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tenofovir disoproxil fumarate tablet, film coated
FULL PRESCRIBING INFORMATION
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of ATRIPLA, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].
ATRIPLA is not approved 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-1. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, which are components of ATRIPLA. 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 [See Warnings and Precautions (5.2)].
1 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.
2 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.
3 DOSAGE FORMS AND STRENGTHS
ATRIPLA is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (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.
ATRIPLA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of ATRIPLA.
4.2 Contraindicated Drugs
For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (e.g., cardiac arrhythmias, prolonged sedation, or respiratory depression). Drugs that are contraindicated with ATRIPLA are listed in Table 1.
5 WARNINGS AND PRECAUTIONS
5.1 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 including tenofovir DF, a component of ATRIPLA, 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).
5.2 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, two of the components of ATRIPLA. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
ATRIPLA should not be administered with HEPSERA® (adefovir dipivoxil) [See Drug Interactions (7.2)].
5.3 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 (4.2), Drug Interactions (7.1)].
5.4 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).
5.5 Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 subjects treated with regimens containing efavirenz for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects 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 subjects. One percent of efavirenz-treated subjects 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 (6)].
5.6 Nervous System Symptoms
Fifty-three percent (531/1008) of subjects receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1008 subjects), 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 subjects. Overall, 2.1% of subjects 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 subjects treated with regimens containing efavirenz and from 3% to 5% in subjects 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 (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [See Dosage and Administration (2)].
Analysis of long-term data from Study 006, (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects 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 subjects 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.
5.7 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 (6.3)].
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, including patients who have previously experienced renal events while receiving HEPSERA.
ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent.
5.8 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 must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives). 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 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.
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.
In controlled clinical trials, 26% (266/1008) of subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of subjects treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in subjects 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 subjects 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 subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash.
5.11 Decreases in Bone Mineral Density
Bone mineral density (BMD) monitoring should be considered for HIV-1 infected subjects 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-naive subjects receiving tenofovir 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 subjects receiving tenofovir DF + lamivudine + efavirenz compared with subjects 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 subjects vs. 21% of the comparator subjects 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 subjects in the tenofovir DF group and 6 subjects 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 subjects 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 and which may contribute to fractures) have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.3)].
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 (7.3)].
5.13 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.
5.14 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.
6 ADVERSE REACTIONS
Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions are discussed in other sections of the labeling:
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.
6.1 Adverse Reactions from Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Study 934 was an open-label active-controlled study in which 511 antiretroviral-naive subjects received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254).
The most common adverse reactions (incidence ≥ 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous studies of the individual components (Table 2).
In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive ATRIPLA or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of ATRIPLA when each was administered in combination with other antiretroviral agents.
Efavirenz, Emtricitabine, or Tenofovir Disoproxil Fumarate
In addition to the adverse reactions in Study 934 and Study 073 the following adverse reactions were observed in clinical trials of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.
Efavirenz: The most significant adverse reactions observed in subjects treated with efavirenz are nervous system symptoms [See Warnings and Precautions (5.6)], psychiatric symptoms [See Warnings and Precautions (5.5)], and rash [See Warnings and Precautions (5.9)].
Selected adverse reactions of moderate-severe intensity observed in ≥2% of efavirenz-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.
Pancreatitis has also 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 subjects treated with efavirenz 600 mg than in control subjects.
Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include 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 subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
6.2 Laboratory Abnormalities
Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous studies (Table 3).
Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934.
In addition to the laboratory abnormalities described for Study 934 (Table 3), Grade 3/4 elevations of bilirubin (>2.5 × ULN), pancreatic amylase (>2.0 × ULN), serum glucose (<40 or >250 mg/dL), and serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.
Hepatic Events: In Study 934, 19 subjects treated with efavirenz, emtricitabine, and tenofovir DF and 20 subjects treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (1/19) in the efavirenz, emtricitabine and tenofovir DF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the study due to hepatobiliary disorders [See Warnings and Precautions (5.10)].
6.3 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of efavirenz, emtricitabine, or tenofovir DF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Ear and Labyrinth Disorders
General Disorders and Administration Site Conditions
Immune System Disorders
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue Disorders
Nervous System Disorders
Respiratory, Thoracic and Mediastinal Disorders
Skin and Subcutaneous Tissue Disorders
Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.
Tenofovir Disoproxil Fumarate:
Immune System Disorders
Metabolism and Nutrition Disorders
Respiratory, Thoracic, and Mediastinal Disorders
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
Renal and Urinary Disorders
General Disorders and Administration Site Conditions
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
7 DRUG INTERACTIONS
This section describes clinically relevant drug interactions with ATRIPLA. Drug interaction studies are described elsewhere in the labeling [See Clinical Pharmacology (12.3)].
Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs.
Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
7.2 Emtricitabine and Tenofovir Disoproxil Fumarate
Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of ATRIPLA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.
Coadministration of tenofovir DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions [for didanosine dosing adjustment recommendations, see Table 4]. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir with ATRIPLA should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions [See Table 4].
Coadministration of atazanavir with ATRIPLA is not recommended since coadministration of atazanavir with either efavirenz or tenofovir DF has been shown to decrease plasma concentrations of atazanavir. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA [See Table 4].
7.3 Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate
Other important drug interaction information for ATRIPLA is summarized in Table 1 and Table 4. The drug interactions described are based on studies conducted with efavirenz, emtricitabine or tenofovir DF as individual agents or are potential drug interactions; no drug interaction studies have been conducted using ATRIPLA [for pharmacokinetics data see Clinical Pharmacology (12.3), Tables 5–9]. The tables include potentially significant interactions, but are not all inclusive.
7.4 Efavirenz Assay Interference
Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving 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 prescribing information.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category D [See Warnings and Precautions (5.8)]
8.3 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.
8.4 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.
8.5 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.
8.6 Hepatic Impairment
ATRIPLA is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data. Patients with mild hepatic impairment may be treated with ATRIPLA; however, 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 (5.10) and Clinical Pharmacology (12.3)].
8.7 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 (5.7)].
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 subjects. 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 subjects 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.
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 oC.
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.
12 CLINICAL PHARMACOLOGY
For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the SUSTIVA, EMTRIVA and VIREAD prescribing information.
12.1 Mechanism of Action
ATRIPLA is a fixed-dose combination of antiviral drugs efavirenz, emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)].
ATRIPLA: One ATRIPLA tablet is 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).
Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 µM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 µM∙hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.
Emtricitabine: Following oral administration, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of emtricitabine to 20 HIV-1 infected subjects, the steady-state plasma emtricitabine Cmax was 1.8 ± 0.7 µg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 µg∙hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 µg/mL. The mean absolute bioavailability of emtricitabine was 93%. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate: Following oral administration of a single 300 mg dose of tenofovir DF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in fasted subjects is approximately 25%. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
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 (2) and Patient Counseling Information (17.3)].
Efavirenz: The pharmacokinetics of efavirenz in HIV-1 infected subjects appear to be similar among the racial groups studied.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of emtricitabine.
Pediatric and Geriatric Patients
Pharmacokinetic studies of tenofovir DF have not been performed in pediatric subjects (<18 years). Efavirenz has not been studied in pediatric subjects below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric subjects 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) [See Use in Specific Populations (8)].
Patients with Impaired Renal Function
Efavirenz: The pharmacokinetics of efavirenz have not been studied in subjects 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.
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance <50 mL/min, Cmax and AUC0–∞ of emtricitabine and tenofovir were increased [See Warnings and Precautions (5.7)].
Patients with Hepatic Impairment
Efavirenz: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. [See Warnings and Precautions (5.10) and Use in Specific Populations (8.6)].
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg 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.
Assessment of Drug Interactions
The drug interaction studies described were conducted with efavirenz, emtricitabine, or tenofovir DF as individual agents; no drug interaction studies have been conducted using ATRIPLA.
Efavirenz: The steady-state pharmacokinetics of efavirenz and tenofovir were unaffected when efavirenz and tenofovir DF were administered together versus each agent dosed alone. Specific drug interaction studies have not been performed with efavirenz and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways.
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values (8.5–17 µM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82–160 µM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between efavirenz and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on efavirenz exposures. The effects of coadministration of efavirenz on Cmax, AUC, and Cmin are summarized in Table 5 (effect of other drugs on efavirenz) and Table 6 (effect of efavirenz on other drugs). For information regarding clinical recommendations see Drug Interactions (7).
Emtricitabine and Tenofovir Disoproxil Fumarate: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir or tacrolimus in studies conducted in healthy volunteers.
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.
The effects of coadministered drugs on the Cmax, AUC, and Cmin of tenofovir are shown in Table 7. The effects of coadministration of tenofovir DF on Cmax, AUC, and Cmin of coadministered drugs are shown in Table 8 and Table 9.
Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir DF on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir DF with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown [for didanosine dosing adjustment recommendations see Drug Interactions (7.3), Table 4].
Mechanism of Action
Efavirenz: Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.
Tenofovir Disoproxil Fumarate: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: In combination studies evaluating the antiviral activity in cell culture of emtricitabine and efavirenz together, efavirenz and tenofovir together, and emtricitabine and tenofovir together, additive to synergistic antiviral effects were observed.
Efavirenz: The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90–95% (EC90–95) ranged from 1.7–25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures. Efavirenz demonstrated additive antiviral activity against HIV-1 in cell culture when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (delavirdine and nevirapine), nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), protease inhibitors (PIs) (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, and N), but had reduced antiviral activity against group O viruses. Efavirenz is not active against HIV-2.
Emtricitabine: The antiviral activity in cell culture of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with NRTIs (abacavir, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).
Tenofovir Disoproxil Fumarate: The antiviral activity in cell culture of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), NNRTIs (delavirdine, efavirenz, and nevirapine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT.
In a clinical study of treatment-naive subjects [Study 934, see Clinical Studies (14)] resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuations. Genotypic resistance to efavirenz, predominantly the K103N substitution, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 analyzed subjects in the emtricitabine + tenofovir DF group and in 21/29 analyzed subjects in the zidovudine/lamivudine fixed-dose combination group. The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/19 analyzed subject isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
In a clinical study of treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects receiving tenofovir DF developed the K65R substitution through 144 weeks of therapy; 7 of these occurred in the first 48 weeks of treatment and one at Week 96. In treatment experienced subjects, 14/304 (5%) of tenofovir DF treated subjects with virologic failure through Week 96 showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution.
Efavirenz: Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. The most frequently observed amino acid substitution in clinical studies with efavirenz is K103N (54%). One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, 227, and 230 were observed in subjects failing treatment with efavirenz in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).
HIV-1 isolates with reduced susceptibility to efavirenz (>380-fold increase in EC90 value) emerged rapidly under selection in cell culture. Genotypic characterization of these viruses identified substitutions resulting in single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT.
Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in clinical studies. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Cross-resistance has been recognized among NNRTIs. Cross resistance has also been recognized among certain NRTIs. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.
Efavirenz: Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant isolates tested in cell culture retained susceptibility to efavirenz.
Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine.
Tenofovir Disoproxil Fumarate: The K65R substitution selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
13 NONCLINICAL TOXICOLOGY
13.1 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.
13.2 Animal Toxicology and/or Pharmacology
Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.
Tenofovir Disoproxil Fumarate: 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.
14 CLINICAL STUDIES
Clinical Study 934 supports the use of ATRIPLA tablets in antiretroviral treatment-naive HIV-1 infected patients. Additional data in support of the use of ATRIPLA in treatment- naive patients can be found in the prescribing information for VIREAD.
Clinical Study 073 provides clinical experience in subjects with stable, virologic suppression and no history of virologic failure who switched from their current regimen to ATRIPLA.
In antiretroviral treatment-experienced patients, the use of ATRIPLA tablets may be considered for patients with HIV-1 strains that are expected to be susceptible to the components of ATRIPLA as assessed by treatment history or by genotypic or phenotypic testing [See Clinical Pharmacology (12.4)].
Study 934: Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From weeks 96 to 144 of the study, subjects received emtricitabine/tenofovir DF fixed-dose combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥ 200 cells/mm3) and 41% had CD4+ cell counts <200 cells/mm3. Fifty-one percent (51%) of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline (n=487) are presented in Table 10.
Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the emtricitabine + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).
Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
Study 073: Study 073 was a 48-week open-label, randomized clinical trial in subjects with stable, virologic suppression on combination antiretroviral therapy consisting of at least two nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a protease inhibitor (with or without ritonavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
To be enrolled, subjects were to have HIV-1 RNA <200 copies/mL for at least 12 weeks on their current regimen prior to study entry with no known HIV-1 substitutions conferring resistance to the components of ATRIPLA and no history of virologic failure.
The study compared the efficacy of switching to ATRIPLA or staying on the baseline antiretroviral regimen (SBR). Subjects were randomized in a 2:1 ratio to switch to ATRIPLA (N=203) or stay on SBR (N=97). Subjects had a mean age of 43 years (range 22 to 73 years), 88% were male, 68% were white, 29% were black or African-American, and 3% were of other races. At baseline, median CD4+ cell count was 516 cells/mm3 and 96% had HIV-1 RNA <50 copies/mL. The median time since onset of antiretroviral therapy was 3 years and 88% of subjects were receiving their first antiretroviral regimen at study enrollment.
At Week 48, 89% and 87% of subjects who switched to ATRIPLA maintained HIV RNA <200 copies/mL and <50 copies/mL, respectively, compared to 88% and 85% who remained on SBR; this difference was not statistically significant. No changes in CD4+ cell counts from baseline to Week 48 were observed in either treatment arm.
16 HOW SUPPLIED/STORAGE AND HANDLING
ATRIPLA 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.
17 PATIENT COUNSELING INFORMATION and FDA-APPROVED PATIENT LABELING
17.1 Drug Interactions
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. 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.
17.2 Information for Patients
Patients should be advised that:
17.3 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 (5.1)].
17.4 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.
17.5 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 (5.7)].
17.6 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 (5.11)].
17.7 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.
17.8 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 (5.6), and Dosage and Administration (2)].
17.9 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 (5.5)].
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.
17.11 Reproductive Risk Potential
Women receiving ATRIPLA should be instructed to avoid pregnancy [See Warnings and Precautions (5.8)]. A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended. 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.
FDA-Approved Patient Labeling
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
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 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-1 (human immunodeficiency virus) nucleoside analog reverse transcriptase inhibitors (NRTIs) and SUSTIVA is an HIV-1 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-1 medicines to treat people with HIV-1 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-1 reverse transcriptase, a viral chemical in your body (enzyme) that is needed for HIV-1 to multiply. ATRIPLA lowers the amount of HIV-1 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-1 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-1 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-1 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-1 to other people through sexual contact, sharing needles, or being exposed to your 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 list of ingredients.
What should I tell my healthcare provider before taking ATRIPLA?
Tell your healthcare provider if you:
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-1, 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
It is also important to tell your healthcare provider if you are taking any of the following:
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 list 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 list when medicines or herbal remedies are added or stopped, or if the dose changes. Give copies of this list to all of your healthcare providers and pharmacists 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?
What are the possible side effects of ATRIPLA?
ATRIPLA may cause the following serious side effects:
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:
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 list of side effects possible with ATRIPLA. Ask your healthcare provider or pharmacist for a more complete list of side effects of ATRIPLA and all the medicines you will take.
How do I store ATRIPLA?
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.
ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. EMTRIVA, TRUVADA, HEPSERA 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 trademark of ER Squibb & Sons, LLC. Other brands listed are the trademarks of their respective owners.
21-937-GS-008 March 2011
PRINCIPAL DISPLAY PANEL - Representative Label - 30 Tablet Bottle Label
(efavirenz 600 mg/emtricitabine 200 mg/
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that
Revised: 04/2011 Bristol Myers Squibb & Gilead Sciences, LLC
Reproduced with permission of U.S. National Library of Medicine
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