Efavirenz 600 mg Tablet, Film Coated, 30-count

5 WARNINGS AND PRECAUTIONS QTc prolongation: Consider alternatives to efavirenz in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. ( 5.2 ) Do not use as a single agent or add on as a sole agent to a failing regimen. Consider potential for cross-resistance when choosing other agents.

( 5.3 ) Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. ( 5.4 ) Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. ( 5.5 , 17 ) Nervous system symptoms (NSS): NSS are frequent and usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks.

Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 5.6 , 6.1 , 17 ) Embryo-Fetal Toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur.

( 5.7 , 8.1 ) Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. ( 5.9 , 6.1 , 8.6 ) Rash: Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks.

Discontinue if severe rash develops. ( 5.8 , 6.1 , 17 ) Convulsions: Use caution in patients with a history of seizures. ( 5.10 ) Lipids: Total cholesterol and triglyceride elevations.

Monitor before therapy and periodically thereafter. ( 5.11 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.12 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.

( 5.13 , 17 )

5.1Drug 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 or CYP2B6. The most prominent effect of efavirenz at steady state is induction of CYP3A and CYP2B6 [see Dosage and Administration (2.2) and Drug Interactions (7.1) ].

5.2QTc Prolongation QTc prolongation has been observed with the use of efavirenz [see Drug Interactions (7.3 , 7.4 ) and Clinical Pharmacology (12.2) ] . Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

5.3Resistance Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.

5.4Coadministration with Related Products Coadministration of efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients.

5.5Psychiatric 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…

6 ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz are: psychiatric symptoms [see Warnings and Precautions (5.5) ] nervous system symptoms [see Warnings and Precautions (5.6) ] rash [see Warnings and Precautions (5.8) ] hepatotoxicity [see Warnings and Precautions (5.9)] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.

Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenz b + ZDV/LAM (n=412) 180 weeks c Efavirenz b + Indinavir (n=415) 102 weeks c Indinavir + ZDV/LAM (n=401) 76 weeks c Efavirenz b + Nelfinavir + NRTIs (n=64) 71.1 weeks c Efavirenz b + NRTIs (n=65) 70.9 weeks c Nelfinavir + NRTIs (n=66) 62.7 weeks c a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006.

Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM = lamivudine. Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Psychiatric Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritus <1% 1% 1% 9% 5% 9% Pancreatitis has been reported, although a causal relationship with efavirenz has not been established.

Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities ). Nervous System Symptoms For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and dep…

7 DRUG INTERACTIONS Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy. (7)

7.1Potential for Efavirenz to Affect other Drugs Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz.

7.2Potential for Other Drugs to Affect Efavirenz Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2) ].

7.3QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology (12.2) ] . Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes.

7.4Established and Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3) ] Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive.

Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction * The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive.

Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir Calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations 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 efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.

Protease inhibitor: Atazanavir ↓ atazanavir* Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended. Protease inhibitor: Indinavir ↓ indinavir* 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* Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz.

See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients. Protease inhibitor: Ritonavir ↑ ritonavir* ↑ efavirenz* Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Protease inhibitor: Saquinavir ↓ saquinavir* Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.

NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full…