Schedule H1

Oral

Formulation Strength

Tablets 25 mg, 50 mg, 100 mg, 200 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Treatment-Resistant Schizophrenia (TRS)

(Reserved for patients with inadequate response to at least two antipsychotics including one atypical, at adequate doses and duration)

Parameter Recommendation

Starting dose 12.5 mg once or twice daily on Day 1

Titration Increase by 25–50 mg/day as tolerated; target therapeutic dose over 2–3 weeks

Usual maintenance dose 300–450 mg/day in divided doses

Maximum dose 900 mg/day (exceptional cases only; specialist supervision mandatory)

Clinical Notes:

• Mandatory ANC monitoring due to risk of agranulocytosis

• Clinical response typically observed within 2–6 weeks of reaching therapeutic dose

• Administer in divided doses during initiation to minimise hypotension and sedation

• Re-titration required if treatment interrupted for ≥48 hours (restart from 12.5 mg)

• Seizure risk increases significantly at doses >600 mg/day

• Prescribe only in settings with capacity for mandatory haematological monitoring

Secondary Indications — Adults Only (Off-label, if any)

Indication Dose Duration Notes Evidence

Parkinson's disease psychosis Starting: 6.25–12.5 mg at night; Titration: Increase by 6.25–12.5 mg every 3–5 days; Maintenance: 25–50 mg/day Ongoing with regular reassessment OFF-LABEL; Specialist only (movement disorder specialist/neuropsychiatrist) Indian movement disorder specialist practice; small RCTs supportive

Recurrent suicidal behaviour in schizophrenia Same as TRS dosing Long-term OFF-LABEL; Specialist only; Use where suicidality persists despite optimised treatment International RCTs (InterSePT trial); cautious use in Indian practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Treatment-Resistant Schizophrenia — Adolescents ≥15 years

Parameter Recommendation

Starting dose 12.5 mg once daily

Titration Increase by 25 mg/day every 2–3 days based on tolerability (individualised)

Usual maintenance dose 200–300 mg/day in divided doses

Maximum dose 600 mg/day

Clinical Notes:

• Use only under tertiary psychiatric care with paediatric psychiatrist supervision

• Mandatory weekly ANC monitoring as per adult protocol

• Enhanced monitoring for sedation, seizures, metabolic effects, and weight gain

Secondary Indications — Paediatric Doses (Off-label, if any)

Not applicable.

Safety Statement:

• Not recommended below 15 years of age except in research protocols or under specialist supervision at tertiary centres

• Safety and efficacy not established in children <15 years in Indian context

• Risk of metabolic syndrome, seizures, and agranulocytosis same as adults

Severe impairment (eGFR <30) Use with caution; slower titration; monitor for adverse effects

Haemodialysis Avoid unless benefit outweighs risk; clozapine is not dialyzable

• History of clozapine-induced agranulocytosis or severe granulocytopenia

• Baseline ANC <1500/mm³ (or <1000/mm³ in patients with benign ethnic neutropenia)

• Uncontrolled epilepsy

• Paralytic ileus or history of toxic megacolon

• Severe CNS depression or coma

• Severe cardiac disease (active myocarditis, cardiomyopathy, severe heart failure)

• Known hypersensitivity to clozapine or any excipient

• Concurrent use with drugs that cause agranulocytosis (e.g., carbamazepine, co-trimoxazole for prolonged use)

• Inability to comply with mandatory blood monitoring

• History of seizure disorder — dose-dependent risk; prophylactic anticonvulsant may be needed at higher doses

• Cardiovascular disease — risk of myocarditis and cardiomyopathy, particularly during first 8 weeks

• Elderly patients with dementia-related psychosis — increased risk of stroke and mortality (black box warning)

• Constipation — risk of progression to serious paralytic ileus; proactive bowel management essential

• Concurrent benzodiazepine use — increased risk of respiratory depression and cardiovascular collapse

• Smoking status — tobacco smoking induces CYP1A2, significantly affecting clozapine levels

• Diabetes mellitus or risk factors for metabolic syndrome

• Orthostatic hypotension risk — especially during initiation

• Rapid dose reduction or abrupt discontinuation — risk of rebound psychosis and cholinergic rebound symptoms

• Prostatic hypertrophy or urinary retention

Parameter Recommendation

Risk category Limited human data; potential risk of neonatal withdrawal symptoms and extrapyramidal effects

Preferred alternatives Risperidone, olanzapine, or haloperidol (more safety data available in Indian obstetric practice)

When to use Only if patient already stable on clozapine and switching poses greater risk; specialist psychiatric input mandatory

Monitoring Fetal growth (serial ultrasound); neonatal monitoring for motor abnormalities, sedation, feeding difficulties, and withdrawal symptoms post-delivery

Parameter Recommendation

Compatibility Not recommended; significant excretion in breast milk

Preferred alternatives Risperidone or quetiapine (if antipsychotic required); consider alternatives to breastfeeding if clozapine essential

Drug levels in milk Moderate to high (variable; infant exposure potentially significant)

Infant monitoring Sedation, poor feeding, weight gain, neutropenia (theoretical risk)

Parameter Recommendation

Starting dose 12.5 mg once daily

Titration Very slow — increase by 12.5 mg every 3–5 days

Usual maintenance dose Lower than younger adults; typically 100–200 mg/day

Special risks Orthostatic hypotension (falls risk), excessive sedation, confusion, anticholinergic effects (constipation, urinary retention), metabolic effects

Precautions Avoid in dementia-associated psychosis — increased mortality; enhanced cardiovascular and metabolic monitoring

Interacting Drug/Class Effect Mechanism Management

Carbamazepine Additive risk of agranulocytosis; reduced clozapine levels Bone marrow suppression + CYP3A4 induction Contraindicated

Other myelosuppressive agents (co-trimoxazole, chloramphenicol, sulfonamides long-term) Increased agranulocytosis risk Additive bone marrow toxicity Avoid combination

Ciprofloxacin Marked increase in clozapine levels (toxicity risk) Potent CYP1A2 inhibition Avoid or reduce clozapine dose by 50%; use alternative antibiotic

Fluvoxamine Marked increase in clozapine levels (3–10 fold) Potent CYP1A2 inhibition Avoid combination; if essential, reduce clozapine dose significantly

Tobacco smoking Reduced clozapine levels (30–50% lower in smokers) CYP1A2 induction by polycyclic aromatic hydrocarbons Adjust dose based on smoking status; abrupt smoking cessation can cause toxicity

Benzodiazepines (especially during initiation) Hypotension, respiratory depression, cardiovascular collapse Additive CNS and cardiovascular depression Avoid during initiation phase; if required later, use lowest doses with monitoring

QT-prolonging drugs (haloperidol, amiodarone, fluoroquinolones) Additive QT prolongation; risk of arrhythmias Pharmacodynamic interaction Monitor ECG; avoid combination if possible

Interacting Drug/Class Effect Management

Valproate May increase clozapine levels slightly; additive sedation; theoretical increased seizure threshold benefit Monitor for sedation; may be used adjunctively

SSRIs (sertraline, escitalopram — except fluvoxamine) Mild increase in clozapine levels Monitor for adverse effects; generally safe

Rifampicin Significantly reduced clozapine levels CYP induction — may need dose increase; avoid if possible

Phenytoin, phenobarbital Reduced clozapine levels CYP induction — monitor clinical response

Anticholinergic drugs (trihexyphenidyl, antihistamines) Additive anticholinergic effects (constipation, urinary retention, cognitive impairment) Monitor bowel function; avoid polypharmacy

Caffeine (high intake) Increased clozapine levels CYP1A2 inhibition — significant changes in caffeine intake can alter clozapine levels

Erythromycin, clarithromycin Moderate increase in clozapine levels CYP3A4 inhibition — monitor for adverse effects

Lithium Increased risk of NMS and seizures Use with caution; monitor closely

• Sedation/drowsiness (very common, especially initially)

• Sialorrhoea/hypersalivation (especially nocturnal — 30–80%)

• Constipation (common; potentially serious)

• Tachycardia

• Weight gain (significant; dose-related)

• Orthostatic hypotension (especially during titration)

• Dizziness

• Dyslipidaemia

• Tremor

• Fever (transient; first 3 weeks — distinguish from infection/myocarditis)

• Nausea

Adverse Effect Action Required

Agranulocytosis (ANC <500/mm³) Discontinue immediately; hospitalisation; do not rechallenge ever

Neutropenia (ANC 500–1500/mm³) Discontinue; close monitoring; rechallenge possible under specialist guidance if ANC recovers

Myocarditis / Cardiomyopathy Discontinue; cardiology evaluation; monitor troponin, CRP, ECG, echocardiogram; typically occurs within first 8 weeks

Seizures Dose-dependent (risk >600 mg/day); consider dose reduction; add anticonvulsant if continuation essential

Severe constipation / Paralytic ileus May be life-threatening; discontinue if ileus develops; proactive bowel management mandatory

Neuroleptic Malignant Syndrome (NMS) Discontinue immediately; supportive care; hospitalisation

Diabetic ketoacidosis / Severe hyperglycaemia May occur with or without prior diabetes; discontinue or manage aggressively

Pulmonary embolism / Deep vein thrombosis Higher risk during clozapine treatment; maintain mobility

QTc prolongation / Torsades de pointes Rare; discontinue if significant prolongation

Phase Parameters

Baseline CBC with ANC; ECG; troponin; CRP; LFTs; RFTs; fasting blood glucose; fasting lipid profile; weight; BMI; blood pressure; waist circumference

After initiation / dose change ANC: Weekly for first 18 weeks → Fortnightly for next 1 year → Monthly thereafter (lifelong); ECG and troponin: Repeat if any cardiac symptoms or during first 8 weeks; Temperature monitoring daily for first 3 weeks; Blood pressure and heart rate during titration

Long-term Fasting glucose: Every 3–4 months for first year, then annually; Lipid profile: Every 6 months; Weight/BMI: Monthly for first 3 months, then quarterly; LFTs: Every 6 months; Annual echocardiogram if cardiac risk factors; Regular assessment for constipation (may need laxative prophylaxis)

Sizopin Sun Pharma Tablets 25 mg, 50 mg, 100 mg, 200 mg

Clozaril (Limited availability) Tablets 25 mg, 100 mg

Clozapine (Generic) Various Tablets 25 mg, 50 mg, 100 mg

Lozapin Intas Tablets 25 mg, 50 mg, 100 mg

Zapiz — Tablets 25 mg, 100 mg

Note: Availability may vary by region; ensure brand is registered with CDSCO

Notes:

• Included in NLEM 2022 — price capped for scheduled formulations

• Available in government mental health programs (District Mental Health Programme)

• Cost of mandatory blood monitoring adds to overall treatment expense

1. Start low, go slow: Initiate at 12.5 mg and titrate gradually to minimise hypotension, sedation, and seizure risk — rapid titration increases adverse event rates

1. ANC monitoring is non-negotiable: Without infrastructure for regular blood monitoring, clozapine cannot be safely prescribed; ensure patient compliance with blood tests

1. Smoking status is critical: Smokers require higher doses; sudden smoking cessation (e.g., hospitalisation) can precipitate clozapine toxicity — reduce dose by 30–50% if patient stops smoking

1. Never rechallenge after agranulocytosis: Previous clozapine-induced agranulocytosis is a permanent contraindication; maintain documentation

1. Sialorrhoea management: Nocturnal hypersalivation is distressing but manageable — consider hyoscine patch, glycopyrrolate, or low-dose clonidine; placing towel on pillow may help

1. Constipation can kill: Proactive bowel care (dietary fibre, adequate hydration, laxatives if needed) is essential — clozapine-induced ileus has caused deaths

clozapine; treatment-resistant schizophrenia; atypical antipsychotic; agranulocytosis; ANC monitoring; myocarditis; seizure risk; metabolic syndrome; Schedule H1; NLEM India; psychiatry

RxIndia v1.0 — 10 Jun 2025

• CDSCO (Central Drugs Standard Control Organisation) Product Inserts

• Indian Pharmacopoeia / National Formulary of India (IP/NFI)

• NLEM 2022

• API Textbook of Medicine

• AIIMS Psychiatry Prescribing Protocols

• Indian Psychiatric Society Treatment Guidelines

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• RCT/Meta-analysis (for Parkinson's disease psychosis — off-label use)