Schedule H

Oral

• Tablet: 0.5 mg, 1 mg

• Oral solution: 0.05 mg/mL (limited availability)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Chronic Hepatitis B Infection – Nucleoside-Naïve Adults

For patients with compensated liver disease and evidence of active viral replication with elevated ALT or histological evidence of active disease

Component Details

Starting dose 0.5 mg once daily

Titration Not applicable

Usual maintenance dose 0.5 mg once daily

Maximum dose 0.5 mg once daily

Clinical Notes:

• Administer on an empty stomach (at least 2 hours before or 2 hours after a meal)

• Duration: Long-term; continue until treatment endpoints achieved (HBeAg seroconversion with undetectable HBV DNA for at least 12 months in HBeAg-positive patients; indefinite in cirrhosis)

• Monitor HBV DNA every 3–6 months

1. Chronic Hepatitis B Infection – Lamivudine-Refractory or Resistant Adults

For patients with documented lamivudine resistance (rtM204V/I ± rtL180M mutations)

Component Details

Starting dose 1 mg once daily

Titration Not applicable

Usual maintenance dose 1 mg once daily

Maximum dose 1 mg once daily

Clinical Notes:

• Confirm lamivudine resistance by genotypic testing before dose escalation

• Higher dose required due to reduced susceptibility in lamivudine-resistant HBV

• Administer on empty stomach

1. Chronic Hepatitis B Infection – Decompensated Cirrhosis (Child-Pugh B or C)

Component Details

Starting dose 1 mg once daily

Titration Not applicable

Usual maintenance dose 1 mg once daily

Maximum dose 1 mg once daily

Clinical Notes:

• Indefinite therapy required; do not discontinue

• Monitor closely for lactic acidosis, especially with hepatic decompensation

• Coordinate care with hepatology specialist

Secondary Indications – Adults (Off-label)

Not applicable. Entecavir is not recommended for conditions other than chronic hepatitis B in India. Not first-line for HIV-HBV co-infection — tenofovir-based regimens preferred per NACO guidelines.

PAEDIATRIC DOSING (Specialist Only)

Primary Indication: Chronic Hepatitis B Infection

Minimum age: 2 years

Eligibility: Children with documented active HBV replication (elevated HBV DNA) and evidence of liver disease

Weight-based dosing (nucleoside-naïve patients):

10–11 kg 0.15 mg Oral solution

11–14 kg 0.2 mg Oral solution

14–17 kg 0.25 mg Oral solution

17–20 kg 0.3 mg Oral solution

20–23 kg 0.35 mg Oral solution

23–26 kg 0.4 mg Oral solution

26–30 kg 0.45 mg Oral solution

30 kg 0.5 mg Tablet or oral solution

Component Details

Starting dose Weight-based as per table above

Titration Not applicable

Usual maintenance dose As per weight band

Maximum dose 0.5 mg once daily

Administration:

• Give on empty stomach (2 hours before or after meals)

• Oral solution preferred for accurate dosing in lower weight bands

• Tablets may be used in children >30 kg who can swallow whole

Safety Monitoring:

• HBV DNA and ALT every 3–6 months

• Serum creatinine at baseline and periodically

• Growth parameters (height, weight)

• Monitor for signs of lactic acidosis

Secondary Indications – Paediatrics (Off-label)

Not applicable.

Age restriction: Not recommended below 2 years of age. Use in children requires specialist paediatric hepatology/gastroenterology supervision.

Required — entecavir is primarily renally excreted

For Nucleoside-Naïve Patients (usual dose 0.5 mg):

Creatinine Clearance (mL/min) Dose Frequency

≥50 0.5 mg Once daily

30–49 0.25 mg Once daily OR 0.5 mg every 48 hours

10–29 0.15 mg Once daily OR 0.5 mg every 72 hours

<10 or on haemodialysis 0.05 mg Once daily OR 0.5 mg every 5–7 days

For Lamivudine-Refractory/Decompensated Cirrhosis (usual dose 1 mg):

Creatinine Clearance (mL/min) Dose Frequency

≥50 1 mg Once daily

30–49 0.5 mg Once daily OR 1 mg every 48 hours

10–29 0.3 mg Once daily OR 1 mg every 72 hours

<10 or on haemodialysis 0.1 mg Once daily OR 1 mg every 5–7 days

Haemodialysis: Administer dose after dialysis session on dialysis days

Note: Oral solution required for intermediate doses not achievable with tablets

• Mild impairment (Child-Pugh A): No dose adjustment required

• Moderate impairment (Child-Pugh B): No dose adjustment; use 1 mg daily dose; monitor closely for efficacy and adverse effects

• Severe impairment (Child-Pugh C): Use 1 mg daily dose; increased risk of lactic acidosis; close specialist monitoring essential; do not discontinue therapy

• Known hypersensitivity to entecavir or any component of the formulation

• HIV co-infection in patients not receiving fully suppressive antiretroviral therapy (risk of selecting HIV resistance mutations, particularly M184V)

• HIV co-infection: Must confirm patient is on fully suppressive ART before initiating entecavir; alternatively, use tenofovir-based regimen active against both HIV and HBV

• Prior lamivudine or telbivudine exposure: Increased risk of entecavir resistance; consider genotypic testing

• Decompensated liver disease: Monitor for lactic acidosis and hepatic decompensation

• Chronic kidney disease: Requires dose adjustment; monitor renal function

• Risk of severe acute HBV exacerbation upon discontinuation: Counsel patient; monitor LFTs for several months after stopping therapy

• Concurrent use of nephrotoxic agents

Aspect Details

Overall safety Limited human data; animal studies show no teratogenicity at therapeutic doses

Preferred alternatives Tenofovir disoproxil fumarate (TDF) is preferred for HBV treatment in pregnancy per ICMR and WHO guidelines

When entecavir may be used Only if tenofovir is contraindicated or not tolerated; specialist decision

Monitoring Liver function tests monthly; HBV DNA; fetal growth and anomaly scans

Aspect Details

Compatibility Unknown; likely excreted in breast milk based on animal data

Preferred alternatives Tenofovir preferred if antiviral therapy required during breastfeeding

Drug levels in milk Unknown in humans

Infant monitoring Gastrointestinal disturbances, feeding adequacy, weight gain

• Recommended starting dose: Same as younger adults; adjust for renal function

• Titration: Not applicable; however, assess renal function before each dose adjustment

• Extra risks:

• Age-related decline in renal function — dose adjustment often required

• Higher susceptibility to lactic acidosis if hepatic reserve is compromised

• Monitor for drug accumulation

Interacting Drug Effect/Mechanism Recommendation

Antiretroviral drugs (in HIV co-infection without full ART) Risk of selecting HIV resistance (M184V mutation) if entecavir used without suppressive ART Avoid entecavir monotherapy in HIV-HBV co-infection; use tenofovir-based regimen instead

Nephrotoxic drugs (aminoglycosides, amphotericin B, cidofovir, foscarnet) Additive nephrotoxicity; increased entecavir accumulation Avoid combination or monitor renal function very closely

Interacting Drug Effect/Mechanism Recommendation

Lamivudine Cross-resistance possible; no additive benefit Use entecavir monotherapy; lamivudine resistance may reduce entecavir efficacy

NSAIDs (chronic use) May reduce renal function Monitor renal function; avoid prolonged NSAID use

Loop diuretics (furosemide) May affect renal clearance Monitor renal function and entecavir efficacy

Adefovir Sequential use may select for resistance mutations Specialist decision; monitor HBV genotype

• Headache

• Fatigue

• Dizziness

• Nausea

• Diarrhoea

• Upper abdominal pain

• Transient ALT elevation (hepatitis flare on initiation)

• Insomnia

• Lactic acidosis with hepatic steatosis — rare but potentially fatal; more common in decompensated cirrhosis; discontinue immediately if suspected

• Severe acute exacerbation of hepatitis B — upon discontinuation; may be life-threatening; monitor LFTs for several months after stopping

• Hepatic decompensation — in patients with advanced cirrhosis

• Peripheral neuropathy — rare

→ Serious adverse effects require immediate discontinuation and specialist consultation

Phase Parameters

Baseline HBV DNA (quantitative PCR), HBeAg/anti-HBe status, LFTs (ALT, AST, bilirubin), serum creatinine/eGFR, HIV serology (mandatory before initiation), complete blood count, prothrombin time (if cirrhosis suspected)

After initiation (12 weeks) HBV DNA, ALT, serum creatinine

Long-term (every 3–6 months) HBV DNA, LFTs, renal function; HBeAg/anti-HBe annually (in HBeAg-positive non-cirrhotic patients)

After discontinuation LFTs monthly for at least 6 months; monitor for hepatitis flare

• Baraclude® (Bristol-Myers Squibb)

• Entavir® (Cipla)

• Entehep® (Zydus Cadila)

• Enteca® (Dr. Reddy's)

• X-Vir® (Natco)

• Cronivir® (Ranbaxy/Sun Pharma)

• Entaliv® (Alkem)

• NLEM status: Yes (0.5 mg and 1 mg tablets included in NLEM 2022)

• NPPA controlled: Price ceiling applicable

• Government supply: Available under National Viral Hepatitis Control Programme (NVHCP) at designated centres

• Always check HIV status before initiating — entecavir monotherapy in undiagnosed HIV-HBV co-infection can select for HIV resistance (M184V); use tenofovir-based regimen if HIV co-infected

• Empty stomach dosing is essential — food significantly reduces absorption; advise patients to take at least 2 hours before or after meals

• Do not discontinue abruptly — risk of severe hepatitis flare; if discontinuation necessary, monitor LFTs monthly for at least 6 months

• Preferred over lamivudine for long-term HBV suppression due to higher genetic barrier to resistance

• Tenofovir preferred in pregnancy and HIV-HBV co-infection — entecavir is second-line in these settings

• Not indicated for acute hepatitis B — only for chronic HBV infection with evidence of active replication

Entecavir; hepatitis B; HBV; antiviral; nucleoside analogue; cirrhosis; NLEM India; renal-dose-adjust; HIV-caution; NVHCP

RxIndia v1.1 — 18 Jan 2025

• CDSCO approved prescribing information (Baraclude, Entavir)

• Indian Pharmacopoeia 2018

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

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

• ICMR National Guidelines for Diagnosis and Management of Viral Hepatitis

• AIIMS Viral Hepatitis Management Protocol

• National Viral Hepatitis Control Programme (NVHCP) Operational Guidelines

• WHO Guidelines on Hepatitis B (supportive)

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