SUSTIVA (Page 2 of 10)

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) ].

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