Atripla

Generic Name: efavirenz, emtricitabine and tenofovir disoproxil fumarate
Dosage Form: tablets

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.

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

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

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.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

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

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 (eg cardiac arrhythmias, prolonged sedation, or respiratory depression). Drugs that are contraindicated with Atripla are listed in Table 1.

Table 1 Drugs That Are Contraindicated or Not Recommended for Use With Atripla

Drug Class: Drug Name	Clinical Comment
Antifungal: voriconazole	Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. Because Atripla is a fixed dose combination product, the dose of efavirenz cannot be altered. [See Clinical Pharmacology (12.3) Tables 5 and 6]
Ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Benzodiazepines: midazolam, triazolam	Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Calcium channel blocker: bepridil	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
GI motility agent: cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Neuroleptic: pimozide	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
St. John's wort (Hypericum perforatum)	May lead to loss of virologic response and possible resistance to efavirenz or to the class of NNRTIs.

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

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. In some patients infected with HBV and treated with emtricitabine, the exacerbations of Hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Atripla. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

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 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits [See Adverse Reactions (6)].

5.6 Nervous System Symptoms

Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild-moderate (50.7%); symptoms were severe in 2.0% of patients. Overall, 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2–4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [See Warnings and Precautions (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 patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.

Patients receiving Atripla should be alerted to the potential for additive central nervous system effects when Atripla is used concomitantly with alcohol or psychoactive drugs.

Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.

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.

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 should always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of Atripla. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

There are no adequate and well-controlled studies of Atripla in pregnant women. Atripla should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.

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

Efavirenz: As of July 2006, the Antiretroviral Pregnancy Registry has received prospective reports of 322 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (316 pregnancies). Birth defects occurred in 6 of 255 live births (first-trimester exposure) and 1 of 17 live births (second/third-trimester exposure). None of these prospectively reported defects were neural tube defects. However, there have been four retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.

Malformations have been observed in 3 of 20 fetuses/infants from efavirenz-treated cynomolgus monkeys (versus 0 of 20 concomitant controls) in a developmental toxicity study. The pregnant monkeys were dosed throughout pregnancy (postcoital days 20–150) with efavirenz 60 mg/kg daily, a dose which resulted in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz. Anencephaly and unilateral anophthalmia were observed in one fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus. Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations. Efavirenz has been shown to cross the placenta in rats and rabbits and produces fetal blood concentrations of efavirenz similar to maternal concentrations. An increase in fetal resorptions was observed in rats at efavirenz doses that produced peak plasma concentrations and AUC values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of efavirenz. Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of efavirenz.

5.9 Rash

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). Atripla can be reinitiated in patients interrupting therapy because of rash. Atripla should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash.

Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash.

5.10 Liver Enzymes

In patients with known or suspected history of Hepatitis B or C infection and in patients treated with other medications associated with liver toxicity, monitoring of liver enzymes is recommended [See also Warnings and Precautions (5.2)]. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Atripla needs to be weighed against the unknown risks of significant liver toxicity [See Adverse Reactions (6.2)].

5.11 Decreases in Bone Mineral Density

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

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

Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.3)].

5.12 Convulsions

Convulsions have been observed in patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.

Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [See Drug Interactions (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:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].
• Severe Acute Exacerbations of Hepatitis B [See Boxed Warning, Warnings and Precautions (5.2)].
• Psychiatric Symptoms [See Warnings and Precautions (5.5)],
• Nervous System Symptoms [See Warnings and Precautions (5.6)],
• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.7)].
• Rash [See Warnings and Precautions (5.9)].
• Decreases in Bone Mineral Density [See Warnings and Precautions (5.11)].
• Immune Reconstitution Syndrome [See Warnings and Precautions (5.13)].
• Drug Interactions [See Contraindications (4.2), Warnings and Precautions (5.3) and Drug Interactions (7)]

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 patients 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).

Table 2 Selected Treatment-Emergent Adverse Reactions* (Grades 2–4) Reported in ≥5% in Either Treatment Group in Study 934 (0–144 Weeks)

	FTC + TDF + EFV†	AZT/3TC + EFV
	N=257	N=254
* Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † From Weeks 96 to 144 of the study, patients received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. ‡ Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.
Gastrointestinal Disorder
Diarrhea	9%	5%
Nausea	9%	7%
Vomiting	2%	5%
General Disorders and Administration Site Condition
Fatigue	9%	8%
Infections and Infestations
Sinusitis	8%	4%
Upper respiratory tract infections	8%	5%
Nasopharyngitis	5%	3%
Nervous System Disorders
Headache	6%	5%
Dizziness	8%	7%
Psychiatric Disorders
Anxiety	5%	4%
Depression	9%	7%
Insomnia	5%	7%
Skin and Subcutaneous Tissue Disorders
Rash Event‡	7%	9%

In addition to the adverse reactions in Study 934, 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 patients 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 patients 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 patients treated with efavirenz 600 mg than in control patients.

Emtricitabine and Tenofovir Disoproxil Fumarate: Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve patients 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 patients; 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).

Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Either Treatment Group in Study 934 (0–144 Weeks)

	FTC + TDF + EFV*	AZT/3TC + EFV
	N=257	N=254
* From Weeks 96 to 144 of the study, patients received emtricitabine/tenofovir DF administered in combination with efavirenz in place of emtricitabine + tenofovir DF with efavirenz.
Any ≥ Grade 3 Laboratory Abnormality	30%	26%
Fasting Cholesterol (>240 mg/dL)	22%	24%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	9%	7%
Serum Amylase (>175 U/L)	8%	4%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%
ALT (M: >215 U/L) (F: >170 U/L)	2%	3%
Hemoglobin (<8.0 mg/dL)	0%	4%
Hyperglycemia (>250 mg/dL)	2%	1%
Hematuria (>75 RBC/HPF)	3%	2%
Glycosuria (≥3+)	<1%	1%
Neutrophils (<750/mm3)	3%	5%
Fasting Triglycerides (>750 mg/dL)	4%	2%

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 patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.

Hepatic Events: In Study 934, 19 patients treated with efavirenz, emtricitabine, and tenofovir DF and 20 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected patients, one patient (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 patients (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected patient discontinued from the study due to hepatobiliary disorders [See Warnings and Precautions (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.

Efavirenz:

Cardiac Disorders
Palpitations

Ear and Labyrinth Disorders
Tinnitus

Endocrine Disorders
Gynecomastia

Eye Disorders
Abnormal vision

Gastrointestinal Disorders
Constipation, malabsorption

General Disorders and Administration Site Conditions
Asthenia

Hepatobiliary Disorders
Hepatic enzyme increase, hepatic failure, hepatitis

Immune System Disorders
Allergic reactions

Metabolism and Nutrition Disorders
Redistribution/accumulation of body fat [See Warnings and Precautions (5.14)], Hypercholesterolemia, hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders
Arthralgia, myalgia, myopathy

Nervous System Disorders
Abnormal coordination, ataxia, convulsions, hypoesthesia, paresthesia, neuropathy, tremor

Psychiatric Disorders
Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide

Respiratory, Thoracic and Mediastinal disorders
Dyspnea

Skin and Subcutaneous Tissue Disorders
Flushing, erythema multiforme, nail disorders, photoallergic dermatitis, skin discoloration, Stevens-Johnson syndrome

Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir Disoproxil Fumarate:

Immune System Disorders
Allergic reaction

Metabolism and Nutrition Disorders
Hypophosphatemia, lactic acidosis

Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea

Gastrointestinal Disorders
Abdominal pain, increased amylase, pancreatitis

Hepatobiliary disorders
Increased liver enzymes (most commonly AST, ALT, gamma GT), hepatitis

Skin and Subcutaneous Tissue Disorders
Rash

Musculoskeletal and Connective Tissue Disorders
Myopathy, osteomalacia (both associated with proximal renal tubulopathy)

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

General Disorders and Administration Site Conditions
Asthenia

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)].

7.1 Efavirenz

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 2C9, 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 (eg, 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.

Table 4 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name	Effect	Clinical Comment
* This table is not all inclusive.
Antiretroviral agents
Protease inhibitor:   atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with Atripla is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. 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.
Protease inhibitor:   fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and Atripla with respect to safety and efficacy have not been established.   Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when Atripla is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when Atripla is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor:   indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor:   lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. Atripla should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor:   ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when Atripla is used in combination with ritonavir.
Protease inhibitor:   saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with Atripla.
NRTI:   didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with Atripla. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of Atripla and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant:   warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants:   carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for Atripla. Alternative anticonvulsant treatment should be used.
phenytoin   phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant:   sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals:   itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction studies with Atripla and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective:   clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of Atripla is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with Atripla.
Antimycobacterial:   rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial:   rifampin	↓ efavirenz concentration	Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of Atripla and rifampin have not been established.
Calcium channel blockers:   diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of Atripla is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of the CYP3A4 enzyme. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors:   atorvastatin   pravastatin   simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Narcotic analgesic:   methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.
Oral contraceptive:   ethinyl estradiol	↑ ethinyl estradiol concentration	Clinical significance unknown. Because the potential interaction of efavirenz with oral contraceptives has not been fully characterized, a reliable method of barrier contraception should be used in addition to oral contraceptives.

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

8.1 Pregnancy

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

The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Atripla to these patients [See Warnings and Precautions (5.10)].

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)].

10 OVERDOSAGE

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

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

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

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

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

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir DF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

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

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

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

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

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

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

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

12.3 Pharmacokinetics

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 patients time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 patients 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 P450 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 patients 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 patients 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)].

Special Populations

Race

Efavirenz: The pharmacokinetics of efavirenz in patients appear to be similar among the racial groups studied.

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

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

Gender

Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate: Efavirenz, emtricitabine, and tenofovir pharmacokinetics are similar in male and female patients.

Pediatric and Geriatric Patients

Pharmacokinetic studies of tenofovir DF have not been performed in pediatric patients (<18 years). Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 13 kg. Emtricitabine has been studied in pediatric patients from 3 months to 17 years of age. Atripla is not recommended for pediatric administration. Pharmacokinetics of efavirenz, emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years) [See Use in Specific Populations (8)].

Patients with Impaired Renal Function

Efavirenz: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.

Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir DF are altered in patients with renal impairment. In patients 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: The pharmacokinetics of efavirenz have not been adequately studied in patients with hepatic impairment [See Warnings and Precautions (5.10) and Use in Specific Populations (8.6)].

Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in patients 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 patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients.

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 P450 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).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Efavirenz in the Presence of the Coadministered Drug

				Mean % Change of Efavirenz Pharmacokinetic Parameters* (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	Efavirenz Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
* Increase = ↑; Decrease = ↓; No Effect = ↔ † Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for efavirenz alone. ‡ 95% CI § Soft Gelatin Capsule ¶ 90% CI not available # Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).
Indinavir	800 mg q8h × 14 days	200 mg × 14 days	11	↔	↔	↔
Lopinavir/ ritonavir	400/100 mg q12h × 9 days	600 mg × 9 days	11, 12†	↔	↓ 16 (↓ 38 to ↑ 15)	↓ 16 (↓ 42 to ↑ 20)
Nelfinavir	750 mg q8h × 7 days	600 mg × 7 days	10	↓ 12 (↓ 32 to ↑ 13)‡	↓ 12 (↓ 35 to ↑ 18)‡	↓ 21 (↓ 53 to ↑ 33)
Ritonavir	500 mg q12h × 8 days	600 mg × 10 days	9	↑ 14 (↑ 4 to ↑ 26)	↑ 21 (↑ 10 to ↑ 34)	↑ 25 (↑ 7 to ↑ 46)‡
Saquinavir SGC§	1200 mg q8h × 10 days	600 mg × 10 days	13	↓ 13 (↓ 5 to ↓ 20)	↓ 12 (↓ 4 to ↓ 19)	↓ 14 (↓ 2 to ↓ 24)‡
Clarithromycin	500 mg q12h × 7 days	400 mg × 7 days	12	↑ 11 (↑ 3 to ↑ 19)	↔	↔
Itraconazole	200 mg q12h × 14 days	600 mg × 28 days	16	↔	↔	↔
Rifabutin	300 mg qd × 14 days	600 mg × 14 days	11	↔	↔	↓ 12 (↓ 24 to ↑ 1)
Rifampin	600 mg × 7 days	600 mg × 7 days	12	↓ 20 (↓ 11 to ↓ 28)	↓ 26 (↓ 15 to ↓ 36)	↓ 32 (↓ 15 to ↓ 46)
Atorvastatin	10 mg qd × 4 days	600 mg × 15 days	14	↔	↔	↔
Pravastatin	40 mg qd × 4 days	600 mg × 15 days	11	↔	↔	↔
Simvastatin	40 mg qd × 4 days	600 mg × 15 days	14	↓ 12 (↓ 28 to ↑ 8)	↔	↓ 12 (↓ 25 to ↑ 3)
Carbamazepine	200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 15 days	600 mg × 35 days	14	↓ 21 (↓ 15 to ↓ 26)	↓ 36 (↓ 32 to ↓ 40)	↓ 47 (↓ 41 to ↓ 53)
Diltiazem	240 mg × 14 days	600 mg × 28 days	12	↑ 16 (↑ 6 to ↑ 26)	↑ 11 (↑ 5 to ↑ 18)	↑ 13 (↑ 1 to ↑ 26)
Ethinyl estradiol	50 µg single dose	400 mg × 10 days	13	↔	↔	↔
Sertraline	50 mg qd × 14 days	600 mg × 14 days	13	↑ 11 (↑ 6 to ↑ 16)	↔	↔
Voriconazole	400 mg po q12h × 1 day then 200 mg po q12h × 8 days	400 mg × 9 days	NA	↑ 38¶	↑ 44¶	NA
	300 mg po q12h days 2–7	300 mg × 7 days	NA	↓ 14# (↓ 7 to ↓ 21)	↔#	NA
	400 mg po q12h days 2–7	300 mg × 7 days	NA	↔#	↑ 17# (↑ 6 to ↑ 29)	NA

Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Efavirenz

				Mean % Change of Coadministered Drug Pharmacokinetic Parameters* (90% CI)
Coadministered Drug	Dose of Coadministered Drug (mg)	Efavirenz Dose (mg)	N	Cmax	AUC	Cmin
NA = not available
* Increase = ↑; Decrease = ↓; No Effect = ↔ † Compared with atazanavir 400 mg qd alone. ‡ Comparator dose of indinavir was 800 mg q8h × 10 days. § Parallel-group design; N for efavirenz + lopinavir/ritonavir, N for lopinavir/ritonavir alone. ¶ Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent efavirenz. # 95% CI Þ Soft Gelatin Capsule ß Not available because of insufficient data. à 90% CI not available è Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
Atazanavir	400 mg qd with a light meal d 1–20	600 mg qd with a light meal d 7–20	27	↓ 59 (↓ 49 to ↓ 67)	↓ 74 (↓ 68 to ↓ 78)	↓ 93 (↓ 90 to ↓ 95)
	400 mg qd d 1–6, then 300 mg qd d 7–20 with ritonavir 100 mg qd and a light meal	600 mg qd 2 h after atazanavir and ritonavir d 7–20	13	↑ 14† (↓ 17 to ↑ 58)	↑ 39† (↑ 2 to ↑ 88)	↑ 48† (↑ 24 to ↑ 76)
Indinavir	1000 mg q8h × 10 days	600 mg × 10 days	20
	After morning dose			↔‡	↓ 33‡ (↓ 26 to ↓ 39)	↓ 39‡ (↓ 24 to ↓ 51)
	After afternoon dose			↔‡	↓ 37‡ (↓ 26 to ↓ 46)	↓ 52‡ (↓ 47 to ↓ 57)
	After evening dose			↓ 29‡ (↓ 11 to ↓ 43)	↓ 46‡ (↓ 37 to ↓ 54)	↓ 57‡ (↓ 50 to ↓ 63)
Lopinavir/ ritonavir	400/100 mg q12h × 9 days	600 mg × 9 days	11, 7§	↔¶	↓ 19¶ (↓ 36 to ↑ 3)	↓ 39¶ (↓ 3 to ↓ 62)
Nelfinavir	750 mg q8h × 7 days	600 mg × 7 days	10	↑ 21 (↑ 10 to ↑ 33)	↑ 20 (↑ 8 to ↑ 34)	↔
Metabolite AG-1402				↓ 40 (↓ 30 to ↓ 48)	↓ 37 (↓ 25 to ↓ 48)	↓ 43 (↓ 21 to ↓ 59)
Ritonavir	500 mg q12h × 8 days	600 mg × 10 days	11
	After AM dose			↑ 24 (↑ 12 to ↑ 38)	↑ 18 (↑ 6 to ↑ 33)	↑ 42 (↑ 9 to ↑ 86)#
	After PM dose			↔	↔	↑ 24 (↑ 3 to ↑ 50)#
Saquinavir SGCÞ	1200 mg q8h × 10 days	600 mg × 10 days	12	↓ 50 (↓ 28 to ↓ 66)	↓ 62 (↓ 45 to ↓ 74)	↓ 56 (↓ 16 to ↓ 77)#
Clarithromycin	500 mg q12h × 7 days	400 mg × 7 days	11	↓ 26 (↓ 15 to ↓ 35)	↓ 39 (↓ 30 to ↓ 46)	↓ 53 (↓ 42 to ↓ 63)
14-OH metabolite				↑ 49 (↑ 32 to ↑ 69)	↑ 34 (↑ 18 to ↑ 53)	↑ 26 (↑ 9 to ↑ 45)
Itraconazole	200 mg q12h × 28 days	600 mg ×14 days	18	↓ 37 (↓ 20 to ↓ 51)	↓ 39 (↓ 21 to ↓ 53)	↓ 44 (↓ 27 to ↓ 58)
Hydroxy-itraconazole				↓ 35 (↓ 12 to ↓ 52)	↓ 37 (↓ 14 to ↓ 55)	↓ 43 (↓ 18 to ↓ 60)
Rifabutin	300 mg qd × 14 days	600 mg × 14 days	9	↓ 32 (↓ 15 to ↓ 46)	↓ 38 (↓ 28 to ↓ 47)	↓ 45 (↓ 31 to ↓ 56)
Atorvastatin	10 mg qd × 4 days	600 mg × 15 days	14	↓ 14 (↓ 1 to ↓ 26)	↓ 43 (↓ 34 to ↓ 50)	↓ 69 (↓ 49 to ↓ 81)
Total active (including metabolites)				↓ 15 (↓ 2 to ↓ 26)	↓ 32 (↓ 21 to ↓ 41)	↓ 48 (↓ 23 to ↓ 64)
Pravastatin	40 mg qd × 4 days	600 mg × 15 days	13	↓ 32 (↓ 59 to ↑ 12)	↓ 44 (↓ 26 to ↓ 57)	↓ 19 (↓ 0 to ↓ 35)
Simvastatin	40 mg qd × 4 days	600 mg × 15 days	14	↓ 72 (↓ 63 to ↓ 79)	↓ 68 (↓ 62 to ↓ 73)	↓ 45 (↓ 20 to ↓ 62)
Total active (including metabolites)				↓ 68 (↓ 55 to ↓ 78)	↓ 60 (↓ 52 to ↓ 68)	NAß
Carbamazepine	200 mg qd × 3 days, 200 mg bid × 3 days, then 400 mg qd × 29 days	600 mg × 14 days	12	↓ 20 (↓ 15 to ↓ 24)	↓ 27 (↓ 20 to ↓ 33)	↓ 35 (↓ 24 to ↓ 44)
Epoxide metabolite				↔	↔	↓ 13 (↓ 30 to ↑ 7)
Diltiazem	240 mg × 21 days	600 mg × 14 days	13	↓ 60 (↓ 50 to ↓ 68)	↓ 69 (↓ 55 to ↓ 79)	↓ 63 (↓ 44 to ↓ 75)
Desacetyl diltiazem				↓ 64 (↓ 57 to ↓ 69)	↓ 75 (↓ 59 to ↓ 84)	↓ 62 (↓ 44 to ↓ 75)
N-monodesmethyl diltiazem				↓ 28 (↓ 7 to ↓ 44)	↓ 37 (↓ 17 to ↓ 52)	↓ 37 (↓ 17 to ↓ 52)
Ethinyl estradiol	50 µg single dose	400 mg × 10 days	13	↔	↑ 37 (↑ 25 to ↑ 51)	NA
Methadone	Stable maintenance 35–100 mg daily	600 mg × 14–21 days	11	↓ 45 (↓ 25 to ↓ 59)	↓ 52 (↓ 33 to ↓ 66)	NA
Sertraline	50 mg qd × 14 days	600 mg × 14 days	13	↓ 29 (↓ 15 to ↓ 40)	↓ 39 (↓ 27 to ↓ 50)	↓ 46 (↓ 31 to ↓ 58)
Voriconazole	400 mg po q12h × 1 day then 200 mg po q12h × 8 days	400 mg × 9 days	NA	↓ 61à	↓ 77à	NA
	300 mg po q12h days 2–7	300 mg × 7 days	NA	↓ 36è (↓ 21 to ↓ 49)	↓ 55è (↓ 45 to ↓ 62)	NA
	400 mg po q12h days 2–7	300 mg × 7 days	NA	↑ 23è (↓ 1 to ↑ 53	↓ 7è (↓ 23 to ↑ 13)	NA

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, adefovir dipivoxil, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir 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.

Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug*,†

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Tenofovir Pharmacokinetic Parameters‡ (90% CI)
			Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers. † Patients received tenofovir DF 300 mg once daily. ‡ Increase = ↑; Decrease = ↓; No Effect = ↔ § Reyataz Prescribing Information
Atazanavir§	400 once daily × 14 days	33	↑ 14 (↑ 8 to ↑ 20)	↑ 24 (↑ 21 to ↑ 28)	↑ 22 (↑ 15 to ↑ 30)
Didanosine (enteric-coated)	400 once	25	↔	↔	↔
Didanosine (buffered)	250 or 400 once daily × 7 days	14	↔	↔	↔
Lopinavir/ ritonavir	400/100 twice daily × 14 days	24	↔	↑ 32 (↑ 25 to ↑ 38)	↑ 51 (↑ 37 to ↑ 66)

Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate*,†

Coadministered Drug	Dose of Coadministered Drug (mg)	N	Mean % Change of Coadministered Drug Pharmacokinetic Parameters‡ (90% CI)
			Cmax	AUC	Cmin
* All interaction studies conducted in healthy volunteers. † Patients received tenofovir DF 300 mg once daily. ‡ Increase = ↑; Decrease = ↓; No Effect = ↔ § Reyataz Prescribing Information ¶ In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
Atazanavir§	400 once daily × 14 days	34	↓ 21 (↓ 27 to ↓ 14)	↓ 25 (↓ 30 to ↓ 19)	↓ 40 (↓ 48 to ↓ 32)
	Atazanavir/ritonavir 300/100 once daily × 42 days	10	↓ 28 (↓ 50 to ↑ 5)	↓ 25¶ (↓ 42 to ↓ 3)	↓ 23¶ (↓ 46 to ↑ 10)
Lopinavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔
Ritonavir	Lopinavir/ritonavir 400/100 twice daily × 14 days	24	↔	↔	↔

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.

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir Disoproxil Fumarate*,†

Didanosine Dose (mg)/Method of Administration‡	Tenofovir DF Method of Administration†,‡	N	Mean % Change (90% CI) vs. Didanosine 400 mg Alone, Fasted§
			Cmax	AUC
* All interaction studies conducted in healthy volunteers. † Patients received tenofovir DF 300 mg once daily. ‡ Administration with food was with a light meal (~373 kcal, 20% fat). § Increase = ↑; Decrease = ↓; No Effect = ↔ ¶ Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily¶ × 7 days	Fasted 1 hour after didanosine	14	↑ 28 (↑ 11 to ↑ 48)	↑ 44 (↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted	With food, 2 hr after didanosine	26	↑ 48 (↑ 25 to ↑ 76)	↑ 48 (↑ 31 to ↑ 67)
400 once, with food	Simultaneously with didanosine	26	↑ 64 (↑ 41 to ↑ 89)	↑ 60 (↑ 44 to ↑ 79)
250 once, fasted	With food, 2 hr after didanosine	28	↓ 10 (↓ 22 to ↑ 3)	↔
250 once, fasted	Simultaneously with didanosine	28	↔	↑ 14 (0 to ↑ 31)
250 once, with food	Simultaneously with didanosine	28	↓ 29 (↓ 39 to ↓ 18)	↓ 11 (↓ 23 to ↑ 2)

12.4 Microbiology

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.

Antiviral Activity

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 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).

Resistance

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-naïve patients [Study 934, see Clinical Studies (14)] resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure patients 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 patients in the emtricitabine + tenofovir DF group and in 21/29 analyzed patients 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 patient isolates in the emtricitabine + tenofovir DF group and in 10/29 analyzed patient isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no patients developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

In a clinical study of treatment-naïve patients, isolates from 8/47 (17%) analyzed patients 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 patients, 14/304 (5%) of tenofovir DF treated patients 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 patients failing treatment with efavirenz in combination with other antiretrovirals. Other resistance substitutions observed to emerge commonly included L100I (7%), K101E/Q/R (14%), V108I