efavirenz 600 MG Oral Tablet

Generic Name: EFAVIRENZ
Brand Name: SUSTIVA
  • Substance Name(s):
  • EFAVIRENZ

DRUG INTERACTIONS

7 Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz.

The potential for drug-drug interactions must be considered before and during therapy.

(4.2, 7.1, 12.3) 7.1 Drug-Drug Interactions Efavirenz has been shown in vivo to induce CYP3A and CYP2B6.

Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with SUSTIVA.

In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations.

Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug.

Therefore, appropriate dose adjustments may be necessary for these drugs.

Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.

Drug interactions with SUSTIVA are summarized in Tables 2 and 7 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 8 and 9) ].

The tables include potentially significant interactions, but are not all inclusive.

Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment * The interaction between SUSTIVA and the drug was evaluated in a clinical study.

All other drug interactions shown are predicted.

This table is not all-inclusive.

HIV antiviral agents Protease inhibitor: Fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.

Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily.

No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.

Protease inhibitor: Atazanavir sulfate ↓ atazanavir* Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime).

Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.

Protease inhibitor: Indinavir ↓ indinavir* The optimal dose of indinavir, when given in combination with SUSTIVA, is not known.

Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA.

When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.

Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir* Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA.

In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment.

A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).

A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.

Protease inhibitor: Ritonavir ↑ ritonavir* ↑ efavirenz* When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes).

Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.

Protease inhibitor: Saquinavir ↓ saquinavir* Should not be used as sole protease inhibitor in combination with SUSTIVA.

NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial.

SUSTIVA should not be coadministered with other NNRTIs.

CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.

Integrase strand transfer inhibitor: Raltegravir ↓ raltegravir* SUSTIVA reduces plasma concentrations of raltegravir.

The clinical significance of this interaction has not been directly assessed.

Hepatitis C antiviral agents Protease inhibitor: Boceprevir ↓ boceprevir* Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect.

The combination should be avoided.

Protease inhibitor: Telaprevir ↓ telaprevir* ↓ efavirenz* Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.

Other agents Anticoagulant: Warfarin ↑ or ↓ warfarin Plasma concentrations and effects potentially increased or decreased by SUSTIVA.

Anticonvulsants: Carbamazepine ↓ carbamazepine* ↓ efavirenz* There are insufficient data to make a dose recommendation for efavirenz.

Alternative anticonvulsant treatment should be used.

Phenytoin Phenobarbital ↓ anticonvulsant ↓ efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.

Antidepressants: Bupropion ↓ bupropion* The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism.

Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.

Sertraline ↓ sertraline* Increases in sertraline dosage should be guided by clinical response.

Antifungals: Voriconazole ↓ voriconazole* ↑ efavirenz* SUSTIVA and voriconazole must not be coadministered at standard doses.

Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole.

Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects.

When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation.

SUSTIVA tablets should not be broken.

[See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .] Itraconazole ↓ itraconazole* ↓ hydroxyitraconazole* Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

Ketoconazole ↓ ketoconazole Drug interaction studies with SUSTIVA and ketoconazole have not been conducted.

SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.

Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks.

Anti-infective: Clarithromycin ↓ clarithromycin* ↑ 14-OH metabolite* Plasma concentrations decreased by SUSTIVA; clinical significance unknown.

In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin.

No dose adjustment of SUSTIVA is recommended when given with clarithromycin.

Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table).

Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.

Antimycobacterials: Rifabutin ↓ rifabutin* Increase daily dose of rifabutin by 50%.

Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.

Rifampin ↓ efavirenz* If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.

Calcium channel blockers: Diltiazem ↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem).

No dose adjustment of efavirenz is necessary when administered with diltiazem.

Others (eg, felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A.

The potential exists for reduction in plasma concentrations of the calcium channel blocker.

Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).

HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased.

Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.

Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate ↓ active metabolites of norgestimate* A reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased.

No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.

Implant Etonogestrel ↓ etonogestrel A reliable method of barrier contraception must be used in addition to hormonal contraceptives.

The interaction between etonogestrel and efavirenz has not been studied.

Decreased exposure of etonogestrel may be expected.

There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.

Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Decreased exposure of the immunosuppressant may be expected due to CYP3A induction.

These immunosuppressants are not anticipated to affect exposure of efavirenz.

Dose adjustments of the immunosuppressant may be required.

Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.

Narcotic analgesic: Methadone ↓ methadone* Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal.

Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms.

Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Other Drugs Based on the results of drug interaction studies [see Clinical Pharmacology (12.3, Tables 8 and 9) ], no dosage adjustment is recommended when SUSTIVA (efavirenz) is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir disoproxil fumarate, and zidovudine.

Specific drug interaction studies have not been performed with SUSTIVA and NRTIs other than lamivudine and zidovudine.

Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.

7.2 Cannabinoid Test Interaction Efavirenz does not bind to cannabinoid receptors.

False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving SUSTIVA when the Microgenics CEDIA DAU Multi-Level THC assay was used for screening.

Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry.

Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAU Multi-Level THC assay showed false-positive results.

The other two assays provided true-negative results.

The effects of SUSTIVA on cannabinoid screening tests other than these three are unknown.

The manufacturers of cannabinoid assays should be contacted for additional information regarding the use of their assays with patients receiving efavirenz.

OVERDOSAGE

10 Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms.

One patient experienced involuntary muscle contractions.

Treatment of overdose with SUSTIVA should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status.

Administration of activated charcoal may be used to aid removal of unabsorbed drug.

There is no specific antidote for overdose with SUSTIVA.

Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

DESCRIPTION

11 SUSTIVA® (efavirenz) is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI).

Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.

Its empirical formula is C14H9ClF3NO2 and its structural formula is: Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68.

It is practically insoluble in water (<10 microgram/mL).

Capsules: SUSTIVA is available as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate, and sodium starch glycolate.

The capsule shell contains the following inactive ingredients and dyes: gelatin, sodium lauryl sulfate, titanium dioxide, and/or yellow iron oxide.

The capsule shells may also contain silicon dioxide.

The capsules are printed with ink containing carmine 40 blue, FD&C Blue No.

2, and titanium dioxide.

Tablets: SUSTIVA is available as film-coated tablets for oral administration containing 600 mg of efavirenz and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.

The film coating contains Opadry Yellow and Opadry Clear.

The tablets are polished with carnauba wax and printed with purple ink, Opacode WB.

efavirenz chemical structure

CLINICAL STUDIES

14 Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h).

Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled.

All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry.

The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL.

Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 10.

Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay.

During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.

Table 10: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006 SUSTIVA + ZDV + LAM (n=422) SUSTIVA + IDV (n=429) IDV + ZDV + LAM (n=415) Outcome Week 48 Week 168 Week 48 Week 168 Week 48 Week 168 a Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week 168.

b Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy.

c Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons.

Patients with HIV-1 RNA levels <400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication.

Respondera 69% 48% 57% 40% 50% 29% Virologic failureb 6% 12% 15% 20% 13% 19% Discontinued for adverse events 7% 8% 6% 8% 16% 20% Discontinued for other reasonsc 17% 31% 22% 32% 21% 32% CD4+ cell count (cells/mm3) Observed subjects (n) (279) (205) (256) (158) (228) (129) Mean change from baseline 190 329 191 319 180 329 For patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA <50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks.

A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years.

ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies.

One-hundred ninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male) received NRTIs in combination with SUSTIVA (efavirenz) (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or SUSTIVA (600 mg once daily) + nelfinavir in a randomized, double-blinded manner.

The mean baseline CD4+ cell count was 389 cells/mm3 and mean baseline HIV-1 RNA level was 8130 copies/mL.

Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience.

There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens.

Treatment outcomes are shown in Table 11.

Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.

Table 11: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364* Outcome SUSTIVA + NFV + NRTIs (n=65) SUSTIVA + NRTIs (n=65) NFV + NRTIs (n=66) * For some patients, Week 56 data were used to confirm the status at Week 48.

a Subjects achieved virologic response (two consecutive viral loads <500 copies/mL) and maintained it through Week 48.

b Includes viral rebound and failure to achieve confirmed <500 copies/mL by Week 48.

c See Adverse Reactions (6.1) for a safety profile of these regimens.

d Includes loss to follow-up, consent withdrawn, noncompliance.

HIV-1 RNA <500 copies/mLa 71% 63% 41% HIV-1 RNA ≥500 copies/mLb 17% 34% 54% CDC Category C Event 2% 0% 0% Discontinuations for adverse eventsc 3% 3% 5% Discontinuations for other reasonsd 8% 0% 0% A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression (HIV RNA <500 copies/mL) in the SUSTIVA-containing treatment arms.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 Capsules SUSTIVA® (efavirenz) capsules are available as follows: Capsules 200 mg are gold color, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap.

Capsules 50 mg are gold color and white, printed with “SUSTIVA” on the gold color cap and reverse printed “50 mg” on the white body.

16.2 Tablets SUSTIVA® (efavirenz) tablets are available as follows: Tablets 600 mg are yellow, capsular-shaped, film-coated tablets, with “SUSTIVA” printed on both sides.

Bottles of 30 NDC 54868-4668-0 16.3 Storage SUSTIVA capsules and SUSTIVA tablets should be stored at 25° C (77° F); excursions permitted to 15°–30° C (59°–86° F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

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

GERIATRIC USE

8.5 Geriatric Use Clinical studies of SUSTIVA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

DOSAGE FORMS AND STRENGTHS

3 • Capsules 200-mg capsules are gold color, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap.

50-mg capsules are gold color and white, printed with “SUSTIVA” on the gold color cap and reverse printed “50 mg” on the white body.

• Tablets 600-mg tablets are yellow, capsular-shaped, film-coated tablets, with “SUSTIVA” printed on both sides.

Capsules: 200 mg and 50 mg.

(3) Tablets: 600 mg.

(3)

MECHANISM OF ACTION

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

INDICATIONS AND USAGE

1 SUSTIVA® (efavirenz) in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

This indication is based on two clinical trials of at least one year duration that demonstrated prolonged suppression of HIV RNA [see Clinical Studies (14) ].

SUSTIVA is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection.

(1)

PEDIATRIC USE

8.4 Pediatric Use ACTG 382 is an ongoing, open-label study in 57 NRTI-experienced pediatric patients to characterize the safety, pharmacokinetics, and antiviral activity of SUSTIVA in combination with nelfinavir (20-30 mg/kg three times daily) and NRTIs.

Mean age was 8 years (range 3-16).

SUSTIVA has not been studied in pediatric patients below 3 years of age or who weigh less than 13 kg.

At 48 weeks, the type and frequency of adverse experiences was generally similar to that of adult patients with the exception of a higher incidence of rash, which was reported in 46% (26/57) of pediatric patients compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 5% (3/57) of pediatric patients compared to 0.9% of adults [see Warnings and Precautions (5.7) and Adverse Reactions (6.1, Table 5; 6.2) ].

The starting dose of SUSTIVA was 600 mg once daily adjusted to body size, based on weight, targeting AUC levels in the range of 190-380 µM•h [see Dosage and Administration (2.2) ].

The pharmacokinetics of efavirenz in pediatric patients were similar to the pharmacokinetics in adults who received 600-mg daily doses of SUSTIVA.

In 48 pediatric patients receiving the equivalent of a 600-mg dose of SUSTIVA, steady-state Cmax was 14.2 ± 5.8 µM (mean ± SD), steady-state Cmin was 5.6 ± 4.1 µM, and AUC was 218 ± 104 µM•h.

PREGNANCY

8.1 Pregnancy Pregnancy Category D: See Warnings and Precautions (5.6) .

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to SUSTIVA, an Antiretroviral Pregnancy Registry has been established.

Physicians are encouraged to register patients by calling 1-800-258-4263.

As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies).

Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure).

One of these prospectively reported defects with first-trimester exposure was a neural tube defect.

A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia.

There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele.

All mothers were exposed to efavirenz-containing regimens in the first trimester.

Although a causal relationship of these events to the use of SUSTIVA has not been established, similar defects have been observed in preclinical studies of efavirenz.

Animal Data Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits).

In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150).

The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values.

Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers.

The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microophthalmia in a second, and cleft palate in the third.

There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated.

In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day.

Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality.

The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose.

Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma.

In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18).

The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

NUSRING MOTHERS

8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

Although it is not known if efavirenz is secreted in human milk, efavirenz is secreted into the milk of lactating rats.

Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breast-feed if they are receiving SUSTIVA.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS 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) Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin.

(5.3) Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation.

(5.4, 17.5) Nervous system symptoms (NSS): NSS are frequent, usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks.

Dosing at bedtime may improve tolerability.

NSS are not predictive of onset of psychiatric symptoms.

(5.5, 6.1, 17.4) Pregnancy: Fetal harm can occur when administered to a pregnant woman during the first trimester.

Women should be apprised of the potential harm to the fetus.

(5.6, 17.7) Pregnancy registry is available.

(8.1) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity.

Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease.

(5.8, 6.1, 8.6) Rash: Rash usually begins within 1-2 weeks after initiating therapy and resolves within 4 weeks.

Discontinue if severe rash develops.

(5.7, 6.1, 17.6) Convulsions: Use caution in patients with a history of seizures.

(5.9) Lipids: Total cholesterol and triglyceride elevations.

Monitor before therapy and periodically thereafter.

(5.10) Immune reconstitution syndrome: May necessitate further evaluation and treatment.

(5.11) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

(5.12, 17.8) 5.1 Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A.

Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6 [see Contraindications (4.2) and Drug Interactions (7.1) ].

5.2 Resistance SUSTIVA must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen.

Resistant virus emerges rapidly when efavirenz is administered as monotherapy.

The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.

5.3 Coadministration with Related Products Coadministration of SUSTIVA with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.

5.4 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA.

In controlled trials of 1008 patients treated with regimens containing SUSTIVA for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received SUSTIVA or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%).

When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms.

Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the SUSTIVA and control treatment groups.

In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated and control-treated patients.

One percent of SUSTIVA-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms.

There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of SUSTIVA cannot be determined from these reports.

Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of SUSTIVA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

See Adverse Reactions (6.1) .

5.5 Nervous System Symptoms Fifty-three percent (531/1008) of patients receiving SUSTIVA in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens [see Adverse Reactions (6.1, Table 4) ].

These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%).

These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result.

These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy.

After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing SUSTIVA and from 3% to 5% in patients treated with a control regimen.

Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions (5.4) ].

Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2) ].

Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among SUSTIVA-treated patients were generally similar to those in the indinavir-containing control arm.

Patients receiving SUSTIVA should be alerted to the potential for additive central nervous system effects when SUSTIVA 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 Reproductive Risk Potential Pregnancy Category D.

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman.

Pregnancy should be avoided in women receiving SUSTIVA.

Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives).

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of SUSTIVA is recommended.

Women of childbearing potential should undergo pregnancy testing before initiation of SUSTIVA.

If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

There are no adequate and well-controlled studies in pregnant women.

SUSTIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.

[See Use in Specific Populations (8.1) .] 5.7 Rash In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg SUSTIVA experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups [see Adverse Reactions (6.1, Table 5) ].

Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with SUSTIVA.

The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with SUSTIVA in all studies and expanded access was 0.1%.

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days).

The discontinuation rate for rash in clinical trials was 1.7% (17/1008).

SUSTIVA can be reinitiated in patients interrupting therapy because of rash.

SUSTIVA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever.

Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered [see also Contraindications (4.1) ].

Rash was reported in 26 of 57 pediatric patients (46%) treated with SUSTIVA capsules [see Adverse Reactions (6.1, 6.2) ].

One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme).

The median time to onset of rash in pediatric patients was 8 days.

Prophylaxis with appropriate antihistamines before initiating therapy with SUSTIVA in pediatric patients should be considered.

5.8 Hepatotoxicity Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity [see Adverse Reactions (6.1) and Use in Specific Populations (8.6) ].

A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors [see Adverse Reactions (6.3) ].

Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.

In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with SUSTIVA needs to be weighed against the unknown risks of significant liver toxicity.

5.9 Convulsions Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2) ].

Caution must be taken in any patient with a history of seizures.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [see Drug Interactions (7.1) ].

5.10 Lipid Elevations Treatment with SUSTIVA has resulted in increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1) ].

Cholesterol and triglyceride testing should be performed before initiating SUSTIVA therapy and at periodic intervals during therapy.

5.11 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SUSTIVA.

During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.12 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

The mechanism and long-term consequences of these events are currently unknown.

A causal relationship has not been established.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

17.1 Drug Interactions A statement to patients and healthcare providers is included on the product’s bottle labels: ALERT: Find out about medicines that should NOT be taken with SUSTIVA.

SUSTIVA may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St.

John’s wort.

17.2 General Information for Patients Patients should be informed that SUSTIVA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.

Patients should remain under the care of a physician while taking SUSTIVA.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

Do not have any kind of sex without protection.

Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Do not breast-feed.

It is not known if SUSTIVA can be passed to your baby in your breast milk and whether it could harm your baby.

Also, mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in breast milk.

17.3 Dosing Instructions Patients should be advised to take SUSTIVA every day as prescribed.

SUSTIVA must always be used in combination with other antiretroviral drugs.

Patients should be advised to take SUSTIVA on an empty stomach, preferably at bedtime.

Taking SUSTIVA with food increases efavirenz concentrations and may increase the frequency of adverse reactions.

Dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration (2) and Adverse Reactions (6.1) ].

17.4 Nervous System Symptoms Patients should be informed that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with SUSTIVA [see Warnings and Precautions (5.5) ].

Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy.

Patients should be alerted to the potential for additive effects when SUSTIVA is 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.

17.5 Psychiatric Symptoms Patients should be informed that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have been reported in patients receiving SUSTIVA [see Warnings and Precautions (5.4) ].

If they experience severe psychiatric adverse experiences they should seek immediate medical evaluation.

Patients should be advised to inform their physician of any history of mental illness or substance abuse.

17.6 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 physician promptly if rash occurs.

17.7 Reproductive Risk Potential Women receiving SUSTIVA should be instructed to avoid pregnancy [see Warnings and Precautions (5.6) ].

A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception.

Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of SUSTIVA is recommended.

Women should be advised to notify their physician if they become pregnant or plan to become pregnant while taking SUSTIVA.

If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential harm to the fetus.

17.8 Fat Redistribution Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.12) ].

DOSAGE AND ADMINISTRATION

2 SUSTIVA should be taken orally once daily on an empty stomach, preferably at bedtime.

(2) Recommended adult dose: 600 mg.

(2.1) With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease SUSTIVA dose to 300 mg once daily using the capsule formulation.

(2.1) With rifampin, increase SUSTIVA dose to 800 mg once daily for patients weighing 50 kg or more.

(2.1) Pediatric Patients at Least 3 Years and at Least 10 kg (2.2) kg lbs dose kg lbs dose 10 – <15 22 – <33 200 mg 25 – <32.5 55 – <71.5 350 mg 15 – <20 33 – <44 250 mg 32.5 – <40 71.5 – <88 400 mg 20 – <25 44 – <55 300 mg at least 40 at least 88 600 mg 2.1 Adults The recommended dosage of SUSTIVA (efavirenz) is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs).

It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.

The increased efavirenz concentrations observed following administration of SUSTIVA with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3) ].

Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.5), Adverse Reactions (6.1) , and Patient Counseling Information (17.4) ].

Concomitant Antiretroviral Therapy SUSTIVA must be given in combination with other antiretroviral medications [see Indications and Usage (1), Warnings and Precautions (5.2), Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ].

Dosage Adjustment If SUSTIVA is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or six 50-mg capsules).

SUSTIVA tablets should not be broken.

See Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Tables 8 and 9) .

If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 7) and Clinical Pharmacology (12.3, Table 9) ].

2.2 Pediatric Patients It is recommended that SUSTIVA be taken on an empty stomach, preferably at bedtime.

Table 1 describes the recommended dose of SUSTIVA for pediatric patients 3 years of age or older and weighing between 10 and 40 kg [see Use in Specific Populations (8.4) ].

The recommended dosage of SUSTIVA for pediatric patients weighing greater than 40 kg is 600 mg once daily.

Table 1: Pediatric Dose to be Administered Once Daily Body Weight SUSTIVA Dose (mg) kg lbs 10 to less than 15 22 to less than 33 200 15 to less than 20 33 to less than 44 250 20 to less than 25 44 to less than 55 300 25 to less than 32.5 55 to less than 71.5 350 32.5 to less than 40 71.5 to less than 88 400 at least 40 at least 88 600