Schedule H

Oral

• Tablet: 600 mg

• Capsule: 50 mg, 200 mg

• Oral solution: 30 mg/mL (for paediatric use)

• Fixed-Dose Combinations (FDCs): Tenofovir + Lamivudine + Efavirenz; Tenofovir + Emtricitabine + Efavirenz (multiple strengths)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

HIV-1 Infection (as part of combination antiretroviral therapy)

Adults and Adolescents ≥40 kg:

Component Details

Starting dose 600 mg once daily at bedtime

Titration Not applicable

Usual maintenance dose 600 mg once daily

Maximum dose 600 mg/day

Clinical Notes:

• Administer on an empty stomach or with a light meal (high-fat meals increase absorption and may worsen CNS adverse effects)

• Bedtime dosing recommended to minimise impact of CNS side effects

• Must always be combined with two NRTIs (e.g., Tenofovir + Lamivudine or Tenofovir + Emtricitabine)

• Do not split or reduce dose — risk of subtherapeutic levels and resistance

• Part of preferred first-line ART regimen in NACO guidelines (though being phased out in favour of Dolutegravir-based regimens)

Secondary Indications – Adults (Off-label)

Not applicable. No established off-label indications are routinely used in India beyond approved HIV treatment.

PAEDIATRIC DOSING (Specialist Only)

Primary Indication: HIV-1 Infection

Minimum age: 3 months or ≥3.5 kg body weight

Weight-based dosing (as per NACO/IAP/WHO weight band charts):

Body Weight (kg) Efavirenz Dose (once daily)

3.5–<5 100 mg

5–<7.5 150 mg

7.5–<15 200 mg

15–<20 250 mg

20–<25 300 mg

25–<32.5 350 mg

32.5–<40 400 mg

≥40 600 mg

Component Details

Starting dose As per weight band above

Titration Not routinely required; gradual dose escalation may reduce CNS effects in infants

Usual maintenance dose As per weight band

Maximum dose 600 mg/day

Administration:

• Give once daily at bedtime

• Use oral solution or appropriate capsule strength for children <10 kg

• Capsules may be opened and mixed with soft food if child cannot swallow whole

Safety Monitoring:

• Liver function tests at baseline and periodically

• CNS symptoms (sleep disturbance, vivid dreams, dizziness)

• Growth and developmental parameters

• Rash surveillance (especially first 2–4 weeks)

Secondary Indications – Paediatrics (Off-label)

Not applicable. No established off-label paediatric indications in India.

Age restriction: Not recommended below 3 months of age or <3.5 kg except under specialist supervision in exceptional circumstances.

• No dose adjustment required in renal impairment

• Efavirenz is primarily hepatically metabolised (<1% excreted unchanged in urine)

• Caution: When used in FDC with Tenofovir, assess renal function and adjust Tenofovir component as needed

Haemodialysis/Peritoneal Dialysis: No supplemental dosing required; efavirenz is highly protein-bound and not significantly dialysed

• Mild impairment (Child-Pugh A): Standard dose with close monitoring of liver enzymes

• Moderate impairment (Child-Pugh B): Use with caution; monitor LFTs frequently; consider alternative if possible

• Severe impairment (Child-Pugh C): Avoid use — significantly increased risk of hepatotoxicity and CNS toxicity; specialist only if no alternatives available

• Known hypersensitivity to efavirenz or any component of the formulation

• Severe hepatic impairment (Child-Pugh C)

• Concurrent use with:

• Midazolam or triazolam (risk of prolonged sedation)

• Ergot alkaloids (ergotamine, dihydroergotamine) — risk of severe ergotism

• Pimozide — risk of QT prolongation and arrhythmias

• St. John's Wort — significantly reduces efavirenz levels

• First trimester of pregnancy (unless no alternative available and benefit clearly outweighs risk)

• Pre-existing or history of psychiatric illness (depression, psychosis, suicidal ideation — may be exacerbated)

• History of seizures or epilepsy — may lower seizure threshold

• Hepatitis B or C co-infection — increased risk of hepatotoxicity; monitor closely

• Dyslipidaemia — may worsen lipid profile

• History of severe rash with other NNRTIs

• QT prolongation risk factors

• Women of childbearing potential not using effective contraception

• Fat redistribution/lipodystrophy with long-term use

Aspect Details

Overall safety Avoid in first trimester due to historical concerns regarding neural tube defects; recent data suggests lower risk than previously thought, but caution remains

Preferred alternatives Dolutegravir-based regimen (NACO 2021 preferred first-line ART in pregnancy)

When it may be used May continue in second/third trimester if patient is stable and virologically suppressed on efavirenz-based regimen

Monitoring Detailed fetal anomaly scan (especially neural tube) if exposure in first trimester; maternal LFTs

Note: Women of childbearing potential should use effective contraception. Counsel regarding need to inform prescriber if planning pregnancy.

Aspect Details

Compatibility Compatible with breastfeeding as per NACO and WHO guidelines

Drug levels in milk Low to moderate

Preferred alternatives Dolutegravir-based regimen if initiating new ART

Infant monitoring Rash, feeding adequacy, neurodevelopmental milestones, growth parameters

• Recommended starting dose: 600 mg once daily (standard adult dose)

• Titration: Not applicable

• Extra risks:

• Increased susceptibility to CNS adverse effects (dizziness, confusion, falls)

• Hepatic function decline — assess baseline liver function

• Monitor for drug interactions with commonly used medications in elderly

• Assess renal function if using Tenofovir-containing FDC

Interacting Drug Effect/Mechanism Recommendation

Rifampicin Potent CYP3A4 inducer — reduces efavirenz levels by ~25% Can be used together; standard 600 mg dose usually adequate per NACO; some specialists use 800 mg — monitor viral load closely

Midazolam, Triazolam CYP3A4 inhibition by efavirenz — prolonged sedation Contraindicated

Ergot alkaloids Risk of severe ergot toxicity Contraindicated

Voriconazole Bidirectional interaction — reduced voriconazole efficacy, increased efavirenz toxicity Avoid combination; if unavoidable, increase voriconazole to 400 mg BD and monitor

Pimozide QT prolongation risk Contraindicated

St. John's Wort Induces CYP3A4 — markedly reduces efavirenz levels Contraindicated

Hormonal contraceptives Reduced contraceptive efficacy Advise additional barrier methods or alternative contraception

Mechanism: Efavirenz is a mixed CYP3A4 inducer/inhibitor and CYP2B6 substrate

Interacting Drug Effect/Mechanism Recommendation

Methadone Reduced methadone levels (CYP induction) Monitor for opioid withdrawal; may need methadone dose increase

Phenytoin, Carbamazepine, Phenobarbital Mutual CYP induction — reduced levels of both drugs Monitor anticonvulsant levels and viral load; consider alternative anticonvulsant

Fluconazole Increased efavirenz concentration Monitor for efavirenz toxicity

Ketoconazole, Itraconazole Reduced azole efficacy Monitor antifungal response

Atazanavir (unboosted) Reduced atazanavir levels Only use ritonavir-boosted atazanavir with efavirenz; specialist decision

Warfarin Altered anticoagulant effect Monitor INR closely

Clarithromycin Reduced clarithromycin levels Consider azithromycin as alternative

Statins (simvastatin, atorvastatin) Reduced statin efficacy May need higher statin doses; monitor lipids

• Dizziness and lightheadedness

• Insomnia, abnormal dreams, vivid nightmares

• Difficulty concentrating, impaired attention

• Headache

• Fatigue

• Rash (usually mild, self-limiting)

• Nausea

• Elevated triglycerides and cholesterol

Note: CNS symptoms typically peak in first 1–2 weeks and usually resolve by 2–4 weeks of continued therapy

• Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) — discontinue immediately; requires hospitalisation

• Severe hepatotoxicity — discontinue if transaminases >5× ULN with symptoms or >10× ULN without symptoms

• Severe psychiatric reactions — psychosis, severe depression, suicidal ideation/attempt; requires immediate discontinuation and psychiatric evaluation

• Seizures — rare; discontinue and evaluate

• QT prolongation / Torsades de pointes — rare

• Immune Reconstitution Inflammatory Syndrome (IRIS) — in patients initiating ART

→ All serious adverse effects require immediate discontinuation and specialist consultation

Phase Parameters

Baseline LFTs (ALT, AST, bilirubin), fasting lipid profile, complete blood count, renal function, HIV viral load, CD4 count, psychiatric history screen, pregnancy test (women of childbearing potential), HBV/HCV serology

After initiation (2–4 weeks) LFTs, assess for rash, CNS symptoms, psychiatric symptoms

At 3 months HIV viral load, LFTs, tolerability assessment

Long-term (every 6–12 months) Fasting lipid profile, LFTs, viral load, CD4 count (as per NACO protocol), body fat distribution assessment

• Efavir® 600 mg, 200 mg (Cipla)

• Sustiva® (MSD — limited availability)

• Efavirenz (Hetero, Mylan, Emcure, Aurobindo)

• FDCs:

• Trustiva® (Cipla)

• NACO-supplied generic FDCs via government ART centres

• NLEM status: Yes (included in NLEM)

• NPPA controlled: Price ceiling applicable

• Government supply: Available free at government ART centres under NACO programme

• Bedtime dosing on empty stomach is key to minimising CNS side effects — counsel patients that dizziness and vivid dreams usually resolve within 2–4 weeks

• Never use as monotherapy — always combine with two NRTIs to prevent resistance

• Avoid in first trimester pregnancy — switch to Dolutegravir-based regimen if pregnancy is planned or confirmed early

• Efavirenz is being phased out in new ART initiations in India — Dolutegravir-based regimens are now preferred per NACO 2021 guidelines

• Check for rifampicin co-administration in TB-HIV co-infection — can be used together at standard dose with close viral load monitoring

• Extensive free availability through government ART centres — always explore access for eligible patients

Efavirenz; HIV; NNRTI; antiretroviral; NACO; ART; CNS-toxicity; pregnancy-caution; hepatitis-risk; NLEM India; free-ART-programme

RxIndia v1.1 — 18 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• NACO National Technical Guidelines on Antiretroviral Therapy (2021)

• API Textbook of Medicine (11th Edition) — HIV chapter

• IAP Guidelines for Paediatric HIV Management

• WHO Consolidated Guidelines on HIV (supportive, for weight band dosing)

• AIIMS HIV Management Protocols

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th Edition)

• National List of Essential Medicines (NLEM) 2022, India