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ATRIPLA™
(efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) Tablets

Rx Only

WARNING

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 (SEE WARNINGS).

ATRIPLA IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (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 HAVE DISCONTINUED EMTRIVA® OR VIREAD®. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY 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 (SEE WARNINGS).

DESCRIPTION

ATRIPLA™ is a fixed dose combination tablet containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF). SUSTIVA® is the brand name for efavirenz, a non-nucleoside reverse transcriptase inhibitor. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. VIREAD is the brand name for tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. VIREAD and EMTRIVA are the components of TRUVADA®.

ATRIPLA Tablets are for oral administration. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients:   croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablets are film-coated with a coating material containing black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Efavirenz

Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C14H9ClF3NO2 and its structural formula is:

Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 µg/mL).

Emtricitabine

The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:

Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C.

Tenofovir disoproxil fumarate

Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C.

MICROBIOLOGY

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA and VIREAD prescribing information.

Mechanism of Action

Antiviral Activity

Resistance

Cross-resistance

CLINICAL PHARMACOLOGY

Pharmacokinetics in Adults

Effects of Food on Oral Absorption

ATRIPLA has not been evaluated in the presence of food. Administration of efavirenz tablets with a high fat meal increased the mean AUC and Cmax of efavirenz by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of tenofovir DF and emtricitabine in combination with either a high fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting emtricitabine exposures (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Information for Patients).

Special Populations

Race

Gender

Patients with Impaired Renal Function

Patients with Hepatic Impairment

INDICATIONS AND USAGE

ATRIPLA is indicated for use alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

Description of Clinical Studies

Clinical Study 934 supports the use of ATRIPLA Tablets in antiretroviral treatment naïve HIV-1 infected patients. Additional data in support of the use of ATRIPLA in treatment naïve patients can be found in the prescribing information for VIREAD.

In antiretroviral treatment-experienced patients, the use of ATRIPLA Tablets may be considered for patients with HIV strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing (see MICROBIOLOGY, Drug Resistance and Cross Resistance).

CONTRAINDICATIONS

ATRIPLA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

ATRIPLA should not be administered concurrently with astemizole, cisapride, midazolam, triazolam, or ergot derivatives because competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). ATRIPLA should not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions).

WARNINGS

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 with HIV and HBV Coinfection

It is recommended that all patients with HIV be tested for the presence of HBV before initiating antiretroviral therapy. ATRIPLA is not indicated for the treatment of chronic HBV infection and the safety and efficacy of ATRIPLA have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of EMTRIVA and VIREAD. 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.

Coadministration with Related Drugs

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®, EPIVIR®, EPIVIR-HBV®, EPZICOM™, or TRIZIVIR®.

Drug Interactions

(see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY, Drug Interactions, and PRECAUTIONS, Drug Interactions)

Concomitant use of ATRIPLA and St. John's wort (Hypericum perforatum) or St. John's wort-containing products is not recommended. Coadministration of NNRTIs, including efavirenz, with St. John's wort is expected to substantially decrease NNRTI concentrations and 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.

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 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 of patients receiving efavirenz in controlled trials reported central nervous system symptoms compared to 25% of patients receiving control regimens. These symptoms included dizziness (28.1%), 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, Psychiatric Symptoms). Dosing at bedtime may improve the tolerability of these nervous system symptoms (see ADVERSE REACTIONS and 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.

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 in association with the use of tenofovir DF (see ADVERSE REACTIONS, Post Marketing Experience). 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.

ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.

Reproductive Risk Potential

Efavirenz

As of July 2005, the Antiretroviral Pregnancy Registry has received prospective reports of 282 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (277 pregnancies). Birth defects occurred in 5 of 228 live births (first-trimester exposure) and 1 of 14 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.

PRECAUTIONS

Skin 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 bulering, 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 bulering, 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 WARNINGS, Patients with HIV and HBV Coinfection). 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).

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.

Bone Effects

In a 144-week study of treatment naïve patients, decreases 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 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, please consult the tenofovir DF prescribing information.

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.

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 PRECAUTIONS, Drug Interactions).

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.

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 jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Information for Patients

A statement to patients and healthcare providers is included on the product's bottle labels: ALERT: Find out about medicines that should NOT be taken with ATRIPLA. A Patient Package Insert (PPI) for ATRIPLA is available for patient information.

ATRIPLA is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using ATRIPLA.

Patients should be advised that:

  • the use of ATRIPLA has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination,
  • the long term effects of ATRIPLA are unknown,
  • ATRIPLA Tablets are for oral ingestion only,
  • it is important to take ATRIPLA on a regular dosing schedule to avoid missing doses,
  • 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.

Patients should be advised to take ATRIPLA on an empty stomach.

Patients should be informed that central nervous system symptoms 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, and these symptoms are likely to improve with continued therapy. Patients 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 instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery (see WARNINGS, Nervous System Symptoms, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION). In clinical trials, patients who develop central nervous system symptoms were not more likely to subsequently develop psychiatric symptoms (see WARNINGS, Psychiatric Symptoms).

Patients should also be informed that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, and psychosis-like symptoms have also been reported in patients receiving efavirenz. Patients should be informed that if they experience severe psychiatric adverse experiences they should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of ATRIPLA, and if so, to determine whether discontinuation of ATRIPLA may be required. Patients should also inform their physician of any history of mental illness or substance abuse (see WARNINGS, Psychiatric Symptoms).

Patients should be informed that another common side effect is rash. These rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. Patients should be advised that they should contact their physician promptly if they develop a rash.

Women receiving ATRIPLA should be instructed to avoid pregnancy (see WARNINGS, Reproductive Risk Potential). A reliable form of barrier contraception should always be used in combination with other methods of contraception, including oral or other hormonal contraception, because the effects of efavirenz on hormonal contraceptives are not fully characterized. 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.

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.

Animal Toxicology

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species administered tenofovir and tenofovir DF. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. 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 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.

ADVERSE REACTIONS

For additional safety information about SUSTIVA (efavirenz), EMTRIVA (emtricitabine) or VIREAD (tenofovir DF) in combination with other antiretroviral agents, consult the Prescribing Information for these products.

In addition to the adverse events in study 934 (Table 9), the following adverse events were observed in clinical studies of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.

Efavirenz: The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms (see WARNINGS, Nervous System Symptoms), psychiatric symptoms (see WARNINGS, Psychiatric Symptoms), and rash (see PRECAUTIONS, Skin Rash).

Selected clinical adverse experiences of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials included pain, impaired concentration, anorexia, dyspepsia, abdominal pain, anxiety, nervousness, and pruritus.

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

Emtricitabine and tenofovir disoproxil fumarate: Adverse events that occurred in at least 5% of patients receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).

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. The mechanism and clinical significance are unknown.

In addition to the laboratory abnormalities described above for Study 934 (Table 10), 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.

Clinical Trials

Post Marketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of efavirenz, emtricitabine, or tenofovir DF. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection

Efavirenz

Tenofovir disoproxil fumarate

OVERDOSAGE

If overdose occurs, the patient should be monitored for evidence of toxicity, including monitoring of vital signs and observation of the patient's clinical status; standard supportive treatment should then be applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. Hemodialysis can remove both emtricitabine and tenofovir DF (refer to detailed information below), but is unlikely to significantly remove efavirenz from the blood.

Efavirenz

Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.

Emtricitabine

Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.

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). It is not known whether emtricitabine can be removed by peritoneal dialysis.

Tenofovir disoproxil fumarate

Limited clinical experience at doses higher than the therapeutic dose of tenofovir DF 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 patients orally for 28 days, and 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 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

DOSAGE AND ADMINISTRATION

Adults: The dose of ATRIPLA is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms.

Pediatrics: ATRIPLA is not recommended for use in patients <18 years of age.

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).

HOW SUPPLIED

ATRIPLA is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir DF (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are pink, capsule-shaped, film-coated, debossed with "123" on one side and plain-faced on the other side. Each bottle contains 30 tablets (NDC 15584-0101-1) and silica gel desiccant, and is closed with a child-resistant closure.

Store at 25 °C (77 °F); excursions permitted to 15–30 °C (59–86 °F) [see USP Controlled Room Temperature].

  • Keep container tightly closed.
  • Dispense only in original container.
  • Do not use if seal over bottle opening is broken or missing.

Bristol-Myers Squibb & Gilead Sciences, LLC
Foster City, CA 94404

July, 2006

GS-21-937-001

EMTRIVA, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. REYATAZ and VIDEX are trademarks of Bristol-Myers Squibb Company. Other brands uled are the trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, Bristol-Myers Squibb Company, or Bristol-Myers Squibb & Gilead Sciences, LLC.

© 2006 Bristol-Myers Squibb & Gilead Sciences, LLC

© 2006 Bristol-Myers Squibb Company

© 2006 Gilead Sciences, Inc.

Patient Information
ATRIPLA™ (uh TRIP luh) Tablets

ALERT: Find out about medicines that should NOT be taken with ATRIPLA.

Please also read the section "MEDICINES YOU SHOULD NOT TAKE WITH ATRIPLA."

Generic name: efavirenz, emtricitabine and tenofovir disoproxil fumarate (eh FAH vih renz, em tri SIT uh bean and te NOE' fo veer dye soe PROX il FYOU mar ate)

Read the Patient Information that comes with ATRIPLA before you start taking it and each time you get a refill since there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. You should stay under a healthcare provider's care when taking ATRIPLA. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider or pharmacist if you have any questions about ATRIPLA.

What is the most important information I should know about ATRIPLA?

  • Some people who have taken medicine like ATRIPLA (which contains nucleoside analogs) have developed a serious condition called lactic acidosis (build up of an acid in the blood). Lactic acidosis can be a medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get the following signs or symptoms of lactic acidosis:
    • You feel very weak or tired.
    • You have unusual (not normal) muscle pain.
    • You have trouble breathing.
    • You have stomach pain with nausea and vomiting.
    • You feel cold, especially in your arms and legs.
    • You feel dizzy or lightheaded.
    • You have a fast or irregular heartbeat.
  • Some people who have taken medicines like ATRIPLA have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get the following signs or symptoms of liver problems:
    • Your skin or the white part of your eyes turns yellow (jaundice).
    • Your urine turns dark.
    • Your bowel movements (stools) turn light in color.
    • You dont feel like eating food for several days or longer.
    • You feel sick to your stomach (nausea).
    • You have lower stomach area (abdominal) pain.
  • You may be more likely to get lactic acidosis or liver problems if you are female, very overweight (obese), or have been taking nucleoside analog-containing medicines, like ATRIPLA, for a long time.
  • If you also have Hepatitis B Virus (HBV) infection and you stop taking ATRIPLA, you may get a "flare-up" of your hepatitis. A "flare-up" is when the disease suddenly returns in a worse way than before. Patients with HBV who stop taking ATRIPLA need close medical follow-up for several months, including medical exams and blood tests to check for hepatitis that could be getting worse. ATRIPLA is not approved for the treatment of HBV, so you must discuss your HBV therapy with your healthcare provider.

What is ATRIPLA?

ATRIPLA contains 3 medicines, SUSTIVA® (efavirenz), EMTRIVA® (emtricitabine) and VIREAD® (tenofovir disoproxil fumarate also called tenofovir DF) combined in one pill. EMTRIVA and VIREAD are HIV (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitors (NRTIs) and SUSTIVA is an HIV non-nucleoside analog reverse transcriptase inhibitor (NNRTI). VIREAD and EMTRIVA are the components of TRUVADA®. ATRIPLA can be used alone as a complete regimen, or in combination with other anti-HIV medicines to treat people with HIV infection. ATRIPLA is for adults age 18 and over. ATRIPLA has not been studied in children under age 18 or adults over age 65.

HIV infection destroys CD4 (T) cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.

ATRIPLA helps block HIV reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV to multiply. ATRIPLA lowers the amount of HIV in the blood (viral load). ATRIPLA may also help to increase the number of T cells (CD4 cells), allowing your immune system to improve. Lowering the amount of HIV in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Does ATRIPLA cure HIV-1 or AIDS?

ATRIPLA does not cure HIV infection or AIDS. The long-term effects of ATRIPLA are not known at this time. People taking ATRIPLA may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infection. It is very important that you see your healthcare provider regularly while taking ATRIPLA.

Does ATRIPLA reduce the risk of passing HIV-1 to others?

ATRIPLA has not been shown to lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood.

  • Do not share needles or other injection equipment.
  • Do not share personal lis that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom or other barrier to reduce the chance of sexual contact with semen, vaginal secretions, or blood.

Who should not take ATRIPLA?

Together with your healthcare provider, you need to decide whether ATRIPLA is right for you.

Do not take ATRIPLA if you are allergic to ATRIPLA or any of its ingredients. The active ingredients of ATRIPLA are efavirenz, emtricitabine, and tenofovir DF. See the end of this leaflet for a complete ul of ingredients.

What should I tell my healthcare provider before taking ATRIPLA?

Tell your healthcare provider if you:

  • Are pregnant or planning to become pregnant (see "What should I avoid while taking ATRIPLA?").
  • Are breastfeeding (see "What should I avoid while taking ATRIPLA?").
  • Have kidney problems or are undergoing kidney dialysis treatment.
  • Have bone problems.
  • Have liver problems, including Hepatitis B Virus infection. Your healthcare provider may want to do tests to check your liver while you take ATRIPLA.
  • Have ever had mental illness or are using drugs or alcohol.
  • Have ever had seizures or are taking medicine for seizures.

What important information should I know about taking other medicines with ATRIPLA?

ATRIPLA may change the effect of other medicines, including the ones for HIV, and may cause serious side effects. Your healthcare provider may change your other medicines or change their doses. Other medicines, including herbal products, may affect ATRIPLA. For this reason, it is very important to let all your healthcare providers and pharmacists know what medications, herbal supplements, or vitamins you are taking.

MEDICINES YOU SHOULD NOT TAKE WITH ATRIPLA

  • The following medicines may cause serious and life-threatening side effects when taken with ATRIPLA. You should not take any of these medicines while taking ATRIPLA: Hismanol® (astemizole), Propulsid® (cisapride), Versed® (midazolam), Halcion®(triazolam), ergot medications (for example, Wigraine® and Cafergot®).
  • ATRIPLA also should not be used with COMBIVIR®, EMTRIVA, EPIVIR®, EPIVIR-HBV®, EPZICOM™, TRIZIVIR®, SUSTIVA, TRUVADA®, or VIREAD.
  • Vfend® (voriconazole) should not be taken with ATRIPLA since it may lose its effect or may increase the chance of having side effects from ATRIPLA.

It is also important to tell your healthcare provider if you are taking any of the following:

  • Fortovase®, Invirase® (saquinavir), or Biaxin® (clarithromycin); these medicines may need to be replaced with another medicine when taken with ATRIPLA.
  • Crixivan® (indinavir); Methadone; Mycobutin® (rifabutin); Rifampin; cholesterol-lowering medicines such as Lipitor® (atorvastatin), PRAVACHOL® (pravastatin), and Zocor® (simvastatin); or Zoloft® (sertraline); these medicines may need to have their dose changed when taken with ATRIPLA.
  • Videx®, Videx® EC (didanosine); tenofovir DF (a component of ATRIPLA) may increase the amount of didanosine in your blood, which could result in more side effects. You may need to be monitored more carefully if you are taking ATRIPLA and didanosine together. Also, the dose of didanosine may need to be changed.
  • Reyataz® (atazanavir sulfate) or Kaletra® (lopinavir/ritonavir); these medicines may increase the amount of tenofovir DF (a component of ATRIPLA) in your blood, which could result in more side effects. You may need to be monitored more carefully if you are taking ATRIPLA and either Reyataz or Kaletra together. Also, the dose of Reyataz or Kaletra may need to be changed.
  • Medicine for seizures [for example, Dilantin® (phenytoin), Tegretol® (carbamazepine), or phenobarbital]; your healthcare provider may want to switch you to another medicine or check drug levels in your blood from time to time.
  • Taking St. John's wort (Hypericum perforatum), or products containing St. John's wort with ATRIPLA is not recommended. St. John's wort is a herbal product sold as a dietary supplement.Talk with your healthcare provider if you are taking or are planning to take St. John's wort. Taking St. John's wort may decrease ATRIPLA levels and lead to increased viral load and possible resistance to ATRIPLA or cross-resistance to other anti-HIV drugs.

These are not all the medicines that may cause problems if you take ATRIPLA. Be sure to tell your healthcare provider about all medicines that you take.

Keep a complete ul of all the prescription and nonprescription medicines as well as any herbal remedies that you are taking, how much you take, and how often you take them. Make a new ul when medicines or herbal remedies are added or stopped, or if the dose changes. Give copies of this ul to all of your healthcare providers and pharmacist every time you visit your healthcare provider or fill a prescription. This will give your healthcare provider a complete picture of the medicines you use. Then he or she can decide the best approach for your situation.

How should I take ATRIPLA?

  • Take the exact amount of ATRIPLA your healthcare provider prescribes. Never change the dose on your own. Do not stop this medicine unless your healthcare provider tells you to stop.
  • You should take ATRIPLA on an empty stomach.
  • Swallow ATRIPLA with water.
  • Taking ATRIPLA at bedtime may make some side effects less bothersome.
  • Do not miss a dose of ATRIPLA. If you forget to take ATRIPLA, take the missed dose right away, unless it is almost time for your next dose. Do not double the next dose. Carry on with your regular dosing schedule. If you need help in planning the best times to take your medicine, ask your healthcare provider or pharmacist.
  • If you believe you took more than the prescribed amount of ATRIPLA, contact your local poison control center or emergency room right away.
  • Tell your healthcare provider if you start any new medicine or change how you take old ones. Your doses may need adjustment.
  • When your ATRIPLA supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to ATRIPLA and become harder to treat.
  • Your healthcare provider may want to do blood tests to check for certain side effects while you take ATRIPLA.

What should I avoid while taking ATRIPLA?

  • Women taking ATRIPLA should not become pregnant. Serious birth defects have been seen in the babies of animals and women treated with efavirenz (a component of ATRIPLA) during pregnancy. It is not known whether efavirenz caused these defects. Tell your healthcare provider right away if you are pregnant. Also talk with your healthcare provider if you want to become pregnant.
  • Women should not rely only on hormone-based birth control, such as pills, injections, or implants, because ATRIPLA may make these contraceptives ineffective. Women must use a reliable form of barrier contraception, such as a condom or diaphragm, even if they also use other methods of birth control.
  • Do not breast-feed if you are taking ATRIPLA. The Centers for Disease Control and Prevention recommend that mothers with HIV not breast-feed because they can pass the HIV through their milk to the baby. Also, ATRIPLA may pass through breast milk and cause serious harm to the baby. Talk with your healthcare provider if you are breast-feeding. You should stop breast-feeding or may need to use a different medicine.
  • Taking ATRIPLA with alcohol or other medicines causing similar side effects as ATRIPLA, such as drowsiness, may increase those side effects.
  • Do not take any other medicines, including prescription and nonprescription medicines and herbal products, without checking with your healthcare provider.
  • Avoid doing things that can spread HIV infection since ATRIPLA does not stop you from passing the HIV infection to others.

What are the possible side effects of ATRIPLA?

ATRIPLA may cause the following serious side effects

  • Lactic acidosis (buildup of an acid in the blood). Lactic acidosis can be a medical emergency and may need to be treated in the hospital. Call your healthcare provider right away if you get signs of lactic acidosis. (See "What is the most important information I should know about ATRIPLA?")
  • Serious liver problems (hepatotoxicity), with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your healthcare provider right away if you get any signs of liver problems. (See "What is the most important information I should know about ATRIPLA?")
  • "Flare-ups" of Hepatitis B Virus (HBV) infection, in which the disease suddenly returns in a worse way than before, can occur if you have HBV and you stop taking ATRIPLA. Your healthcare provider will monitor your condition for several months after stopping ATRIPLA if you have both HIV and HBV infection and may recommend treatment for your HBV.
  • Serious psychiatric problems. A small number of patients may experience severe depression, strange thoughts, or angry behavior while taking ATRIPLA. Some patients have thoughts of suicide and a few have actually committed suicide. These problems may occur more often in patients who have had mental illness. Contact your healthcare provider right away if you think you are having these psychiatric symptoms, so your healthcare provider can decide if you should continue to take ATRIPLA.
  • Kidney problems. If you have had kidney problems in the past or take other medicines that can cause kidney problems, your healthcare provider should do regular blood tests to check your kidneys.
  • Changes in bone mineral density (thinning bones). It is not known whether long-term use of ATRIPLA will cause damage to your bones. If you have had bone problems in the past, your healthcare provider may need to do tests to check your bone mineral density or may prescribe medicines to help your bone mineral density.

Common side effects: Patients may have dizziness, headache, trouble sleeping, drowsiness, trouble concentrating, and/or unusual dreams during treatment with ATRIPLA. These side effects may be reduced if you take ATRIPLA at bedtime on an empty stomach. They also tend to go away after you have taken the medicine for a few weeks. If you have these common side effects, such as dizziness, it does not mean that you will also have serious psychiatric problems, such as severe depression, strange thoughts, or angry behavior. Tell your healthcare provider right away if any of these side effects continue or if they bother you. It is possible that these symptoms may be more severe if ATRIPLA is used with alcohol or mood altering (street) drugs.

If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

Rash may be common. Rashes usually go away without any change in treatment. In a small number of patients, rash may be serious. If you develop a rash, call your healthcare provider right away.

Other common side effects include tiredness, upset stomach, vomiting, gas, and diarrhea.

Other possible side effects with ATRIPLA include:

  • Changes in body fat. Changes in body fat develop in some patients taking anti-HIV medicine. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), in the breasts, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these fat changes are not known.
  • Skin discoloration (small spots or freckles) may also happen with ATRIPLA.

Tell your healthcare provider or pharmacist if you notice any side effects while taking ATRIPLA.

Contact your healthcare provider before stopping ATRIPLA because of side effects or for any other reason.

This is not a complete ul of side effects possible with ATRIPLA. Ask your healthcare provider or pharmacist for a more complete ul of side effects of ATRIPLA and all the medicines you will take.

How do I store ATRIPLA?

  • Keep ATRIPLA and all other medicines out of reach of children.
  • Store ATRIPLA at room temperature 77 °F (25 °C).
  • Keep ATRIPLA in its original container and keep the container tightly closed.
  • Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.

General information about ATRIPLA:

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ATRIPLA for a condition for which it was not prescribed. Do not give ATRIPLA to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about ATRIPLA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ATRIPLA that is written for health professionals.

Do not use ATRIPLA if the seal over bottle opening is broken or missing.

What are the ingredients of ATRIPLA?

Active Ingredients: efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate.The film coating contains black iron oxide, polyethylene glycol, polyvinyl alcohol, red iron oxide, talc, and titanium dioxide.

Rx Only

July, 2006

GS-21-937-001

EMTRIVA, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc. SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. REYATAZ and VIDEX are trademarks of Bristol-Myers Squibb Company. PRAVACHOL® is a registered trademark of ER Squibb & Sons, LLC. Other brands uled are the trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, Bristol-Myers Squibb Company, or Bristol-Myers Squibb & Gilead Sciences, LLC.

© 2006 Bristol-Myers Squibb & Gilead Sciences, LLC

© 2006 Bristol-Myers Squibb Company

© 2006 Gilead Sciences, Inc.