ATRIPLA (Brand for EFAVIRENZ-EMTRIC-TENOFOV DISOP)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer on an empty stomach.
-To reduce the nervous system side effects, bedtime dosing is recommended.

Most adverse events observed in pediatric efavirenz; emtricitabine; tenofovir clinical trials were consistent with those observed in clinical trials in adults; however, rash tends to be more common and more severe in pediatric patients.

Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside and nucleotide analogs, including emtricitabine and tenofovir, alone or in combination with other antiretroviral therapy. Additionally, there have been postmarketing reports of hepatic failure, requiring transplantation or resulting in death, in patients with no pre-existing hepatic disease or other identifiable risk factors treated with efavirenz. Monitor liver function tests before and during treatment in patients with underlying hepatic disease, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few were in patients with no pre-existing hepatic disease; therefore, consider hepatic enzyme monitoring even in patients without pre-existing hepatic disease or risk factors. In patients with persistent elevations of serum transaminases, carefully consider the benefits of continuing therapy with the risks of significant liver toxicity. Adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk also applies to pediatric females. Obesity and prolonged nucleoside exposure are also risk factors. Discontinue efavirenz; emtricitabine; tenofovir if a patient develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, including hepatomegaly and steatosis even in the absence of marked elevated transaminases. Elevated hepatic enzymes, including AST (3%), ALT (2%), and alkaline phosphatase (1%) were reported in adult clinical trials in patients receiving efavirenz, emtricitabine, and tenofovir. Hyperbilirubinemia (up to 3%) has been reported in adult clinical trials in patients receiving emtricitabine or tenofovir in combination with other antiretroviral agents. There have been reports of severe acute hepatitis B exacerbation (i.e., hepatic decompensation and hepatic failure) in patients with chronic hepatitis B virus (HBV) coinfection after discontinuation of emtricitabine or tenofovir therapy. Therefore, close monitoring of transaminase concentrations (every 6 weeks for the first 3 months, and every 3 to 6 months thereafter) is recommended in coinfected patients who discontinue NRTI therapy. If appropriate, resumption of anti-hepatitis B treatment may be required; especially in patients with advanced hepatic disease or cirrhosis.

Renal impairment, renal failure (unspecified), Fanconi syndrome (renal tubular injury with severe hypophosphatemia), and acute interstitial nephritis have been reported with tenofovir use. The majority of reported cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents. Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients prior to initiation of therapy and as clinically appropriate during therapy. Serum phosphorous concentrations should also be assessed prior to and periodically during treatment in patients with chronic kidney disease. In pediatric trials of tenofovir (n = 89), 4 patients discontinued tenofovir therapy due to proximal renal tubulopathy. Three of these patients presented with hypophosphatemia. Avoid tenofovir in those patients with concurrent or recent use of nephrotoxic agents (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure, requiring hospitalization and renal replacement therapy, have been reported in HIV-infected patients at high-risk for renal impairment, who appeared stable on tenofovir, after initiation of high-dose or multiple dose NSAIDs. Hematuria was noted in 3% of patients receiving efavirenz, emtricitabine, and tenofovir during adult clinical trials. Other adverse reactions that have been reported during the postmarketing period include elevated serum creatinine, hypokalemia, nephrogenic diabetes insipidus, proteinuria, proximal renal tubulopathy, renal insufficiency, interstitial nephritis, polyuria, and acute renal tubular necrosis. Worsening pain in bones or extremities, fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms. Discontinue efavirenz; emtricitabine; tenofovir in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Greater decreases in bone mineral density (BMD) have been associated with tenofovir relative to comparators in clinical studies. Normally, BMD increases rapidly in pediatric patients; however, in studies of tenofovir-treated pediatric patients, bone effects were similar to those noted in adult patients, suggesting increased bone turnover. Assessment of BMD is recommended in patients with a history of bone fractures or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected, appropriate consultation should be obtained. One study evaluating HIV-infected children aged 2-12 years found total body BMD gains in recipients of tenofovir to be lower than the gains observed in patients receiving either stavudine or zidovudine. Additionally, at treatment week 48, 1 tenofovir-treated patient experienced significant (> 4%) BMD loss in the lumbar spine; significant BMD losses were not observed in the stavudine or zidovudine treatment groups. In another study involving adolescents aged 12-17 years, the mean rate of BMD gain was less in the tenofovir-treated patients compared to the placebo group. Six tenofovir treated adolescents and 1 placebo treated adolescent had significant (> 4%) lumbar spine BMD loss in 48 weeks. A third study involving pediatric patients ages 12-17 years with chronic hepatitis B also observed smaller gains in lumbar and total body BMD for those patients receiving tenofovir (+ 5% and + 3%, respectively) compared to the placebo group (+ 8% and + 5%, respectively). After 72 weeks of treatment, significant (> 4%) lumbar spine BMD losses occurred in 3 tenofovir patients and 2 placebo patients. In all 3 pediatric studies, the skeletal growth height appeared to be unaffected. Osteomalacia has also been reported with tenofovir use (post-marketing), including cases associated with proximal renal tubulopathy. Worsening pain in bones or extremities, bone fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms.

While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome, consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, breast enlargement, gynecomastia, and other Cushingoid features, has been reported in patients receiving long-term highly active antiretroviral therapy (HAART), including efavirenz. Lipodystrophy often accompanies other metabolic complications such as insulin resistance, dyslipidemia, and lactic acidosis. The prevalence of lipodystrophy in pediatric patients treated with HAART has ranged from approximately 20% to 50% in most clinical studies. One study of pediatric patients receiving lamivudine, stavudine, and either nevirapine or efavirenz reported an increasing incidence with longer therapy; a rate as high as 65% was reported 144 weeks after HAART initiation. Older age (preadolescents and adolescents vs. younger children) and long-term HAART therapy have been shown to increase the risk of lipodystrophy. Unlike in adults, most studies in children have not found a higher incidence of lipodystrophy in girls vs. boys. However, one study in children receiving NNRTI-based therapy did find a higher prevalence of lipodystrophy in females (61% vs. 39%; p = 0.04) and those with advanced HIV disease (73% vs. 51%; p = 0.04). The mechanism by which HAART may cause body fat changes is not known. It has been suggested that mitochondrial damage of adipocytes by these agents may play a role.

Gastrointestinal (GI) adverse reactions are common with antiretroviral agents. During adult HIV clinical trials in patients who received efavirenz, emtricitabine, and tenofovir, the most common GI adverse events were diarrhea (9%), nausea (9%), and vomiting (2%). Other GI effects seen in >= 2% of patients treated with efavirenz, emtricitabine, and/or tenofovir in adult clinical trials include anorexia, dyspepsia, and abdominal pain. Similar GI effects are seen in children receiving efavirenz, emtricitabine, and tenofovir. There have been post-marketing reports of pancreatitis in patients receiving efavirenz, emtricitabine, and/or tenofovir. Hyperamylasemia (> 175 units/L; 8%) and increased lipase (<= 3%) were noted in clinical trials with efavirenz, emtricitabine, and/or tenofovir. Cases of constipation and malabsorption have been reported during post-marketing use of efavirenz.

Nervous system-related adverse reactions are likely due to the efavirenz component of efavirenz; emtricitabine; tenofovir. During clinical studies, 53% of efavirenz-treated patients experienced CNS symptoms compared to 25% of patients receiving control regimens. In a pediatric case series, 24% of patients experienced efavirenz-related CNS symptoms with 18% requiring drug discontinuation. Usually, these symptoms begin on the first or second day of therapy and resolve within 2 to 4 weeks; however, in some patients, late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. In one report, 37% of patients experienced persistent symptoms at 12 months, and in another report, half of treatment discontinuations occurred after 12 months. Reported nervous system adverse events included drowsiness or somnolence (7%), headache (6%), hallucinations (1.2%), dizziness (8% to 28.1%), impaired cognition (8.3%), insomnia (5% to 16.3%), and abnormal dreams/nightmares (6.2%). These symptoms were severe in 2% of patients and 2.1% of patients discontinued treatment as a result. In clinical practice, up to 65% of patients experience CNS symptoms they describe as 'feeling stoned'. After 4 weeks of treatment, the prevalence of nervous system symptoms of at least moderate severity ranges from 5% to 9%. Dosing at bedtime may improve the tolerability of these reactions. Additional CNS side effects reported with efavirenz include agitation, amnesia, abnormal thinking, confusion, depersonalization, euphoria, and stupor. Paresthesias and peripheral neuritis and peripheral neuropathy have been reported in 5% or more of adult patients receiving treatment with emtricitabine or tenofovir in combination with other antiretroviral agents during clinical trials. Cerebellar coordination, abnormal coordination, ataxia, convulsions or seizures, encephalopathy, tremor, hypoesthesia, visual impairment (abnormal vision), tinnitus, and vertigo or balance disturbances have been noted in postmarketing surveillance. In one pediatric study in children younger than 36 months of age, 9% (n = 4/44) of patients experienced new onset-seizures; in 2 of these patients, seizures were due to alternative causes.

Psychiatric related adverse reactions are likely due to the efavirenz component of efavirenz; emtricitabine; tenofovir; these symptoms can be serious. Patients should be counseled regarding these symptoms and that they usually resolve with continued use, but in some patients, neuropsychiatric symptoms may persist for months. The most commonly reported psychiatric related adverse reactions in efavirenz adult controlled trials and in an open-label active-control study involving antiretroviral-naive patients who received efavirenz in combination with emtricitabine and tenofovir included anxiety (13% or less), nervousness (7% or less), and depression (2.4% to 9%). Other serious psychiatric adverse reactions reported during controlled trials (including 1,008 efavirenz-treated patients and 635 patients treated with control regimens) included suicidal ideation (0.7% vs. 0.3%, respectively), nonfatal suicide attempts (0.5% vs. 0), aggressive behavior (0.4% vs. 0.5%), paranoid reactions (paranoia/psychosis) (0.4% vs. 0.3%), and manic reactions (mania) (0.2% vs. 0.3%). Patients with a history of psychiatric disorders appear to be at greater risk for these serious psychiatric reactions, with the frequency of events ranging from 0.3% for manic reactions to 2% for both severe depression and suicidal ideation. There have also been postmarketing reports of death by suicide, delusions, catatonia, emotional lability, neurosis, and psychosis-like behavior. Patients who experience serious psychiatric events 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.

Rash (unspecified) occurred in 32% of pediatric patients who received treatment with efavirenz in clinical trials. Compared to adults, children tend to have more frequent and severe rashes; the manufacturer recommends considering prophylactic antihistamine administration prior to therapy initiation in pediatric patients. During clinical trials, Grade 3 rash (vesicular rash, moist skin desquamation, skin ulcer formation) occurred in 1.1% of children and Grade 4 rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis requiring surgery, exfoliative dermatitis) occurred in 2.2% of children. A discontinuation rate for rash was 2.7% of pediatric patients in clinical trials. Skin rash usually consists of mild-to-moderate maculopapular rash that occurs within the first 2 weeks of initiating therapy. In most cases, the rash resolves with continuing efavirenz therapy within 1 month. Treatment with efavirenz should be discontinued in patients with blistering, desquamation, mucosal involvement, or pyrexia. Efavirenz can be reinitiated in patients interrupting therapy because of rash. Use of appropriate antihistamines and/or corticosteroids may be considered when efavirenz is restarted. Rash events (including rash, pruritus, maculopapular rash, urticaria, vesiculo-bullous rash, pustular rash, and allergic reaction) have also been observed in adult clinical trials in >= 5% of patients receiving emtricitabine or tenofovir with other antiretroviral agents. During post-marketing experience with efavirenz, flushing and photosensitivity (photoallergic dermatitis) have been reported. Angioedema has also been noted in post-marketing reports for tenofovir.

In clinical trials of emtricitabine, skin hyperpigmentation was reported with a higher frequency in patients treated with emtricitabine than placebo. According to the manufacturer, the incidence of hyperpigmentation was higher in pediatric patients (32%) than in adults. This skin discoloration manifested on the palms of the hands and/or soles of the feet, was generally mild and asymptomatic, and was predominantly reported in non-Caucasian patients. The mechanism and clinical significance are unknown. Additionally, skin discoloration, although undefined, was reported during post-marketing use of efavirenz. Similar events may be expected with the use of efavirenz; emtricitabine; tenofovir.

Fatigue was reported in 9% of patients during adult clinical trials with efavirenz, emtricitabine, and tenofovir. Musculoskeletal adverse events experienced by >= 5% of patients receiving treatment with emtricitabine or tenofovir in combination with other antiretroviral agents during adult clinical trials included arthralgia, back pain, chest pain (unspecified) (3%), myalgia, and generalized pain. Elevations in creatine kinase (Male: > 990 units/L; Female: > 845 units/L) were also observed in 9% of patients during adult clinical trials with efavirenz, emtricitabine, and tenofovir. Rhabdomyolysis, myopathy, muscular weakness, and asthenia have been noted during post-marketing surveillance. Worsening bone pain, pain in extremities, fractures and/or muscular pain or myasthenia may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms.

Dyslipidemia (hypercholesterolemia, hypertriglyceridemia) is relatively common in children receiving HAART and is often associated with lipodystrophy. Hypercholesterolemia (> 240 mg/dL; 22%) and hypertriglyceridemia (> 750 mg/dL; 4%) were reported in patients who received efavirenz, emtricitabine, and tenofovir in adult clinical trials. Other metabolic abnormalities reported included hyperglycemia (> 250 mg/dL; 2%) and glycosuria (>= 3+; < 1%). Hypoglycemia (< 40 mg/dL; <= 3%) has been reported in adult clinical trials of emtricitabine or tenofovir in combination with other antiretroviral agents.

Infections, including sinusitis (8%), upper respiratory tract infection (8%), and naso-pharyngitis (5%), have been reported in patients receiving efavirenz, emtricitabine, and tenofovir in adult clinical trials. Other adverse events reported in >= 5% of patients receiving emtricitabine or tenofovir in combination with other antiretroviral agents in adult clinical trials include increased cough, fever, pneumonia, and rhinitis. Dyspnea and palpitations have been noted in post-marketing reports with efavirenz.

Anemia was noted in 7% of pediatric patients during emtricitabine clinical trials. Neutropenia (< 750/mm3) was reported in 3% of patients receiving efavirenz, emtricitabine, and tenofovir in adult clinical trials.

QT prolongation has been reported with the use of efavirenz.

Efavirenz; emtricitabine; tenofovir is contraindicated in patients with a known hypersensitivity to the drug or any components of the product.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in patients receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific assay is recommended.

Both emtricitabine and tenofovir are eliminated by the kidney; avoid use of efavirenz; emtricitabine; tenofovir in patients with creatinine clearance less than 50 mL/minute. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been associated with tenofovir administration. The majority of such cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents; some cases, however, occurred in patients with no identifiable risk factors. Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients prior to initiation of therapy and as clinically appropriate during therapy. Serum phosphorous concentrations should also be assessed prior to and periodically during treatment in patients with chronic kidney disease. In addition, closely evaluate the renal function of patients who experience persistent or worsening bone pain, pain in extremities, bone fractures, and muscle pain or weakness while receiving the drug as these may be manifestations of proximal renal tubulopathy. Avoid efavirenz; emtricitabine; tenofovir with concurrent or recent use of a nephrotoxic agent (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure, requiring hospitalization and renal replacement therapy, have been reported in HIV-infected patients at high-risk for renal impairment, who appeared stable on tenofovir, after initiation of high-dose or multiple dose NSAIDs. Patients at risk for renal dysfunction should be given alternative therapy to NSAIDs, if required. Discontinue efavirenz; emtricitabine; tenofovir in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Bone mineral density (BMD) monitoring should be considered for patients receiving efavirenz; emtricitabine; tenofovir who have a history of pathologic bone fractures or are at substantial risk for osteopenia, osteoporosis, or osteomalacia; osteomalacia has been reported in association with tenofovir administration. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with tenofovir therapy. Worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may also be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms. Normally, BMD increases rapidly in children and adolescents; however, in studies of tenofovir-treated pediatric patients, bone effects were similar to those noted in adult patients. One study evaluating HIV-infected children aged 2-12 years found total body BMD gains in recipients of tenofovir to be lower than the gains observed in patients receiving either stavudine or zidovudine. Additionally, at treatment week 48, 1 tenofovir-treated patient experienced significant (> 4%) BMD loss in the lumbar spine; significant BMD losses were not observed in the stavudine or zidovudine treatment groups. In another study involving adolescents aged 12-17 years, the mean rate of BMD gain was less in the tenofovir-treated patients compared to the placebo group. Six tenofovir-treated adolescents and 1 placebo-treated adolescent had significant (> 4%) lumbar spine BMD loss in 48 weeks. A third study involving pediatric patients ages 12-17 years with chronic HBV infection also observed smaller gains in lumbar and total body BMD for those patients receiving tenofovir (+ 5% and + 3%, respectively) compared to the placebo group (+ 8% and + 5%, respectively). After 72 weeks of treatment, significant (> 4%) lumbar spine BMD losses occurred in 3 tenofovir patients and 2 placebo patients. In all 3 pediatric studies, the skeletal growth height appeared to be unaffected. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected, appropriate consultation should be obtained.

Lactic acidosis and hepatotoxicity with steatosis, including fatal cases, have been reported after use of emtricitabine and tenofovir, both alone and in combination with other antiretroviral medications. Suspend treatment with efavirenz; emtricitabine; tenofovir in any patient who develops clinical or laboratory findings suggestive of hepatotoxicity or lactic acidosis, which may include hepatomegaly and steatosis even in the absence of marked elevated hepatic enzymes. Although these adverse reactions may occur in any drug recipient, some risk factors include hepatic disease (e.g., alcoholism), obesity, and prolonged nucleoside exposure. In addition, adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk applies to pediatric females.

Efavirenz; emtricitabine; tenofovir is not recommended in patients with moderate or severe hepatic impairment. Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported with efavirenz. Reports have included patients with underlying hepatic disease, including those with hepatitis B or C, and patients without preexisting hepatic disease or other identifiable risk factors. Monitoring of liver enzymes prior to and during treatment with efavirenz; emtricitabine; tenofovir is recommended in all patients, particularly in patients with mild hepatic impairment. Consider treatment discontinuation in patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal. Discontinue efavirenz; emtricitabine; tenofovir if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. Perform hepatitis B virus (HBV) screening in all patients prior to initiating therapy with efavirenz; emtricitabine; tenofovir to assure appropriate treatment. Patients who are coinfected with HIV and HBV and require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. After discontinuation of emtricitabine or tenofovir in patients with hepatitis B and HIV coinfection, some patients have experienced severe acute hepatitis B exacerbation associated with hepatic decompensation and liver failure. In patients with HBV who discontinue efavirenz; emtricitabine; tenofovir, closely monitor transaminase concentrations (every 6 weeks for the first 3 months, and every 3 to 6 months thereafter). If appropriate, resumption of anti-hepatitis B treatment may be required; especially in patients with advanced hepatic disease or cirrhosis.

Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of antiretroviral agents. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during antiretroviral treatment, possible interventions include dietary modification, use of lipid lowering agents, or modification of treatment regimen. Because monitoring of serum cholesterol and triglycerides is recommended during efavirenz therapy, it is prudent to consider such monitoring during treatment with efavirenz; emtricitabine; tenofovir.

A majority of patients receiving efavirenz during clinical trials experienced CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, euphoria, confusion, agitation, amnesia, stupor, and depersonalization. In most cases, these symptoms were mild to moderate in severity and began during the first or second day of therapy. Inform drug recipients that these common symptoms will likely improve with continued use of the drug (generally after the first 2 to 4 weeks of therapy) and are not predictive of subsequent onset of less frequent psychiatric symptoms. Use of ethanol or other psychoactive drugs may worsen these symptoms, while dosing at bedtime may improve the tolerability. Advise patients to avoid activities requiring coordination and concentration (e.g., riding a bicycle, driving) until they know how efavirenz may affect them. Some patients may experience late-onset neurotoxicity, including ataxia and encephalopathy (i.e., impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), that develops months to years after starting efavirenz therapy. Of note, some cases of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz concentrations despite standard dosing. Serious psychiatric adverse events (i.e., severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, catatonic reactions, manic reactions) have also been associated with efavirenz therapy. Promptly evaluate any patient who presents with signs or symptoms of a serious neurologic adverse reaction. Patients with a history of mental illness (e.g., bipolar disorder, depression, mania, schizophrenia, or psychosis), alcoholism, or substance abuse, may be at increased risk for CNS adverse events, including psychiatric adverse events.

Rash is a common adverse reaction associated with efavirenz therapy. In most patients, it is a self-limiting mild-to-moderate maculopapular eruption that develops within the first 2 weeks of treatment. However, in rare cases, serious rash (e.g., erythema multiforme, Stevens-Johnson syndrome) has been observed. Efavirenz should be discontinued in patients with a rash associated with blistering, desquamation (e.g., exfoliative dermatitis), mucosal involvement, or fever. It can be restarted after interruptions due to rash; however, for those patients experiencing a life-threatening cutaneous reaction (Stevens-Johnson syndrome), an alternative treatment is recommended. Use of appropriate antihistamines and/or corticosteroids may be considered when efavirenz is restarted; these agents may improve the tolerability and hasten the resolution of the rash. Compared with adults, children tend to have more frequent and severe rashes. Prophylaxis with antihistamines prior to initiating therapy with efavirenz in pediatric patients should be considered.

Use efavirenz with caution in patients with a history of seizures. Although infrequent, seizures have been observed in patients receiving efavirenz and these events have typically occurred in the presence of a known medical history of seizure disorder. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital, may require periodic monitoring of anticonvulsant plasma concentrations.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Emtricitabine will not likely be effective in individuals who display resistance to lamivudine, due to the similarities between the two drugs. Clinicians should not expect patients with the M184 mutation associated with lamivudine to benefit from an emtricitabine containing regimen. The M184 mutation confers high-level resistance, and emtricitabine, like lamivudine, selects for the M184 mutation. It is important that persons with detectable viral load who plan to switch therapy from lamivudine to emtricitabine have genotypic testing performed to determine whether the M184V mutation is present. A patient's treatment history is also extremely important; if lamivudine has failed in the past, the 184 is archived, thus rendering emtricitabine ineffective in this patient population. Of note, in patients whom a discontinuation or interruption of efavirenz therapy is planned, there is an increased risk of NNRTI-resistant mutations. Pharmacokinetic data demonstrate the persistence of detectable drug levels for at least 21 days after discontinuation of efavirenz; simultaneously stopping all drugs in a regimen containing efavirenz may result in functional efavirenz monotherapy due to its long half-life. This is further complicated by evidence that certain genetic polymorphisms, more common among some ethnic groups (such as Black patients, Asian patients, and Hispanic patients), may result in a slower rate of clearance. Some experts recommend stopping efavirenz before the other antiretroviral drugs, although the optimal interval is not known. An alternative strategy is to substitute the efavirenz with a protease inhibitor (PI) prior to interruption of all antiretroviral drugs; if this strategy is used, the goal is to ensure that the PI used also achieves complete viral suppression during this interval. Further research to determine the best approach to temporarily discontinuing efavirenz is needed.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to efavirenz; emtricitabine; tenofovir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Counsel adolescent females about the importance of prevention of pregnancy; barrier contraception must always be used in combination with other methods of contraception during therapy and for 12 weeks after efavirenz; emtricitabine; tenofovir therapy has been discontinued. Efavirenz can cause serious fetal harm when administered during the first trimester of pregnancy. Females of childbearing age should undergo pregnancy testing prior to initiating efavirenz; emtricitabine; tenofovir therapy.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Daily efavirenz doses of 600 mg PO administered for 14 days to healthy subjects with CYP2B6 polymorphisms, specifically the CYP2B6 *6/*6 genotype, have resulted in a mean QTc prolongation of 8.7 ms. Health care providers are advised to consider alternatives to efavirenz in patients receiving medications that have the potential to cause Torsade de Pointes (TdP). Further, use efavirenz with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

Description: Efavirenz; emtricitabine; tenofovir (Atripla) is used for the treatment of human immunodeficiency virus (HIV) infection. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir is an acyclic nucleotide analog (i.e., nucleotide reverse transcriptase inhibitor). NNRTI-based regimens, such as this, are commonly prescribed as initial treatment as they typically have a lower pill burden and preserve protease inhibitors (PIs) for later use. The combination product, Atripla, allows for once daily dosing using a single tablet in those patients old enough to receive adult dosing. Due to the similarities between emtricitabine and lamivudine, emtricitabine containing products are not likely to be effective in individuals who display antimicrobial resistance to lamivudine. Although emtricitabine and tenofovir both exhibit activity against hepatitis B virus (HBV), only tenofovir is indicated for this use. The FDA-approved package labeling for Atripla carries a boxed warning stating that severe, acute exacerbations of hepatitis B have been reported in patients co-infected with HIV and HBV who discontinue either emtricitabine or tenofovir. If treatment for HIV infection with Atripla is discontinued in a patient co-infected with HBV, close monitoring of the patient for several months for signs and symptoms of worsening hepatitis infection is recommended. Decreases in bone mineral density (BMD) have been reported with tenofovir therapy in children; therefore, use of tenofovir is only recommended as part of a preferred regimen in adolescents in Tanner stage 4 or 5. Tenofovir may be considered in children in lower Tanner stages as alternative treatment or in special circumstances. Efavirenz; emtricitabine; tenofovir (Atripla) is FDA-approved for use in pediatric patients weighing 40 kg or more.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Efavirenz; emtricitabine; tenofovir is a preferred NNRTI-based regimen for initial therapy for treatment-naive adolescents (Sexual Maturity Rating (SMR) of 4 or 5) in certain clinical situations.
-Efavirenz; emtricitabine; tenofovir is considered an alternative regimen in children 3 to 12 years due to decreases in bone mineral density that may occur with tenofovir. Due to efavirenz; emtricitabine; tenofovir being a fixed-dose combination tablet, use is not recommended in children and adolescents weighing less than 40 kg.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: hepatitis B virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of human immunodeficiency virus (HIV) infection:
Oral dosage:
Children and Adolescents weighing 40 kg or more: 1 tablet (efavirenz 600 mg; emtricitabine 200 mg; tenofovir 300 mg) PO once daily. Bedtime administration may improve tolerability of nervous system adverse reactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
weight less than 40 kg: Safety and efficacy have not been established.
weight 40 kg or more: 600 mg/day efavirenz, 200 mg/day emtricitabine, and 300 mg/day tenofovir PO.
-Adolescents
weight less than 40 kg: Safety and efficacy have not been established.
weight 40 kg or more: 600 mg/day efavirenz, 200 mg/day emtricitabine, and 300 mg/day tenofovir PO.

Patients with Hepatic Impairment Dosing
No dosage adjustment is required in patients with mild hepatic impairment; however, caution is advised when administering to these patients. Avoid use in patients with moderate to severe hepatic impairment (Child Pugh B or C) as data are insufficient to recommend an appropriate dose.

Patients with Renal Impairment Dosing
CrCl 50 mL/minute or more: No dosage adjustment is needed.
CrCl less than 50 mL/minute: Use not recommended.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRT), emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir is a nucleotide reverse transcriptase inhibitor (although sometimes classified with the NRTIs). Combination therapy targets different points in the life cycle of HIV, reducing viral capacity to mutate to drug-resistant strains. In combination studies evaluating the antiviral activity in cell culture of emtricitabine plus efavirenz, efavirenz plus tenofovir, or emtricitabine plus tenofovir, additive to synergistic antiviral effects are observed.
-Efavirenz: As an NNRTI of HIV-1, efavirenz binds directly to a site on reverse transcriptase that is near but distinct from where NRTIs bind. This binding causes disruption of the enzyme's active site, thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase.
-Emtricitabine: Emtricitabine inhibits viral reverse transcriptase and is active in vitro against both HIV-1 and HBV. Emtricitabine is similar in structure and activity to lamivudine, although its activity against HIV-1 is approximately 4-10 fold greater than that of lamivudine. Emtricitabine is a synthetic nucleoside analog of cytosine and is phosphorylated by cellular enzymes to emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of polymerase alpha, beta, epsilon and mitochondrial DNA polymerase-gamma. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains. In combination with another NRTI and efavirenz, emtricitabine has been shown to increase CD4 cell counts and reduce plasma HIV-1 RNA levels.
-Tenofovir: Tenofovir inhibits viral reverse transcriptase and acts as a DNA chain terminator. Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic nucleoside phosphonate (nucleotide) diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir. Tenofovir is then taken up by cells and undergoes phosphorylation to form tenofovir diphosphate (PMPApp). Tenofovir diphosphate competitively inhibits RNA- and DNA-directed reverse transcriptase. Tenofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate (dATP) and, because it lacks a 3' hydroxyl group, causes premature DNA termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, and mitochondrial DNA polymerase-gamma.

Pharmacokinetics: Efavirenz; emtricitabine; tenofovir is administered orally.
-Efavirenz: Efavirenz is highly protein bound (99%), predominantly to albumin. In vitro data suggest that efavirenz is hepatically metabolized, primarily by CYP3A and CYP2B6, to hydroxylated metabolites with subsequent glucuronidation. In adults, efavirenz has a terminal half-life of 52 to 76 hours after a single dose and 40 to 55 hours after multiple doses. Approximately 14% to 34% of radiolabeled efavirenz is excreted in the urine (primarily as metabolites) and 16% to 61% is eliminated in the feces (mostly as parent drug).
-Emtricitabine: Emtricitabine exhibits low plasma protein binding (less than 4%), and protein-binding is independent of plasma concentration. Metabolism occurs via oxidation to 3'-sulfoxide diastereomer (approximately 9% of dose) and via conjugation with glucuronic acid to 2'-O-glucuronide (approximately 4% of dose). Emtricitabine is excreted renally. The renal clearance is greater than the estimated creatinine clearance; elimination is presumed to be by both glomerular filtration and active tubular secretion, suggesting there may be competition for elimination with other compounds that are also renally eliminated. The plasma half-life is approximately 10 hours (range: 7.4 to 18 hours), and the metabolite, emtricitabine-triphosphate, has an intracellular half-life of approximately 39 hours.
-Tenofovir: The in vitro binding to human plasma and serum proteins is less than 0.7% and 7.2%, respectively. Intracellularly, tenofovir undergoes phosphorylation to its active metabolite, tenofovir diphosphate (PMPApp). In vitro studies indicate that neither tenofovir DF nor tenofovir are substrates of cytochrome P450 enzymes. Tenofovir is eliminated by a combination of glomerular filtration and active renal tubular secretion; there may be competition for elimination with other compounds that are also renally eliminated. Approximately 70% to 80% is excreted as unchanged drug in the urine. The plasma half-life is approximately 17 hours (range: 12 to 25.7 hours) in adults, but is shorter in children.

Affected cytochrome P450 isoenzymes and transporters: CYP3A, CYP2B6, CYP2C9, CYP2C19, P-gp, BRCP
Efavirenz plasma concentrations may be altered by coadministration of substrates, inhibitors, or inducers of CYP3A. Efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A and CYP2B6, which is its most prominent effect. In addition, efavirenz inhibits CYP2C9 and CYP2C19 in vitro. Efavirenz is metabolized via CYP3A and CYP2B6. Tenofovir DF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Administration with inhibitors of these transporters may result in increased absorption of tenofovir.


-Route-Specific Pharmacokinetics
Oral Route
After single dose administration to fasting healthy subjects, one Atripla tablet is bioequivalent to the concomitant administration of one Sustiva tablet (600 mg), one Emtriva capsule (200 mg), and one Viread tablet (300 mg). Administration of Atripla tablets has not been evaluated with food, although it is known that when administered with food, efavirenz and tenofovir AUC and Cmax increase; food has no effect on emtricitabine exposure.
-Efavirenz: Peak plasma concentrations are seen 3 to 5 hours after administration of a single dose with steady-state plasma concentrations reached in 6 to 10 days. When administered with a high fat meal, efavirenz AUC and Cmax increase by 28% and 79%, respectively, compared to administration in the fasted state.
-Emtricitabine: Emtricitabine is rapidly absorbed after oral administration with an oral bioavailability of approximately 92%. Peak plasma concentrations are achieved 1 to 2 hours after administration. Administration with food does not affect the systemic exposure.
-Tenofovir: Due to the presence of a phosphonate group, tenofovir is negatively charged at neutral pH, which limits its bioavailability (25%). After absorption, tenofovir DF is rapidly converted to tenofovir. Peak concentrations of tenofovir are achieved approximately 1 hour after administration. Administration with food delays the Cmax by approximately 0.75 hour and increases the AUC and Cmax by approximately 35% and 15%, respectively, compared with administration under fasting conditions.


-Special Populations
Pediatrics
Children and Adolescents
Pharmacokinetic studies evaluating efavirenz equivalent to 600 mg, emtricitabine 200 mg, and tenofovir 300 mg have been conducted in pediatric populations. Data from these studies showed that these doses of emtricitabine in patients 13 to 17 years, tenofovir in patients 12 to 17 years, and efavirenz in patients 3 to 16 years achieved similar exposures to those observed in adults who received similar doses. Due to the fixed-dose combination of efavirenz; emtricitabine; tenofovir, use is not recommended for individuals weighing less than 40 kg.

Hepatic Impairment
No information is available regarding emtricitabine pharmacokinetic parameters in patients with hepatic impairment. Significant effects on efavirenz pharmacokinetics were not observed in patients with mild hepatic impairment (Child-Pugh Class A); data were insufficient to determine if moderate and severe hepatic impairment impact efavirenz pharmacokinetics. No substantial pharmacokinetic changes have been noted after tenofovir administration in patients with moderate to severe hepatic impairment; no change in dosage is required.

Renal Impairment
Efavirenz pharmacokinetic parameters have not been studied in patients with renal impairment; less than 1% is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. However, emtricitabine and tenofovir are renally eliminated and clearance is reduced in patients with moderate to severe renal impairment.

Ethnic Differences
Published literature in adult patients has documented higher efavirenz plasma concentrations in patients of African and Asian descent, as well as Latino patients, compared to White patients. Studies evaluating these racial differences attribute the elevated concentrations to single nucleotide polymorphisms (SNP) in CYP2B6, the enzyme primarily responsible for efavirenz metabolism. Patients with the SNP experience reduced CYP2B6 activity resulting in impaired efavirenz metabolism and elevated plasma concentrations. In a study evaluating the pharmacokinetics of efavirenz in 58 healthy subjects with CYP2B6 polymorphisms, the mean Cmax was found to be 2.25-fold higher in subjects with the CYP2B6 *6/*6 genotype than in those with the CYP2B6 *1/*1 genotype. The implication in pediatric patients is unknown.