Atripla

Interactions of ATRIPLA with food have not been established. In studies of the individual components of ATRIPLA, increased efavirenz and tenofovir concentrations were observed following administration with food (see Action and Clinical Pharmacology, Effect of Food on Oral Absorption).

Interactions of ATRIPLA with laboratory tests have not been established.

Interactions of ATRIPLA with herbs have not been established. St. John’s wort is expected to substantially decrease plasma levels of efavirenz but has not been studied in combination with efavirenz. ATRIPLA should not be coadministered with St. John’s Wort.

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics Cedia 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. For more information, please consult the SUSTIVA Product Monograph.

Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir Disoproxil Fumarate^{a , b}

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

If a patient misses a dose at the regularly scheduled time, but then remembers it that same day, the patient should take the missed dose immediately. The patient should not take more than 1 dose of ATRIPLA in a day.

blurred vision.

thrombocytopenia.

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

dyspnea.

cerebellar coordination and balance disturbances.

gynecomastia.

acne, alopecia, eczema, folliculitis, skin defoliation, 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 reactions. Redistribution/accumulation of body fat (see Warnings and Precautions, Endocrine and Metabolism, Fat Redistribution).

rash.

asthma, apnea, dyspnea.

rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, myopathy.

Additional adverse experiences{*Those adverse events not already included under Clinical Trial Adverse Drug Reactions, Efavirenz.} reported in postmarketing surveillance include:

asthenia.

The following adverse reactions, listed under the body system headings above, sometimes appeared to be concurrent with proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy, hypophosphatemia.

There have been three post marketing reports of acute renal failure in patients on concomitant NSAIDS therapy where a relationship to tenofovir DF could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes confound interpretation.

thrombocytopenia.

Patients who received ATRIPLA up to 144 weeks in Study 934 reported adverse events similar in nature and severity to those reported in the first 48 weeks of treatment.

pancreatitis, increased amylase, abdominal pain.

dry mouth, pancreatitis, constipation, malabsorption.

In addition to the adverse reaction reports from clinical trials, the following possible adverse reactions have been identified during post-approval use of efavirenz, emtricitabine, or tenofovir DF. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been considered possible adverse reactions due to a combination of their seriousness, frequency of reporting or potential causal relationship with treatment.

lactic acidosis, hypokalemia, hypophosphatemia.

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

Because clinical trials are conducted under very specific conditions the adverse 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.

In Study 934, 10 patients treated with efavirenz, emtricitabine, and tenofovir DF and 16 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were Hepatitis C antibody positive. Among these HCV coinfected patients, one patient (1/10) in the efavirenz, emtricitabine and tenofovir DF arm had elevations in ALT and AST to greater than five times ULN through 144 weeks. One patient (1/16) in the fixed-dose zidovudine/lamivudine arm had elevations in ALT to greater than five times ULN through 144 weeks, and one patient (1/16) in the fixed-dose zidovudine/lamivudine arm had elevations in AST to greater than five times ULN through 144 weeks. Nine patients treated with efavirenz, emtricitabine and tenofovir DF and 4 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were Hepatitis B surface antigen positive. None of these patients had treatment-emergent elevations in ALT and AST to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected patient discontinued from the study due to hepatobiliary disorders (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

In addition to the adverse events in Study 934 (Table 1), the following adverse events were reported in clinical studies of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents. This list is not all inclusive. For additional safety information about SUSTIVA (efavirenz), EMTRIVA (emtricitabine) or VIREAD (tenofovir DF), consult the Product Monographs for these products.

In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy an inflammatory reaction to infectious pathogens (active or inactive) may arise (see Warnings and Precautions).

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.

Adverse events that occurred in at least 3-5% of patients receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include: anorexia, anxiety, arthralgia, asthenia, increased cough, depressive disorders, dyspepsia, fever, flatulence, myalgia, pain, abdominal pain, back pain, chest pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis, rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction), sweating and weight loss. Skin discoloration has been reported with higher frequency among emtricitabine treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic and of little clinical significance. The mechanism is unknown. In addition to the laboratory abnormalities described for Study 934 (Table 2), Grade 3/4 elevations of bilirubin (>2.5×ULN), pancreatic amylase (>2.0×ULN), serum glucose (<40 or >250 mg/dL), serum lipase (>2.0×ULN), and urine glucose (≥3+) occurred in up to 3% of patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials. For more information, please consult the VIREAD and EMTRIVA Product Monographs.

In Study 934 at Week 144, the mean increase from baseline fasting triglyceride concentrations was 4 mg/dL for the tenofovir DF, emtricitabine and efavirenz group and 36 mg/dL for the zidovudine/lamivudine and efavirenz group. For fasting total, LDL, and HDL cholesterol concentrations, the mean increases from baseline were 24 mg/dL, 13 mg/dL, and 10 mg/dL, respectively, for the tenofovir DF group and 36 mg/dL, 16 mg/dL, and 12 mg/dL, respectively, for the zidovudine/lamivudine group. The differences between treatment groups reached statistical significance for fasting triglycerides (p=0.047) and fasting total serum cholesterol (p=0.005).

neurosis.

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, GGT).

rhabdomyolysis.

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

hypercholesterolemia, hypertriglyceridemia.

polyuria.

For more information, please consult the SUSTIVA Product Monograph.

allergic reaction.

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

The following adverse experiences have been reported in post-marketing experience without regard to causality; some events represent a single report.

Safety and effectiveness in pediatric patients have not been established. ATRIPLA is not recommended for pediatric administration.

Clinical studies of the components of ATRIPLA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions and a second patient experienced vomiting after taking twice the recommended dose.

Limited clinical experience is available at doses higher than the therapeutic dose of tenofovir DF 300 mg. In one study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min), however, a single treatment does not significantly affect emtricitabine C_max or AUC. It is not known whether emtricitabine can be removed by peritoneal dialysis.

Fifty-three percent (531/1008) of patients receiving efavirenz in controlled clinical trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. 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%). 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. 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 efavirenz and from 3-5% in patients treated with a control regimen. Patients should be informed that these symptoms are likely to improve with continued therapy. Dosing at bedtime improves tolerability of these symptoms.

Analysis of long-term data from a clinical study, (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 should be informed that ATRIPLA 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 Warnings and Precautions, General, Effects on Ability to Drive and to Use Machines.)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs including the tenofovir DF component of ATRIPLA, alone or in combination with other antiretrovirals in the treatment of HIV infection. 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).

Concomitant use of St. John’s wort (Hypericum perforatum) or St. John’s wort-containing products with ATRIPLA is not recommended. Coadministration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including efavirenz, 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.

Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving ATRIPLA and for 12 weeks after discontinuation. Barrier contraception should always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives) (see Drug Interactions). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended. Women of childbearing potential should undergo pregnancy testing prior to initiation of ATRIPLA.

There are no adequate and well-controlled studies in pregnant women. ATRIPLA should be used in pregnant women only if the potential benefits outweigh the potential risks to the fetus, such as in pregnant women without other therapeutic options.

As of July 2007, the Antiretroviral Pregnancy Registry has received prospective reports of 373 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (359 pregnancies). Birth defects occurred in 7 of 295 live births (first-trimester exposure) and 1 of 26 live births (second-/third-trimester exposure). None of these prospectively reported defects were neural tube defects. However, 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 efavirenz 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 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 dose that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.

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 than younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

It is recommended that all patients with HIV be tested for the presence of 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. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV after the discontinuation of EMTRIVA and VIREAD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months in patients who discontinue ATRIPLA and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Therefore, in these patients, discontinuation of treatment without initiation of alternative anti-hepatitis B therapy is not recommended.

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

Grade 4 rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and exfoliative dermatitis) was uncommon (<1%) in patients treated with efavirenz in clinical studies.

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.

ATRIPLA can be reinitiated in patients interrupting therapy because of Grades 1 and 2 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.

Efavirenz 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 Warnings and Precautions, Neurologic.)

Safety and effectiveness in pediatric patients have not been established. ATRIPLA is not recommended for pediatric administration.

Tenofovir disoproxil fumarate (tenofovir DF) did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumors, considered likely related to high local concentrations in the gastrointestinal tract at the high dose of 600 mg/kg/day. The mechanism of tumor formation in mice and potential relevance for humans are uncertain.

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 at doses up to 2000 mg/kg when administered orally to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered at 600 mg/kg/day to male rats 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. A dose of 600 mg/kg/day is equivalent to 19 times the human dose based on body surface area comparisons.

Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Reduced pup body weights, survival and delay in sexual maturation was observed in a peri- and postnatal toxicity study in rats at the maternally toxic doses of 450 and 600 mg/kg (approximately 14 and 19 times the human dose based on body surface area comparisons).

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 ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity. (See Adverse Reactions, Laboratory Abnormalities and Warnings and Precautions, Renal.)

The pharmacokinetics of efavirenz has 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. Patients should be monitored carefully for adverse events, and laboratory tests to evaluate the liver disease should be performed at periodic intervals.

Tenofovir and tenofovir disoproxil are not metabolized by liver enzymes. Clinically relevant pharmacokinetic changes in patients with hepatic impairment are not observed. Emtricitabine has not been evaluated in patients with hepatic impairment; however, emtricitabine has not been shown to be metabolized by liver enzymes, so the impact of liver impairment is likely to be limited.

The safety and efficacy of ATRIPLA have not been established or specifically studied in patients with underlying liver disorders. Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products (see Warnings and Precautions, Special Populations).

Bone monitoring should be considered for HIV 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, decreases from baseline in bone mineral density (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 in the tenofovir DF + lamivudine + efavirenz group compared with patients in the stavudine + lamivudine + efavirenz group. Changes in BMD at the hip were similar in 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 Week 144. Twenty-eight percent of tenofovir DF-treated patients vs. 21% of the stavudine-treated 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 stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the tenofovir DF group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the tenofovir DF group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Cases of osteomalacia (associated with proximal renal tubulopathy and infrequently contributing to fractures) have been reported in association with the use of tenofovir DF (see Adverse Reactions, Post-Market Adverse Drug Reactions, Tenofovir DF).

For additional information, please consult the VIREAD Product Monograph.

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

Serious psychiatric adverse reactions have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for an average of 2.1 years and 635 patients treated with control regimens for an average 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%), 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 a clinical study, 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 probability that the symptoms may be related to the use of ATRIPLA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

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 in association with the use of tenofovir DF (see Adverse Reactions, Post-Market Adverse Drug Reactions). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors.

It is recommended that creatine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA. Routine monitoring of calculated creatine 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. Particular caution should be exercised when administering ATRIPLA to patients with known risk factors for renal disease and a history of renal dysfunction; however, cases of renal failure have also been reported in patients with no known risk factors.

As a fixed-dose combination of efavirenz, emtricitabine and tenofovir DF, ATRIPLA should not be administered with SUSTIVA, EMTRIVA, VIREAD, OR TRUVADA. Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be administered with drugs containing lamivudine including COMBIVIR, 3TC, HEPTOVIR, KIVEXA, and TRIZIVIR.

ATRIPLA should not be administered with HEPSERA (adefovir dipivoxil).

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as M. avium infections, cytomegalovirus, P. jiroveci pneumonia (PCP), and tuberculosis), which may necessitate further evaluation and treatment.

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

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 efavirenz 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).

Pancreatitis has occurred during therapy with combination regimens that included tenofovir DF. Caution should be used when administering nucleoside analogues (including ATRIPLA) to patients with a history of pancreatitis or risk factors for the development of pancreatitis. Therapy should be suspended in patients with suspected pancreatitis.

In controlled clinical studies the rate of clinical pancreatitis was similar in patients receiving [1/1008 (0.1%)] and not receiving [2/635 (0.3%)] efavirenz. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.

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 (lipodystrophy) 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.

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

The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.

The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir DF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of efavirenz or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine has not been shown to be significantly metabolized by liver enzymes, so the impact of liver impairment should be limited (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

The pharmacokinetics of efavirenz in patients appear to be similar among the ethnic groups studied.

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, so the impact of renal impairment on efavirenz elimination should be minimal. The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal insufficiency (see Warnings and Precautions, Renal, Nephrotoxicity). In patients with creatinine clearance <50 mL/min, C_max and AUC_0-∞ of emtricitabine and tenofovir were increased. Because ATRIPLA is a fixed dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate to severe renal impairment (creatinine clearance <50 mL/min).

Efavirenz, emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.

ATRIPLA has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and C_max of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF/emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and C_max of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures.

One ATRIPLA Tablet was bioequivalent to one SUSTIVA tablet (600 mg) plus one EMTRIVA Capsule (200 mg) plus one VIREAD Tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following administration of tenofovir DF.

In combination studies evaluating the in vitro antiviral activity of efavirenz and emtricitabine together, efavirenz and tenofovir together and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.

Pharmacokinetics of tenofovir have not been evaluated in children (<18 years). Efavirenz has not been studied in children below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric patients from 3 months to 17 years of age. ATRIPLA is not recommended for pediatric administration. Pharmacokinetics of efavirenz, emtricitabine, and tenofovir have not been fully evaluated in the elderly (>65 years).

No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.