Efavirenz

• HIV-1 Infection:
• Treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents in adults and pediatric patients aged 3 months and older weighing at least 3.5 kg.
• Combination Therapy:
• Used as part of combination antiretroviral therapy (cART) for treatment-naïve or treatment-experienced patients with HIV-1.
• Off-label Uses:
• Occasionally used in investigational regimens for HIV-1 treatment or prevention, but always in combination with other agents.

• Adults:
• Recommended dose: 600 mg orally once daily, preferably on an empty stomach at bedtime to reduce central nervous system side effects.
• Pediatrics:
• Dosing based on body weight and age; dosing regimens typically range from 200 mg to 600 mg once daily in children ≥3 months and ≥3.5 kg. Weight-band dosing guidelines apply.
• Elderly:
• No specific dose adjustments recommended; monitor for tolerability and comorbid conditions.
• Renal Impairment:
• No dosage adjustment necessary, as renal clearance is minimal.
• Hepatic Impairment:
• Use with caution in moderate to severe hepatic impairment; no established dose adjustment but monitor liver function closely.
• Administration Route: Oral capsules or tablets. Swallow whole; do not crush or chew.
• Duration: Continuous daily dosing as part of antiretroviral regimen.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It binds directly to the HIV-1 reverse transcriptase enzyme at a site distinct from the nucleoside binding site, inducing a conformational change that inhibits the enzyme's activity. This prevents the conversion of viral RNA into DNA, a critical step in viral replication, thereby reducing the viral load and slowing disease progression.

• Absorption: Well absorbed orally; peak plasma concentration reached in 3 to 5 hours.
• Bioavailability: Approximately 40-45%; increased when taken with food, especially high-fat meals, which also increase CNS adverse effects.
• Distribution: Highly protein bound (~99.5%).
• Metabolism: Extensively metabolized in the liver mainly by CYP3A4 and CYP2B6 enzymes to inactive metabolites.
• Half-life: Approximately 40-55 hours, supporting once-daily dosing.
• Excretion: Less than 1% excreted unchanged in urine; primarily eliminated as metabolites via feces and urine.

• Pregnancy:
• FDA Pregnancy Category D (positive evidence of risk). Use during pregnancy only if potential benefits justify risks to the fetus. Associated with potential teratogenicity in animal studies; human data suggest caution, especially in the first trimester.
• Lactation:
• Efavirenz is excreted in human breast milk. Breastfeeding is generally not recommended due to risk of HIV transmission and drug exposure to infant.
• General: Limited safety data in pregnancy; caution advised.

• Primary Class: Antiretroviral agent
• Subclass: Non-nucleoside reverse transcriptase inhibitor (NNRTI)

• Known hypersensitivity to efavirenz or any component of the formulation.
• Concomitant use with ergot derivatives due to risk of serious adverse reactions.
• Co-administration with drugs highly dependent on CYP3A4 for clearance where elevated plasma concentrations may lead to serious or life-threatening events and no alternative treatment is available.

• Central Nervous System Effects: Common and include dizziness, insomnia, vivid dreams, impaired concentration, and mood changes; severe psychiatric symptoms such as depression, suicidal ideation, and psychosis may occur. Monitor patients closely.
• Hepatotoxicity: Monitor liver function tests; higher risk in patients co-infected with hepatitis B or C.
• Rash: May cause severe or life-threatening rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Discontinue immediately if severe rash develops.
• Teratogenicity: Potential risk; avoid use in pregnancy unless benefits outweigh risks.
• Drug Interactions: Extensive CYP450 inducer and substrate; monitor for interactions affecting other medications.
• Lipodystrophy and Metabolic Effects: Monitor for fat redistribution, hyperlipidemia, and insulin resistance during long-term therapy.
• Immune Reconstitution Syndrome: May occur in patients with advanced HIV infection starting therapy.

• Common:
• Central nervous system: dizziness, headache, insomnia, abnormal dreams, somnolence
• Rash (usually mild to moderate)
• Fatigue
• Nausea, vomiting
• Serious (less common):
• Severe rash including Stevens-Johnson syndrome
• Hepatotoxicity
• Psychiatric symptoms: depression, suicidal ideation, psychosis
• Seizures (rare)
• Side effects often occur early during treatment and may improve over time.

• CYP450 Interactions: Efavirenz is both a substrate and inducer of CYP3A4 and CYP2B6, leading to multiple drug interactions.
• Increased Metabolism of: Protease inhibitors, other NNRTIs, benzodiazepines, hormonal contraceptives, warfarin, and certain antiepileptics, reducing their plasma levels and efficacy.
• Drugs Increasing Efavirenz Levels: Concomitant use with CYP3A4 inhibitors (e.g., ketoconazole) may increase efavirenz concentrations and toxicity risk.
• Drug-Food Interactions: High-fat meals increase efavirenz absorption and CNS side effects; recommended to take on an empty stomach.
• Drug-Alcohol: No significant interaction, but alcohol may exacerbate CNS side effects.

• No significant changes in approved indications; remains a first-line NNRTI option in many antiretroviral therapy guidelines.
• Increased emphasis on genotype resistance testing prior to initiation due to resistance potential.
• Updated warnings on CNS effects and recommendations for monitoring mental health.
• Continued recommendations to avoid use in first trimester of pregnancy due to teratogenicity concerns.

• Store at controlled room temperature: 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep container tightly closed.
• Do not freeze.
• Keep out of reach of children.