Schedule H

Oral, Intravenous

• Phenytoin sodium tablets: 50 mg, 100 mg

• Phenytoin sodium chewable tablets: 50 mg

• Phenytoin sodium oral suspension: 125 mg/5 mL (30 mg/mL)

• Phenytoin sodium injection: 50 mg/mL in 2 mL and 5 mL ampoules

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Generalised Tonic-Clonic Seizures and Focal (Partial) Seizures

Oral Loading (when rapid control needed):

Parameter Dose Clinical Notes

Loading dose 15–20 mg/kg Divide into 3 doses given 2 hours apart OR over 2–3 days if GI intolerance

Example (70 kg adult) 1000–1400 mg total loading Monitor for toxicity signs during loading

Oral Maintenance:

Parameter Dose Clinical Notes

Starting dose 3–4 mg/kg/day in 1–2 divided doses Usually 200–300 mg/day initially

Titration Increase by 25–30 mg at 7–14 day intervals Small increments due to nonlinear kinetics

Usual maintenance dose 300–400 mg/day in 1–2 divided doses Guided by serum levels

Maximum dose 600 mg/day Rarely needed; only in refractory cases with level monitoring

Critical Note: Phenytoin exhibits nonlinear (saturation) kinetics — small dose changes can cause disproportionate serum level increases. Target therapeutic range: 10–20 μg/mL (total) or 1–2 μg/mL (free/unbound).

1. Status Epilepticus (IV use — after initial benzodiazepine)

Parameter Dose Clinical Notes

Loading dose 15–20 mg/kg IV Administer at rate ≤50 mg/min in adults

Infusion rate Maximum 50 mg/min Slower in elderly (25 mg/min) and cardiac patients

Dilution Dilute in normal saline only Incompatible with dextrose solutions

Maintenance dose Start 12–24 hours after loading: 100 mg IV/PO every 8 hours Adjust based on levels

Monitoring during IV infusion: Continuous ECG, blood pressure every 5 minutes. Stop infusion if hypotension, bradycardia, or arrhythmia occurs.

1. Seizure Prophylaxis — Neurosurgery / Traumatic Brain Injury

Parameter Dose Clinical Notes

Starting dose 15–18 mg/kg IV loading Given within 24 hours of injury/surgery

Titration Not applicable Fixed short-term regimen

Usual maintenance dose 100 mg IV/PO every 8 hours For 7 days post-injury/surgery

Maximum dose 300 mg/day maintenance

Duration: Limited to 7 days for TBI prophylaxis; long-term continuation only if seizures occur. Beyond 7 days does not reduce late post-traumatic epilepsy.

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

1. Trigeminal Neuralgia (Refractory to carbamazepine) — OFF-LABEL

Parameter Details

Indication Second-line for trigeminal neuralgia when carbamazepine/oxcarbazepine ineffective or not tolerated

Starting dose 100 mg orally twice daily

Titration Increase by 100 mg every 5–7 days based on response

Usual dose 200–300 mg/day in divided doses

Maximum dose 400 mg/day

Duration Long-term; taper if pain-free for extended period

Specialist only Yes — Neurology/Pain medicine

Evidence basis Small trials; Indian specialist clinical practice

1. Cardiac Arrhythmias (Digoxin-induced ventricular arrhythmias) — OFF-LABEL

Parameter Details

Indication Ventricular arrhythmias due to digoxin toxicity

Dose 100 mg IV every 5 minutes until arrhythmia controlled (max 1000 mg)

Duration Acute use only

Specialist only Yes — Cardiology/Critical Care

Evidence basis Historical use; largely replaced by digoxin-specific Fab antibodies

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

1. Generalised Tonic-Clonic and Focal Seizures

Neonates (<1 month) 15–20 mg/kg IV 5 mg/kg/day in 2 divided doses 8 mg/kg/day

Infants (1–12 months) 15–20 mg/kg IV/PO 5–8 mg/kg/day in 2 divided doses 8 mg/kg/day

Children (1–12 years) 15–20 mg/kg IV/PO 4–8 mg/kg/day in 2 divided doses 300 mg/day

Adolescents (>12 years) 15–20 mg/kg (adult protocol) 4–6 mg/kg/day in 1–2 divided doses 400 mg/day

Dosing Notes:

• Starting dose: 5 mg/kg/day in 2 divided doses

• Titration: Increase by 1–2 mg/kg/day every 7–14 days based on seizure control and serum levels

• Usual maintenance dose: 5–8 mg/kg/day (children require higher mg/kg doses than adults due to faster metabolism)

• Maximum dose: 8 mg/kg/day or 300 mg/day (whichever is lower in young children)

Formulation note: Use oral suspension (125 mg/5 mL) for accurate dosing in young children; shake vigorously before each dose to ensure uniform drug distribution.

1. Status Epilepticus (Paediatric IV Loading)

Parameter Dose Comments

Loading dose 15–20 mg/kg IV After initial benzodiazepine failure

Infusion rate ≤1 mg/kg/min (maximum 50 mg/min) Neonates: 0.5 mg/kg/min

Monitoring Continuous ECG, BP every 2–5 minutes Stop if bradycardia or hypotension

Maintenance Begin 12–24 hours after loading As per maintenance table above

Secondary Indications — Paediatrics (Off-label, if any)

Not applicable. No established off-label paediatric indications in routine Indian practice.

Not recommended below 2 weeks of age except under specialist neonatology/neurology supervision with serum level monitoring.

ESRD / Dialysis Total levels may be misleading — monitor free (unbound) phenytoin levels

Haemodialysis Not significantly dialyzed; supplemental dosing generally not needed unless clinically indicated

Peritoneal dialysis No supplementation required

Key point: In uraemia and hypoalbuminaemia, protein binding is reduced → normal total levels may reflect toxic free drug concentrations. Use free phenytoin level (target: 1–2 μg/mL) for accurate assessment.

Monitoring: Free phenytoin levels preferred over total levels in hepatic impairment due to altered protein binding.

• Known hypersensitivity to phenytoin or other hydantoins

• Sinus bradycardia

• Sinoatrial block

• Second-degree and third-degree atrioventricular block

• Adams-Stokes syndrome

• Concurrent use with delavirdine (loss of virologic response)

• IV phenytoin: severe hypotension, decompensated heart failure

• Absence seizures and myoclonic seizures (may worsen seizure control)

• Porphyria (may precipitate acute attack)

• Diabetes mellitus (may impair glycaemic control)

• Hypoalbuminaemia (increased free drug fraction — toxicity risk)

• Elderly patients (altered pharmacokinetics)

• Asian patients with HLA-B*15:02 allele (increased SJS/TEN risk — consider pre-treatment screening if resources permit)

• Patients with pre-existing cardiovascular disease (IV use)

• Psychiatric comorbidities (may aggravate depression, suicidal ideation)

• Chronic alcoholism (enzyme induction, poor compliance)

• Osteoporosis risk with long-term use

Aspect Recommendation

Risk category Teratogenic — Fetal Hydantoin Syndrome (craniofacial abnormalities, digit hypoplasia, growth restriction, cardiac defects)

Use in pregnancy Avoid if possible; use only when no safer alternative and benefit clearly outweighs risk

Preferred alternatives Levetiracetam, lamotrigine (preferred in Indian obstetric/neurology practice for women of childbearing age)

If continued in pregnancy Use lowest effective dose; monotherapy preferred; supplement with high-dose folic acid (5 mg/day) starting preconceptionally

Monitoring Targeted fetal anomaly scan at 18–20 weeks; maternal serum levels (free levels preferred) — levels may decrease in 2nd/3rd trimester requiring dose adjustment

Aspect Recommendation

Compatibility Generally compatible with breastfeeding

Drug levels in milk Low to moderate (milk:plasma ratio ~0.2–0.5)

Preferred alternatives Levetiracetam or lamotrigine if initiating new therapy

Recommendations Continue breastfeeding; use lowest effective maternal dose; monotherapy preferred

Infant monitoring Sedation, poor feeding, irritability, weight gain; rarely methemoglobinaemia in G6PD-deficient infants

Aspect Recommendation

Starting dose 100 mg/day or 2–3 mg/kg/day (lower than standard adult dosing)

Titration Very slow — increments of 25–50 mg every 2–4 weeks

Special risks Increased sensitivity to CNS effects (ataxia, confusion); higher fall/fracture risk; reduced hepatic metabolism; hypoalbuminaemia common

Monitoring Baseline albumin; free phenytoin levels preferred; assess cognitive function regularly

IV use Slower infusion rate (25 mg/min maximum); close cardiac monitoring

Drug Interaction Management

Warfarin Complex interaction: initial displacement increases anticoagulant effect, then CYP induction reduces it Avoid if possible; monitor INR frequently; consider alternative anticoagulant

Oral contraceptives CYP3A4 induction → reduced contraceptive efficacy → contraceptive failure Use high-dose OCP (≥50 μg ethinylestradiol) or non-hormonal methods

Isoniazid CYP2C9 inhibition → markedly increased phenytoin levels and toxicity Reduce phenytoin dose by 30–50%; monitor levels closely

Fluconazole/Voriconazole CYP2C9 inhibition → increased phenytoin toxicity Reduce phenytoin dose; monitor levels

Valproate Displaces phenytoin from protein binding + inhibits metabolism Monitor free phenytoin levels; may need phenytoin dose reduction

Amiodarone CYP2C9 inhibition → increased phenytoin levels Reduce phenytoin dose by 25–33%; monitor levels

Delavirdine Phenytoin reduces delavirdine levels significantly Contraindicated combination

Doxycycline CYP induction → reduced doxycycline efficacy Use alternative antibiotic or increase doxycycline dose

Drug Interaction Management

Rifampicin CYP induction → reduced phenytoin levels May need phenytoin dose increase; monitor levels

Carbamazepine Complex bidirectional induction Monitor levels of both drugs; adjust doses as needed

Phenobarbital Additive CNS depression; variable effect on levels Monitor clinically and with levels

Theophylline CYP induction → reduced theophylline levels Monitor theophylline levels; may need dose increase

Corticosteroids (Dexamethasone, Prednisolone) CYP induction → reduced corticosteroid efficacy May need higher steroid doses; taper carefully

Chloramphenicol CYP inhibition → increased phenytoin levels Monitor for toxicity; reduce phenytoin if needed

Metronidazole CYP inhibition → increased phenytoin levels Monitor phenytoin levels

Ciprofloxacin Variable effects — may increase or decrease phenytoin levels Monitor levels

Digoxin CYP induction → reduced digoxin levels Monitor digoxin levels

Cyclosporine CYP induction → reduced cyclosporine levels Monitor cyclosporine levels; may need dose increase

• Gingival hyperplasia (chronic use — up to 50% of patients)

• Hirsutism and acne

• Coarsening of facial features (chronic use)

• Nystagmus (dose-related — early sign of toxicity)

• Ataxia and dizziness

• Sedation and cognitive slowing

• Nausea, vomiting, constipation

• Maculopapular rash (non-serious)

• Folate deficiency and megaloblastic anaemia

• Peripheral neuropathy (chronic use)

Adverse Effect Clinical Notes

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis Discontinue immediately; higher risk in HLA-B*15:02 positive patients (South Asian populations)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Fever, rash, lymphadenopathy, hepatitis — discontinue and hospitalize

Aplastic anaemia / Agranulocytosis Rare; monitor CBC if unexplained fever, sore throat, bruising

Hepatotoxicity May present as hypersensitivity hepatitis; monitor LFTs

Purple Glove Syndrome Severe distal limb oedema, discolouration, pain after IV extravasation; may require surgical intervention

Cardiac arrhythmias / Hypotension With rapid IV infusion — requires immediate cessation of infusion

Cerebellar atrophy With chronic supratherapeutic levels

Suicidal ideation Class effect with all AEDs — monitor mood

Osteomalacia Chronic use — induces vitamin D metabolism

During IV loading Continuous ECG monitoring, BP every 5 minutes, observation for local phlebitis

After initiation/dose change Serum phenytoin level 5–7 days after dose change (steady state); clinical assessment for toxicity (nystagmus, ataxia)

Long-term monitoring Serum phenytoin level every 6 months or if toxicity/breakthrough seizures; CBC, LFTs every 3–6 months; serum calcium, vitamin D annually; dental examination every 6 months

Special populations Free phenytoin levels in hypoalbuminaemia, renal failure, hepatic impairment, pregnancy

Therapeutic levels: Total phenytoin: 10–20 μg/mL; Free phenytoin: 1–2 μg/mL

• Eptoin (Abbott)

• Dilantin (Pfizer) — limited availability

• Phenytek (Various)

• Phenytoin Sodium (Multiple generic manufacturers)

• Epsolin (Intas)

• Celetoin (Sun Pharma)

• Solphen (Cipla)

Note: Fixed-dose combinations not commonly used for phenytoin.

Government supply: Available free under public health programs and government hospital pharmacies.

1. Nonlinear kinetics are critical — once serum levels exceed 10 μg/mL, small dose increases (even 25–30 mg) can cause disproportionate level rises and toxicity. Always adjust by small increments with level monitoring.

1. Do not switch brands — bioavailability varies significantly between formulations; brand switching can cause breakthrough seizures or toxicity. Document the brand in prescription.

1. Suspension requires vigorous shaking — phenytoin settles in suspension; inadequate mixing causes initial underdosing followed by overdosing as bottle empties.

1. IV phenytoin needs saline only — incompatible with dextrose solutions; crystallization occurs. Use in-line filter if available; flush line with saline before and after.

1. Purple Glove Syndrome prevention — use large-bore IV in large vein; avoid hand/wrist veins; monitor infusion site closely. Consider fosphenytoin if available (reduces this risk).

1. Gingival hyperplasia management — emphasize rigorous oral hygiene from treatment initiation; regular dental follow-up; may partially regress with improved hygiene or drug discontinuation.

1. Pregnancy planning — transition women of childbearing age to levetiracetam or lamotrigine before conception if seizure type permits; if phenytoin must continue, high-dose folic acid (5 mg/day) is essential.

epilepsy; seizure; status epilepticus; antiepileptic; hydantoin; narrow therapeutic index; therapeutic drug monitoring; NLEM India; Schedule H; neurology; TBI prophylaxis

RxIndia v1.0 — 05 May 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• NLEM 2022

• API Textbook of Medicine

• AIIMS Drug Formulary

• ICMR Guidelines on Epilepsy Management

• IAP Guidelines for Paediatric Epilepsy

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (supportive)