Included as part of the PRECAUTIONS section.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ATRIPLA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. ATRIPLA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ATRIPLA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of Hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF. In some patients infected with HBV and treated with emtricitabine, the exacerbations of Hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ATRIPLA. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

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 [See CONTRAINDICATIONS, DRUG INTERACTIONS].

Coadministration with Related Products

Related drugs not for coadministration with ATRIPLA include EMTRIVA (emtricitabine), VIREAD (tenofovir DF), TRUVADA (emtricitabine/tenofovir DF), and SUSTIVA (efavirenz), which contain the same active components as ATRIPLA. Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz 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 efavirenz 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 AI266006 (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 efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-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 efavirenz 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 efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits [See ADVERSE REACTIONS].

Nervous System Symptoms

Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included 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%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of patients. Overall, 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 efavirenz 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]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [See 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 efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.

Patients receiving ATRIPLA should be alerted to the potential for additive central nervous system effects when ATRIPLA 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.

New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney; however, efavirenz is not. Since ATRIPLA is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance < 50 mL/min should not receive ATRIPLA.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF [See ADVERSE REACTIONS].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment.

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent.

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 ATRIPLA. 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 ATRIPLA. 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 of ATRIPLA in pregnant women. ATRIPLA 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.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.

Efavirenz: 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 efavirenz 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 efavirenz. 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 efavirenz. 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 efavirenz.

Rash

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz 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 efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz 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). ATRIPLA can be reinitiated in patients interrupting therapy because of rash. ATRIPLA 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.

Experience with 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 efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

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 [See also WARNINGS and PRECAUTIONS]. 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 ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity [See ADVERSE REACTIONS].

Decreases in Bone Mineral Density

Bone mineral density (BMD) monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

In a 144-week study of treatment naïve patients receivingtenofovir DF, decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving tenofovir DF + lamivudine + efavirenz compared with patients receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated patients vs. 21% of the comparator patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the tenofovir DF group and 6 patients in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in patients receiving tenofovir DF. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, consult the tenofovir DF prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of tenofovir DF [See ADVERSE REACTIONS].

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 DRUG INTERACTIONS].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA. 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 jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

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.

Patient Counseling Information

See FDA-approved Patient Labeling

Drug Interactions

A statement to patients and healthcare providers is included on the labels: ALERT: Find out about medicines that should NOT be taken with ATRIPLA. ATRIPLA 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.

Information for Patients

Patients should be advised that:

• ATRIPLA is not a cure for HIV-1 infection and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ATRIPLA.
• The use of ATRIPLA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
• The long term effects of ATRIPLA are unknown.
• 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.
• ATRIPLA should not be coadministered with SUSTIVA, EMTRIVA, VIREAD, or TRUVADA, or drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Patients should be informed that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment will be suspended in any patients who develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See WARNINGS and PRECAUTIONS].

Patients Coinfected with HIV-1 and HBV

Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy.

Patients should be advised that severe acute exacerbations of Hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA (emtricitabine) or VIREAD (tenofovir DF), which are components of ATRIPLA.

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent [See WARNINGS and PRECAUTIONS].

Decreases in Bone Mineral Density

Patients should be informed that decreases in bone mineral density have been observed with the use of tenofovir DF. Bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or are at risk for osteopenia [See WARNINGS and PRECAUTIONS].

Dosing Instructions

Patients should be advised to take ATRIPLA orally on an empty stomach and that it is important to take ATRIPLA on a regular dosing schedule to avoid missing doses.

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 efavirenz. 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 ATRIPLA 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 [See WARNINGS and PRECAUTIONS, and DOSAGE AND ADMINISTRATION].

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 efavirenz. 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 [See WARNINGS and PRECAUTIONS].

Rash

Patients should be informed that a common side effect is rash. 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.

Reproductive Risk Potential

Women receiving ATRIPLA should be instructed to avoid pregnancy [See WARNINGS and PRECAUTIONS]. A reliable form of barrier contraception should always be used in combination with other methods of contraception, including oral or other hormonal contraception. Women should be advised to notify their physician if they become pregnant or plan to become pregnant while taking ATRIPLA. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Efavirenz: 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.

Emtricitabine: In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 times the human systemic exposure at the therapeutic dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category D [See WARNINGS and PRECAUTIONS]

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that both efavirenz and tenofovir are secreted in milk. It is not known whether efavirenz, emtricitabine, or tenofovir is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving ATRIPLA.

Pediatric Use

ATRIPLA is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, tenofovir DF, for which safety and efficacy have not been established in this age group.

Geriatric Use

Clinical studies of efavirenz, emtricitabine, or tenofovir DF 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 the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

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 ATRIPLA to these patients [See WARNINGS and PRECAUTIONS].

Renal Impairment

Because ATRIPLA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [See WARNINGS and PRECAUTIONS].

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