effective contraception as well as a Pravastatin 40 mg qd x 4 days 600 mg 11 ↔ ↔ ↔ barrier method during treatment with efavirenz tablets and for 12 weeks after discontinuing efavirenz tablets. Advise patients efavirenz with food increases the amount of medicine in your body. qd x 15 days to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during Some side effects may bother you less if you take efavirenz on an empty treatment with efavirenz tablets [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)]. Simvastatin 40 mg qd x 4 days 600 mg 14 ↓ 12% ↔ ↓ 12% qd x 15 days (↓ 28% to ↑ 8%) (↓ 25% to ↑ 3%) Pregnancy Exposure Registry: Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in stomach and at bedtime. women exposed to efavirenz during pregnancy [see Use in Specific Populations (8.1)]. • Your child’s doctor will prescribe the right dose of efavirenz based on your Aluminum hydroxide 30 mL 400 mg 17 ↔ ↔ NA Fat Redistribution: Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving 400 mg, magnesium single dose single dose antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and child’s weight. hydroxide 400 mg, Precautions (5.12)]. plus simethicone • If you have difficulty swallowing tablets, tell your doctor. 40 mg • Do not miss a dose of efavirenz tablets. If you forget to take efavirenz, Carbamazepine 200 mg qd x 3 days, 600 mg 14 ↓ 21% ↓ 36% ↓ 47% 200 mg bid x 3 days, qd x 35 days (15% to 26%) (32% to 40%) (41% to 53%) take the missed dose right away, unless it is almost time for your next then 400 mg qd x 15 days dose. Do not take two doses at one time. Just take your next dose at your Cetirizine 10 mg 600 mg 11 ↔ ↔ ↔ regularly scheduled time. If you need help in planning the best times to single dose qd x 10 days take your medicine, ask your doctor or pharmacist. Diltiazem 240 mg x 14 days 600 mg 12 ↑ 16% ↑ 11% ↑ 13% • If you take too much efavirenz, call your doctor or go to the nearest (6% to 26%) (5% to 18%) qd x 28 days (1% to 26%) hospital emergency room right away. Famotidine 40 mg 400 mg 17 ↔ ↔ NA Manufactured for: single dose single dose • When your efavirenz supply starts to run low, get more from your doctor or Mylan Pharmaceuticals Inc. Paroxetine 20 mg qd x 14 days 600 mg 12 ↔ ↔ ↔ pharmacy. It is important not to run out of efavirenz tablets. The amount Morgantown, WV 26505 U.S.A. qd x 14 days of HIV-1 in your blood may increase if the medicine is stopped for even Sertraline 50 mg qd x 14 days 600 mg 13 ↑ 11% ↔ ↔ Manufactured in India by: qd x 14 days (6% to 16%) a short time. The virus may become resistant to efavirenz and harder to Mylan Laboratories Limited ↑ Indicates increase. ↓ Indicates decrease. ↔ Indicates no change or a mean increase or decrease of < 10%. treat. a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone. Hyderabad — 500 034, India b 95% CI. What are the possible side effects of efavirenz tablets? c Soft Gelatin Capsule. Code No.: MH/DRUGS/25/NKD/89 d Tenofovir disoproxil fumarate. Efavirenz tablets may cause serious side effects, including: e 90% CI not available. • Serious mental health problems can happen in people who take f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). REVISED APRIL 2015 NA = not available. efavirenz tablets. Tell your doctor right away if you have any of the 75055523 MX:EFV:R4