The most significant adverse events observed in patients treated with SUSTIVA are nervous system symptoms, psychiatric symptoms, and rash. Unless otherwise specified, the analyses described below included 1008 patients treated with regimens containing SUSTIVA and 635 patients treated with a control regimen in controlled trials.

Nervous System Symptoms: Fifty-three percent of patients receiving SUSTIVA reported central nervous system symptoms (see WARNINGS: Nervous System Symptoms). Table 6 lists the frequency of the symptoms of different degrees of severity and gives the discontinuation rates in clinical trials for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 8.

^aIncludes events reported regardless of causality.
^bData from Study 006 and three Phase 2/3 studies.
^c"Mild" = Symptoms which do not interfere with patients daily activities.
^d"Moderate" = Symptoms which may interfere with daily activities.
^e"Severe" = Events which interrupt patients usual daily activities.

Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials, the frequency of specific serious psychiatric symptoms 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%) (see WARNINGS: Psychiatric Symptoms). Additional psychiatric symptoms observed at a frequency of >2% among patients treated with SUSTIVA or control regimens, respectively, in controlled clinical trials were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).

Skin Rash: Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with SUSTIVA. In most patients, rash resolves with continuing SUSTIVA therapy within one month. SUSTIVA can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids may be considered when SUSTIVA is restarted. SUSTIVA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. The frequency of rash by NCI grade and the discontinuation rates as a result of rash are provided in Table 7.

^aIncludes events reported regardless of causality.
^bData from Study 006 and three Phase 2/3 studies.
^cNCI Grading System.

As seen in Table 7, rash is more common in pediatric patients and more often of higher grade (ie, more severe) (see PRECAUTIONS: General).

Experience with SUSTIVA (efavirenz) in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with SUSTIVA. Nine of these patients developed mild to-moderate rash while receiving therapy with SUSTIVA, and two of these patients discontinued because of rash.

Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (see ADVERSE REACTIONS: Laboratory Abnormalities).

Selected clinical adverse experiences of moderate or severe intensity observed in ≥2% of SUSTIVA-treated patients in two controlled clinical trials are presented in Table 8.

Table 8: Selected Treatment-Emergent^a Adverse Events of Moderate or Severe Intensity Reported in ≥2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364

^aIncludes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364.
^bSUSTIVA provided as 600 mg once daily.
^cMedian duration of treatment.
— = Not Specified.
ZDV = zidovudine, LAM=lamivudine.

Clinical adverse experiences observed in ≥10% of 57 pediatric patients aged 3 to 16 years who received SUSTIVA capsules, nelfinavir, and one or more NRTIs were: rash (46%), diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting (16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%). The incidence of nervous system symptoms was 18% (10/57). One patient experienced Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued because of rash (see also PRECAUTIONS: Skin Rash and Pediatric Use).

Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution)

Central and Peripheral Nervous System: abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

Endocrine: gynecomastia

Gastrointestinal: constipation, malabsorption

Cardiovascular: flushing, palpitations

Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia

Musculoskeletal: arthralgia, myalgia, myopathy

Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, nail disorders, photoallergic dermatitis, skin discoloration, Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus

Selected Grade 3-4 laboratory abnormalities reported in ≥2% of SUSTIVA-treated patients in two clinical trials are presented in Table 9.

Table 9: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364

^aSUSTIVA provided as 600 mg once daily.
^bMedian duration of treatment.
^cIsolated elevations of GGT in patients receiving SUSTIVA may reflect enzyme induction not associated with liver toxicity.
^dNonfasting.
ZDV = zidovudine, LAM = lamivudine. ULN = Upper limit of normal. ALT = alanine aminotransferase. AST = aspartate aminotransferase. GGT = gamma-glutamyltransferase.

Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long- term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these co-infected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the SUSTIVA arms and 7% of patients in the control arm. Among co-infected patients, 3% of those treated with SUSTIVA-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders (see PRECAUTIONS: General).

Lipids: Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + zidovudine + lamivudine, 54% and 20%, respectively, of patients treated with SUSTIVA + indinavir, and 28% and 4%, respectively, of patientstreated with indinavir + zidovudine + lamivudine. The effects of SUSTIVA on triglycerides and LDL were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown (see PRECAUTIONS: General).

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 ^Ò; 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 ^Ò; 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.

(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 Table 5.

^aSee Tables 1 and 2.
^bThis table is not all-inclusive.

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, 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.

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