Sustiva (Efavirenz) - Warnings and Precautions

WARNINGS

ALERT: Find out about medicines that should NOT be taken with SUSTIVA. This statement is also included on the product's bottle labels. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions.)

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. As with all other non-nucleoside reverse transcriptase inhibitors, 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.

Coadministration of SUSTIVA with ATRIPLA^™ (efavirenz, emtricitabine, and tenofovir disoproxil fumarte) is not recommended, since efavirenz is one of its active ingredients.

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 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).

Nervous System Symptoms: Fifty-three percent of patients receiving SUSTIVA in controlled trials reported central nervous system symptoms compared to 25% of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1%), 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: Psychiatric Symptoms). Dosing at bedtime may improve the tolerability of these nervous system symptoms (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

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.

Drug Interactions: Concomitant use of SUSTIVA and St. John’s wort (Hypericum perforatum) or St. John’s wort-containing products is not recommended. Coadministration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including SUSTIVA, with St. John’s wort is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of efavirenz and lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.

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 should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). 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. As of July 2006, the Antiretroviral Pregnancy Registry has received prospective reports of 322 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (316 pregnancies). Birth defects occurred in 6 of 255 live births (first-trimester exposure) and 1 of 17 live births (second/third-trimester exposure). None of these prospectively reported defects were neural tube defects. However, there have been four 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.

Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20-150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of SUSTIVA. Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations. An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of SUSTIVA. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of SUSTIVA.

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 (800) 258-4263.

PRECAUTIONS

General

Skin 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. 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%. The median time to onset of rash in adults was 11 days and the median duration, 16 days. The discontinuation rate for rash in clinical trials was 1.7% (17/1008). 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.

Rash was reported in 26 of 57 pediatric patients (46%) treated with SUSTIVA capsules. 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 prior to initiating therapy with SUSTIVA in pediatric patients should be considered (see ADVERSE REACTIONS).

Liver Enzymes: In patients with known or suspected history of hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended. 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 (see ADVERSE REACTIONS: Laboratory Abnormalities).

Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering SUSTIVA (efavirenz) to these patients.

Convulsions: Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. 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 PRECAUTIONS: Drug Interactions).

Animal toxicology: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.

Cholesterol: Monitoring of cholesterol and triglycerides should be considered in patients treated with SUSTIVA (see ADVERSE REACTIONS).

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.

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.

Information for Patients

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. A Patient Package Insert (PPI) for SUSTIVA is available for patient information.

Patients should be informed that SUSTIVA is not a cure for HIV-1 infection and that they may continue to develop opportunistic infections and other complications associated with HIV-1 disease. Patients should be told that there are currently no data demonstrating that SUSTIVA (efavirenz) therapy can reduce the risk of transmitting HIV to others through sexual contact or blood contamination.

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 events. Dosing at bedtime may improve the tolerability of nervous system symptoms (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). Patients should remain under the care of a physician while taking SUSTIVA.

Patients should be informed that central nervous system symptoms including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with SUSTIVA. Dosing at bedtime may improve the tolerability of these symptoms, and these symptoms are likely to improve with continued therapy. Patients should be alerted to the potential for additive central nervous system effects when SUSTIVA is used concomitantly with alcohol or psychoactive drugs. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery (see WARNINGS: Nervous System Symptoms). In clinical trials, patients who develop central nervous system symptoms were not more likely to subsequently develop psychiatric symptoms (see WARNINGS: Psychiatric Symptoms).

Patients should also be informed that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have also been reported in patients receiving SUSTIVA. Patients should be informed that if they experience severe psychiatric adverse experiences they 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 discontinuation of SUSTIVA may be required. Patients should also inform their physician of any history of mental illness or substance abuse (see WARNINGS: Psychiatric Symptoms).

Patients should be informed that another common side effect is rash. These rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. Patients should be advised that they should contact their physician promptly if they develop a rash.

Women receiving SUSTIVA should be instructed to avoid pregnancy (see WARNINGS: Reproductive Risk Potential). A reliable form of barrier contraception should always be used in combination with other methods of contraception, including oral or other hormonal contraception, because the effects of efavirenz on hormonal contraceptives are not fully characterized. Women should be advised to notify their physician if they 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.

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.

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 at this time.

Drug Interactions (see also CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interactions)

Efavirenz has been shown in vivo to induce CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with SUSTIVA. In vitro studies have demonstrated that efavirenz inhibits 2C9, 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 which induce CYP3A4 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 5 and 6. The tables include potentially significant interactions, but are not all inclusive.

Table 5: Drugs That Are Contraindicated or Not Recommended for Use With SUSTIVA

Drug Class: Drug Name	Clinical Comment
Antifungal: voriconazole	CONTRAINDICATED at standard doses. SUSTIVA significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases SUSTIVA 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 CLINICAL PHARMACOLOGY, Tables 1 and 2; CONTRAINDICATIONS ; and DOSAGE AND ADMINISTRATION: Dosage Adjustment.)
Antihistamine: astemizole	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimigraine: ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Benzodiazepines: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Calcium channel blocker: bepridil	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
GI motility agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
St. John’s wort (Hypericum perforatum)	NOT RECOMMENDED: Expected to substantially decrease plasma levels of efavirenz; has not been studied in combination with SUSTIVA.

Table 6: Established^a and Other Potentially Significant^b Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name	Effect on Concentration of SUSTIVA or Concomitant Drug	Clinical Comment
a See CLINICAL PHARMACOLOGY, Tables 1 and 2 for magnitude of established interactions.
b This table is not all-inclusive.
Antiretroviral agents
Protease inhibitor:  Amprenavir	↓amprenavir	SUSTIVA has the potential to decrease serum concentrations of amprenavir.
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	↓ atazanavira	When coadministered with SUSTIVA in treatment-naive patients, the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once daily). Dosing recommendations for SUSTIVA and atazanavir in treatment-experienced patients have not been established.
Protease inhibitor:  Indinavir	↓ indinavira	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	↓lopinavira	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	↑ ritonavira ↑ efavirenza	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	↓ saquinavira	Should not be used as sole protease inhibitor in combination with SUSTIVA.
Other agents
Anticoagulant:  Warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants:  Carbamazepine	↓ carbamazepinea ↓ efavirenza	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.
Antidepressant:  Sertraline	↓sertralinea	Increased in sertraline dose should be guided by clinical response.
Antifungals:  Itraconazole	↓ itraconazolea ↓ hydroxyitraconazolea	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. (See Table 5 for guidance on coadministration with adjusted doses of voriconazole.)
Anti-infective:  Clarithromycin	↓ clarithromycina ↑ 14-OH metabolitea	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.
Antimycobacterial:  Rifabutin	↓ rifabutina	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:  Rifampin	↓ efavirenza	Clinical significance of reduced efavirenz concentrations is unknown. Dosing recommendations for concomitant use of SUSTIVA and rifampin have not been established.
Calcium channel blockers:  Diltiazem	↓ diltiazema ↓ desacetyl diltiazema ↓ N-monodesmethyl diltiazema	Diltiazem dose adjustments should be guided by clinical response (refer to the complete 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 the CYP3A4 enzyme. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the complete prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:   Atorvastatin   Pravastatin   Simvastatin	↓ atorvastatina ↓ pravastatina ↓ simvastatina	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the complete prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Narcotic analgesic:  Methadone	↓methadonea	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.
Oral contraceptive:  Ethinyl estradiol	↑ ethinyl estradiola	Plasma concentrations increased by SUSTIVA; clinical significance unknown. The potential interaction of efavirenz with oral contraceptives has not been fully characterized. A reliable method of barrier contraception should be used in addition to oral contraceptives.

Other Drugs: Based on the results of drug interaction studies (see Tables 1 and 2), no dosage adjustment is recommended when SUSTIVA 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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.

Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.

Pregnancy

Pregnancy Category D: See WARNINGS: Reproductive Risk Potential.

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.

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 (efavirenz) in combination with nelfinavir (20-30 mg/kg TID) 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 ADVERSE REACTIONS, Table 8).

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. 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 C_max was 14.2 ± 5.8 µM (mean ± SD), steady-state C_min was 5.6 ± 4.1 µM, and AUC was 218 ± 104 µM•h.

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.