Schedule H

Oral

Form Strengths

Capsules 100 mg, 150 mg, 200 mg

Note: Limited availability in India; often requires procurement through specialty pharmacies or tertiary care hospital pharmacies. Not routinely stocked in retail pharmacies.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Life-threatening Ventricular Arrhythmias (Sustained Ventricular Tachycardia, Ventricular Fibrillation Prophylaxis) — Specialist Use Only

Setting: Under cardiology/electrophysiology supervision; usually reserved when amiodarone or other antiarrhythmics are contraindicated, ineffective, or cause intolerable toxicity.

Parameter Dose

Starting dose 200 mg orally every 8 hours (with food)

Titration Increase by 50–100 mg per dose every 2–3 days based on clinical response and ECG monitoring

Usual maintenance dose 200–300 mg orally three times daily (total: 600–900 mg/day)

Maximum dose 1200 mg/day in divided doses

Clinical Notes:

• Administer with food to minimise gastrointestinal adverse effects

• Monitor QRS duration on ECG; widening >25% from baseline suggests toxicity

• Therapeutic drug monitoring (plasma levels 0.5–2.0 mcg/mL) available at select centres but not routinely performed

• Not first-line therapy; typically used as adjunct to or replacement for amiodarone

Secondary Indications — Adults Only (Off-label)

Indication Dose Duration Notes Evidence Basis

Myotonia (non-dystrophic myotonias, myotonia congenita) — OFF-LABEL Starting: 150–200 mg orally once or twice daily; Titration: Increase by 50–100 mg every 3–5 days; Maintenance: 150–200 mg two to three times daily; Maximum: 600–900 mg/day Long-term; reassess periodically Specialist only (neurology); first-line sodium channel blocker for myotonia International RCTs; Indian neurology specialist practice

Neuropathic pain (diabetic neuropathy, inherited sodium channelopathies like erythromelalgia, SCN9A-related pain) — OFF-LABEL Starting: 100–150 mg orally twice daily; Titration: Increase by 50 mg per dose weekly; Maintenance: 150–200 mg two to three times daily; Maximum: 600 mg/day Trial of 4–8 weeks; continue if effective Specialist only (pain medicine/neurology); limited efficacy data; reserve for refractory cases Small RCTs; limited India-specific data

Long QT Syndrome Type 3 (LQT3, SCN5A mutation-positive) — OFF-LABEL Starting: 100–200 mg orally three times daily; Titration: Based on QTc response and tolerability; Maintenance: 200–300 mg three times daily Long-term Specialist only (electrophysiology); shortens QTc in LQT3; used as adjunct to beta-blockers International guidelines; case series; Indian tertiary centre practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

Not applicable — No approved primary indications for mexiletine in paediatric population in India.

Secondary Indications — Paediatric (Off-label)

1. Inherited Arrhythmia Syndromes (LQT3, SCN5A-related Conditions) — OFF-LABEL

Setting: Paediatric cardiology/electrophysiology supervision only; tertiary care centre

Weight/Age Starting Dose Titration Usual Maintenance Maximum Dose

10–20 kg 2–3 mg/kg/day in 2–3 divided doses Increase by 1–2 mg/kg/day every 3–5 days 5–6 mg/kg/day in 2–3 divided doses 10 mg/kg/day

20–40 kg 3–4 mg/kg/day in 2–3 divided doses Increase by 1–2 mg/kg/day every 3–5 days 5–8 mg/kg/day in 2–3 divided doses 12 mg/kg/day

40 kg 100–150 mg two to three times daily Increase by 50 mg per dose every 3–5 days 200 mg two to three times daily 15 mg/kg/day or 900 mg/day (whichever is lower)

Evidence Basis: International paediatric electrophysiology guidelines; case series; limited India-specific data from tertiary centres

1. Non-dystrophic Myotonias in Children — OFF-LABEL

Parameter Dose

Starting dose 2–3 mg/kg/day orally in 2–3 divided doses

Titration Increase by 1–2 mg/kg/day every 5–7 days based on clinical response

Usual maintenance dose 4–6 mg/kg/day in 2–3 divided doses

Maximum dose 8 mg/kg/day

Evidence Basis: Paediatric neurology specialist practice; case reports

Safety Monitoring (All Paediatric Use):

• Baseline and serial ECG (QRS duration, QTc interval)

• Liver function tests at baseline and periodically

• Monitor for CNS symptoms (tremor, dizziness, irritability)

• Plasma drug level monitoring if available

Age Restriction Statement:

• Not recommended in children <1 year of age

• Use in children 1–6 years only under paediatric electrophysiology/neurology specialist supervision in tertiary centres with access to ECG monitoring

Note: Mexiletine is extensively hepatically metabolised (CYP2D6, CYP1A2); hepatic dysfunction significantly prolongs half-life and increases toxicity risk.

• Second-degree (Mobitz type II) or third-degree AV block without functioning pacemaker

• Cardiogenic shock

• Known hypersensitivity to mexiletine or structurally related local anaesthetics (e.g., lidocaine)

• Severe hepatic impairment

• Acute porphyria

• Pre-existing first-degree AV block or intraventricular conduction delay (risk of progression)

• Sinus node dysfunction

• Epilepsy or conditions lowering seizure threshold (mexiletine can provoke seizures at high doses)

• Hypotension or heart failure (negative inotropic effect, though minimal)

• Concurrent use with other Class I antiarrhythmics (additive proarrhythmic risk)

• CYP2D6 poor metabolisers (higher drug levels, increased toxicity risk)

• Electrolyte disturbances (hypokalaemia, hypomagnesaemia — correct before initiation)

• Elderly patients (increased sensitivity to CNS adverse effects)

Parameter Detail

Risk Category Category C (no formal India classification); animal studies show embryotoxicity at high doses; limited human data

Overall Safety Insufficient human data to establish safety; use only if maternal benefit clearly outweighs fetal risk

Preferred Alternatives Beta-blockers (metoprolol, propranolol) for most arrhythmias in pregnancy; sotalol or flecainide under specialist guidance for specific indications

When May Be Used Life-threatening ventricular arrhythmias unresponsive to safer alternatives; cardiology and maternal-fetal medicine input essential

Monitoring Maternal ECG; fetal heart rate monitoring; serial fetal growth assessment

Parameter Detail

Compatibility Likely compatible with breastfeeding; exercise caution

Expected Milk Levels Low; mexiletine is excreted in breast milk in low concentrations (milk:plasma ratio approximately 1.0–1.4, but absolute amounts are small)

Preferred Alternatives If arrhythmia treatment needed, beta-blockers (metoprolol, propranolol) are preferred in breastfeeding

Infant Monitoring Monitor infant for irritability, poor feeding, excessive sedation, or unusual drowsiness; observe for any cardiac symptoms

Parameter Recommendation

Starting dose 100–150 mg orally twice daily (lower than standard adult dose)

Titration Slower titration; increase dose every 5–7 days rather than 2–3 days

Special Risks Increased susceptibility to CNS adverse effects (tremor, dizziness, confusion, ataxia); falls risk; age-related decline in hepatic and renal function may prolong half-life

Monitoring More frequent ECG monitoring; assess for neurological symptoms at each visit; check renal and hepatic function periodically

Interacting Drug/Class Effect Management

Amiodarone Additive proarrhythmic effect; increased risk of bradycardia and conduction abnormalities Avoid combination if possible; if essential, close ECG monitoring; reduce mexiletine dose

Flecainide, propafenone, other Class I antiarrhythmics Additive sodium channel blockade; significantly increased proarrhythmic and conduction abnormality risk Avoid concurrent use; combination only under specialist supervision with intensive ECG monitoring

Lidocaine (systemic) Additive CNS and cardiac toxicity (structurally similar drugs) Avoid combination

Strong CYP1A2 inhibitors (ciprofloxacin, fluvoxamine) Markedly increased mexiletine plasma levels (CYP1A2 inhibition) Avoid fluvoxamine; if ciprofloxacin essential, reduce mexiletine dose by 25–50% and monitor closely

Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) Increased mexiletine levels Monitor for toxicity; may need dose reduction

Phenytoin Additive CNS toxicity; phenytoin also induces mexiletine metabolism Monitor for CNS effects; mexiletine dose may need adjustment

Theophylline Mexiletine inhibits theophylline metabolism; increased theophylline toxicity risk Monitor theophylline levels; reduce theophylline dose if combination necessary

Interacting Drug/Class Effect Management

Beta-blockers Combined effect on cardiac conduction; may enhance bradycardia or AV block Can be used together (often beneficial combination); monitor heart rate and PR interval

Rifampicin Potent CYP1A2 inducer; significantly reduces mexiletine levels May require substantial mexiletine dose increase; monitor clinical response

Warfarin Mexiletine may alter warfarin metabolism; unpredictable effect on INR Monitor INR more frequently when initiating or adjusting mexiletine

Omeprazole, cimetidine May modestly increase mexiletine levels Monitor for toxicity; usually no dose adjustment needed

Tricyclic antidepressants Additive sodium channel effects; potential for QRS prolongation ECG monitoring; use combination with caution

Smoking (tobacco) Induces CYP1A2; may reduce mexiletine levels Smokers may require higher doses; counsel on smoking cessation

Caffeine Mexiletine inhibits caffeine metabolism Advise limiting caffeine intake; monitor for caffeine-related side effects

• Nausea, vomiting, dyspepsia (most common; reduced by taking with food)

• Dizziness, lightheadedness

• Tremor (dose-related)

• Ataxia, unsteady gait

• Nervousness, insomnia

• Paraesthesias

• Headache

• Visual disturbances (blurred vision)

Adverse Effect Clinical Notes

Ventricular proarrhythmia (new or worsened arrhythmia, torsades de pointes) Requires immediate discontinuation; hospitalisation for monitoring

Seizures More likely at high doses, in hepatic impairment, or in patients with low seizure threshold; discontinue immediately

Severe bradycardia or high-grade AV block May require temporary pacing; discontinue drug

Hepatotoxicity Rare; monitor LFTs; discontinue if significant transaminase elevation

Agranulocytosis Very rare; monitor CBC if unexplained infection or fever

Drug-induced lupus-like syndrome Rare; discontinue if symptoms develop

Stevens-Johnson syndrome / Toxic epidermal necrolysis Extremely rare; discontinue immediately if mucocutaneous lesions appear

After initiation/dose change ECG within 1–2 weeks of each dose adjustment; clinical assessment for CNS side effects

Long-term ECG every 3–6 months; LFTs every 6 months; periodic CBC; reassess clinical efficacy and tolerability

If toxicity suspected Plasma mexiletine level if available (therapeutic range: 0.5–2.0 mcg/mL); ECG for QRS widening

Brand Name Manufacturer Notes

Mexitil® Boehringer Ingelheim (imported) Limited availability

Mexiletine capsules Various (generic imports) Procurement through tertiary hospital pharmacies or specialty importers

Note: Mexiletine has very limited retail availability in India. Most procurement is through hospital pharmacy channels at tertiary cardiac centres or via import on patient-specific basis.

Note: Not included in NLEM 2022; not under NPPA price control. Prices highly variable depending on import source and availability. Government supply not routinely available.

Reserve for specialist use only — Mexiletine is not a first-line antiarrhythmic; typically used when amiodarone is contraindicated, ineffective, or causes intolerable toxicity (pulmonary, thyroid, hepatic)

1. Always administer with food — Gastrointestinal intolerance (nausea, vomiting) is the most common reason for discontinuation; taking with meals significantly improves tolerability

1. Monitor QRS duration closely — QRS widening >25% from baseline indicates sodium channel toxicity and warrants dose reduction or discontinuation

1. Combination with beta-blocker is often beneficial — In ventricular arrhythmias, mexiletine plus beta-blocker may provide synergistic benefit while reducing proarrhythmic risk

1. Particularly useful in LQT3 — Unlike most antiarrhythmics, mexiletine shortens QTc in SCN5A mutation-positive Long QT Syndrome Type 3; valuable adjunct to beta-blockers in this specific population

1. Procurement challenges in India — Counsel patients and families about limited availability; ensure supply chain established before discharge; consider alternative agents if reliable procurement not possible

mexiletine; antiarrhythmic; class IB; sodium channel blocker; ventricular tachycardia; LQT3; myotonia; specialist use; hepatic metabolism; limited availability India; Schedule H

RxIndia v1.0 — 10 Jan 2025

• CDSCO drug database

• Indian Pharmacopoeia (availability verification)

• National Formulary of India

• API Textbook of Medicine

• Harrison's Principles of Internal Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• AIIMS Cardiovascular Drug Protocols

• Cardiological Society of India practice standards (tertiary centre use)

• International RCTs for off-label indications (myotonia, neuropathic pain — clearly marked off-label)