Efavirenz

EFAVIRENZ — efavirenz tablet, film coated
Camber Pharmaceuticals, Inc.

1 INDICATIONS & USAGE

Efavirenz tablets in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.

2 DOSAGE & ADMINISTRATION

2.1 Hepatic Function

Monitor hepatic function prior to and during treatment with efavirenz tablets [see Warnings and Precautions ( 5.9)].Efavirenz tablets are not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populationns (8.6)].

2.2 Adults

The recommended dosage of efavirenz tablets are 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz tablets be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz tablets with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3)].Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6),Adverse Reactions (6.1), and Patient Counseling Information (17)].Efavirenz tablets should be swallowed intact with liquid.
Concomitant Antiretroviral Therapy
Efavirenz tablets must be given in combination with other antiretroviral medications [see Indications and Usage (1),Warnings and Precautions (5.3),Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

2.3 Pediatric Patients

It is recommended that efavirenz tablets be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz tablets for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3)].The recommended dosage of efavirenz tablets for pediatric patients weighing 40 kg or greater is 600 mg once daily.
Table 1: Efavirenz Tablets Dosing in Pediatric Patients

Patient Body Weight Efavirenz Tablets Daily Dose Number of Tabletsb and Strength to Administer
at least 40 kg 600 mg one 600 mg tablet

b Tablets must not be crushed.

3 DOSAGE FORMS & STRENGTHS


Tablets 600 mg tablets are yellow, capsular-shaped, film-coated tablets, with ‘H’ on one side and ‘4’ on the other side.

4 CONTRAINDICATIONS

Efavirenz tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. • Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated [see Warnings and Precautions (5.1)and Drug Interactions ( 7.1)].

5 WARNINGS AND PRECAUTIONS

5.1 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 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)].

5.2 QTc 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 tablets 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.

5.3 Resistance

Efavirenz tablets 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.

5.4 Coadministration with Related Products

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

5.5 Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials of 1,008 patients treated with regimens containing efavirenz tablets 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 tablets 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 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 tablets and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz tablets-treated and control-treated patients. One percent of efavirenz tablets-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, psychosis-like behavior and catatonia, although a causal relationship to the use of efavirenz tablets cannot be determined from these reports. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. 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 tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits. [See Adverse Reactions (6.1).]

5.6 Nervous System Symptoms

Fifty-three percent (531/1,008) of patients receiving efavirenz tablets in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens [see Adverse Reactions (6.1, Table 3)]. These symptoms included, but were not limited to, dizziness (28.1% of the 1,008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2% of patients; and 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 to 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 tablets 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 tablets + zidovudine + lamivudine, efavirenz tablets + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz tablets-treated patients were generally similar to those in the indinavir-containing control arm.
Patients receiving efavirenz tablets should be alerted to the potential for additive central nervous system effects when efavirenz tablets are 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.

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