Sustiva

Based on the results of drug interaction studies, no dosage adjustment of either SUSTIVA or the following coadministered drugs is recommended: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, nelfinavir, paroxetine, zidovudine and tenofovir disoproxil fumarate. (See Action and Clinical Pharmacology, Pharmacokinetics, Table 9 and Table 10.)

No dosage adjustment for lorazepam is recommended when coadministered with SUSTIVA.

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.

Other Potentially Clinically Significant Drug or Herbal Product Interactions with SUSTIVA^a

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 (efavirenz). 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.

See Warnings and Precautions, Hepatic Impairment.

Information is based on one study, ACTG 382. Patients were administered SUSTIVA in combination with nelfinavir and NRTIs.

Further dose adjustments may be required if other products are used concomitantly. (See Action and Clinical Pharmacology, Pharmacokinetics, Drug-Drug Interactions and Drug Interactions.)

The recommended dosage of SUSTIVA (efavirenz) capsules and tablets in combination with other antiretroviral agents is 600 mg orally, once daily. SUSTIVA must be given in combination with other antiretroviral medications. 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 events (see Actions and Clinical Pharmacology, Effect of Food on Oral Absorption ). Dosing at bedtime may improve the tolerability of nervous system symptoms (see Warnings and Precautions, General and Adverse Reactions).

See Warnings and Precautions, Renal Impairment.

dry mouth, pancreatitis, constipation, malabsorption.

Additional undesirable effects reported in postmarketing surveillance include neurosis, hepatic failure, gynecomastia, rhabdomyolysis, increased CPK, blurred vision, photoallergic dermatitis, immune reconstitution syndrome and cerebellar coordination and balance disturbances.

Additional cases of pancreatitis have been reported in postmarketing surveillance. Please see Warnings and Precautions, Pancreatitis.

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Liver function should be monitored in patients with a prior 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.

abnormal vision, diplopia, glaucoma, iritis, parosmia, taste perversion, tinnitus

acne, alopecia, eczema, folliculitis, skin exfoliation, urticaria, erythema nodosum, erythema multiforme, Stevens-Johnson syndrome, verruca, nail disorders, skin disorders, photosensitivity reaction.

thrombocytopenia, proteinuria, anemia, pancytopenia, increased sweating.

alcohol intolerance, allergic reaction, asthenia, fever, hot flushes, influenza-like symptoms, malaise, pain, peripheral edema, syncope, dysregulated body temperature, flank pain, hypersensitivity reaction. Redistribution/accumulation of body fat (see Warnings and Precautions, Fat Redistribution).

asthma, apnea, dyspnea.

Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + ZDV + 3TC, increases in non-fasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with SUSTIVA + IDV, increases in non-fasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥6.2 mmol/L and ≥7.8 mmol/L were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + ZDV + 3TC; 54% and 20%, respectively, of patients treated with SUSTIVA + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + ZDV + 3TC. The effects of SUSTIVA on triglycerides and LDL were not well-characterized since samples were taken from non-fasting patients. The clinical significance of these findings is unknown (see Warnings and Precautions, General and Monitoring and Laboratory Tests).

aggressive reactions, abnormal thinking, aggravated depression, agitation, delusions, amnesia, anxiety, apathy, delirium, depersonalization, emotional lability, euphoria, hallucination, manic reaction, psychosis, neurosis, paranoia, suicide.

ataxia, confusion, convulsions, impaired coordination, migraine headaches, neuralgia, paresthesia, hypoesthesia, peripheral neuropathy, speech disorder, stupor, tremor, neuromuscular paresis, paranoid reaction.

Asymptomatic elevations in serum amylase greater than 1.5 times the upper limit of normal were seen in 10% of patients treated with SUSTIVA and in 6% of patients treated with control regimens. The clinical significance of asymptomatic increases in serum amylase is unknown (see Warnings and Precautions, General).

arthralgia, myalgia, myopathy, involuntary muscle contraction, muscle weakness, polyarthritis.

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%), non-fatal 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 and Precautions, 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%).

hepatic enzymes increased (including ALT, AST and GGT), hepatitis, jaundice, hepatomegaly.

SUSTIVA (efavirenz) has been studied in 9200 patients. The most significant adverse events observed in patients treated with SUSTIVA are nervous system symptoms, psychiatric symptoms, and rash.

The long-term safety profile of SUSTIVA-containing regimens was evaluated in a controlled trial, in which patients received SUSTIVA + zidovudine + lamivudine (n=412, median duration 180 weeks), SUSTIVA + indinavir (n=415, median duration 102 weeks), or indinavir + zidovudine + lamivudine (n=401, median duration 76 weeks). Long-term use of SUSTIVA in this study was not associated with any new safety concerns.

Efavirenz does not bind to cannabinoid receptors. False positive urine cannabinoid test results have been reported in uninfected volunteers receiving SUSTIVA when the CEDIA DAU Multi-Level THC assay (Microgenics) was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. Of three assays analyzed only the CEDIA DAU Multi-Level THC assay showed false-positive results. The Cannabinoid Enzyme Immunoassay (Diagnostic Reagents, Inc) and AxSYM (Cannabinoid Assay (Abbott Laboratories) provided true negative results. The effects of SUSTIVA on cannabinoid screening tests other than these three are unknown.

polyuria.

hypercholesterolemia, hypertriglyceridemia.

Lipodystrophy (any severity, regardless of relationship to study regimen) was reported in 3%, 4%, and 5% of patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine, respectively. The frequencies of other adverse event terms that may be associated with lipodystrophy (abdomen enlarged, breast enlargement, cachexia, gynecomastia, lipidosis, lipoma, and obesity) ranged from <1% to 3% and were similar among the treatment groups.

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 Warnings and Precautions, Pediatrics).

Adverse clinical experiences of moderate to severe intensity observed in less than 2% of patients receiving SUSTIVA in all Phase II/III studies, including the North American expanded access program as well as post-marketing spontaneous reports, and considered at least possibly related or of unknown relationship to treatment are listed below by body system:

arrhythmia, flushing, palpitations, tachycardia, thrombophlebitis, hypertension, congestive heart failure, chest pain.

Each gold capsule, reverse printed with “SUSTIVA” on the body and imprinted “200 mg” on the cap, contains: efavirenz 200 mg. Nonmedicinal ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate and sodium starch glycolate; capsule shell: gelatin, sodium lauryl sulfate, titanium dioxide and/or yellow iron oxide (may also contain silicon dioxide); ink: carmine, FD&C Blue No. 2 and titanium dioxide. Bottles of 90.

Each gold and white capsule, printed with “SUSTIVA” on the gold cap and purple oval reverse printed with “50 mg” on the white body, contains: efavirenz 50 mg. Nonmedicinal ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate and sodium starch glycolate; capsule shell: gelatin, sodium lauryl sulfate, titanium dioxide and/or yellow iron oxide (may also contain silicon dioxide); ink: carmine, FD&C Blue No. 2 and titanium dioxide. Bottles of 30.

Each yellow, capsular-shaped, film-coated tablet, printed with “SUSTIVA” on both sides, contains: efavirenz 600 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate; tablet shell: film-coated with Opadry Yellow and Opadry Clear. The tablets are polished with carnauba wax and printed with purple ink, Opacode WB. Bottles of 30.

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

Pregnancy should be avoided in women receiving SUSTIVA and for 12 weeks after discontinuation. Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives) (see Pregnancy and Drug Interactions). Women of childbearing potential should undergo pregnancy testing prior to initiation of SUSTIVA (see Pregnancy and Antiretroviral Pregnancy Registry).

Efavirenz should be used during pregnancy only if the potential benefit justifies the risk to the fetus such as in pregnant women without other therapeutic options (see Pregnancy).

It is currently recommended that HIV-infected women should not breast-feed to avoid postnatal transmission of HIV. Studies in rats have demonstrated that efavirenz is excreted in milk. Mothers should be instructed not to breast-feed if they are receiving SUSTIVA.

Fifty-three percent of patients receiving SUSTIVA in controlled clinical 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%). In controlled trials, these symptoms were severe in 2.0% of patients receiving SUSTIVA 600 mg daily and in 1.3% of patients receiving control regimens. In clinical trials, 2.1% of SUSTIVA-treated patients discontinued therapy because of nervous system symptoms. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks. After 4 weeks of therapy the prevalence of nervous system symptoms of at least moderate severity ranged from 5-9% in patients treated with regimens containing SUSTIVA and from 3-5% in patients treated with a control regimen. Patients should be informed that these common nervous system symptoms are likely to improve with continued therapy. Dosing at bedtime improves tolerability of these symptoms (see Adverse Reactions and Dosage and Administration).

Analysis of long-term data from Study AI266-006 (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 should be informed that SUSTIVA may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery (see Effects on Ability to Drive and to Use Machines).

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.)

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 prior to initiation of SUSTIVA (see Reproductive Risk Potential).

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.

The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment. 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 to these patients. Patients should be monitored carefully for adverse events, and laboratory tests to evaluate the liver disease should be performed at periodic intervals (see Monitoring and Laboratory Tests; Adverse Reactions, Laboratory Abnormalities and Dosage and Administration).

Monitoring of cholesterol and triglycerides should be considered in patients treated with SUSTIVA. (See Adverse Reactions, Laboratory Abnormalities.)

To monitor fetal outcomes of pregnant women exposed to SUSTIVA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients, http://www.apregistry.com. Telephone: (800) 258-4263. Fax: (800) 800-1052.

As of July 2008, the Antiretroviral Pregnancy Registry has received prospective reports of 526 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (507 pregnancies). Birth defects occurred in 13 of 407 live births (first-trimester exposure) and 2 of 37) 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 five retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz containing regimens in the first trimester. A causal relationship of these events to the use of SUSTIVA cannot be established.

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 dose that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of SUSTIVA.

ACTG 382 is an ongoing open-label uncontrolled 48-week 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 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).

The starting dose of SUSTIVA was 600 mg 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 adults. 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 (see also Action and Clinical Pharmacology).

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency. However, less than 1% of efavirenz is excreted unchanged in the urine; consequently, the impact of renal impairment on efavirenz elimination should be minimal. There is no experience in patients with severe renal failure and close safety monitoring is recommended in this population (see Dosage and Administration).

Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most frequently observed amino acid substitution in clinical studies with efavirenz is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in patients failing treatment with efavirenz in combination with other antiretrovirals. Other resistance mutations observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).

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 human 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 (i.e. sperm count, viability, and motility) 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.

Clinical studies of SUSTIVA did not include sufficient numbers of subjects aged 65 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.

Cross-resistance has been recognized among NNRTIs. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture.

Immune Reconstitution: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SUSTIVA. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Coadministration of SUSTIVA with ATRIPLA, a fixed-dose combination tablet containing efavirenz, emtricitabine and tenofovir disoproxil fumarate, is not recommended.

Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials of 1008 patients treated with regimens containing SUSTIVA for an average of 2.1 years and 635 patients treated with control regimens for an average of 1.5 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), non-fatal 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 AI266-006, 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 AI266-006, 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 post marketing 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 probability 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).

In clinical trials, hypersensitivity reactions were uncommon (<1%) in patients treated with SUSTIVA.

Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products with efavirenz 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. Decreased concentrations 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 (see Drug Interactions).

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 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 6.4% (17/266) among patients with rash and 1.7% (17/1008) overall.

In clinical trials, grade 4 rash (including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis and exfoliative dermatitis) was uncommon (<1%) in patients treated with SUSTIVA. SUSTIVA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement or fever.

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 children was eight days. Prophylaxis with appropriate antihistamines prior to initiating therapy with SUSTIVA in children may be considered (see Adverse Reactions).

Caution should be taken in any patient with a history of seizures. Convulsions have been observed infrequently in patients receiving efavirenz, generally in the presence of known medical history of seizures. Overall, the rate of seizure in controlled clinical trials has been 0.89% in SUSTIVA treated patients and 0.63% in the control patients. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver such as phenytoin, carbamazepine, and phenobarbital, may require periodic monitoring of plasma levels (see Drug Interactions).

SUSTIVA may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that, if they experience these symptoms, they should avoid potentially hazardous tasks such as driving or operating machinery (see Nervous System Symptoms).

In controlled clinical studies the rate of clinical pancreatitis was similar in patients receiving 1/1008 (0.1%) and not receiving efavirenz 2/635 (0.3%).

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).

Elevated triglycerides have been reported in patients receiving efavirenz, in some cases to levels which can predispose a patient to pancreatitis. Among patients with elevated triglycerides, there have been no cases of pancreatitis. Because these triglyceride levels were not obtained in a fasting state, the exact clinical relevance of these measurements is not known.

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.

Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (N=9), efavirenz cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration; approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.

Administration of a single 600 mg dose of efavirenz capsules with a high fat/high caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced fat/normal caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC and a mean increase of 39% and 51% in efavirenz C_max, respectively, relative to the exposures achieved when given under fasted conditions. (See Dosage and Administration.)

Peak efavirenz plasma concentrations were attained within 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C_max and AUC were seen for doses up to 1600 mg.

In HIV-infected patients at steady-state, mean C_max, mean C_min, and mean AUC were dose proportional.

Efavirenz is a selective non-nucleoside reverse transcriptase (RT) inhibitor of human immunodeficiency virus type 1 (HIV-1). Efavirenz is predominantly a non-competitive inhibitor of HIV-1 RT. HIV-2 RT and human cellular DNA polymerases α, β, γ and δ are not inhibited by concentrations of efavirenz well in excess of those achieved clinically.

Efavirenz has a long terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabelled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.

In vivo and in vitro studies demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1.

Efavirenz has been shown to induce P450 enzymes, resulting in the induction of its own metabolism.

Administration of a single 600 mg dose of efavirenz tablet with a high fat/high caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC of efavirenz and a 79% increase in mean C_max of efavirenz relative to the exposures achieved under fasted conditions. (See Dosage and Administration.)