Formulary
Phenytoin: Uses, Dosing, Side Effects and Indian Brand Names
Phenytoin is a first-generation antiepileptic that blocks voltage-gated sodium channels with use-dependent kinetics. It is a second-line agent in status epilepticus and exhibits zero-order pharmacokinetics at therapeutic doses.
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Phenytoin: Uses, Dosing, Side Effects and Indian Brand Names
Phenytoin is a first-generation antiepileptic that blocks voltage-gated sodium channels with use-dependent kinetics. It is a second-line agent in status epilepticus and exhibits zero-order pharmacokinetics at therapeutic doses.
NEET PG High-Yield: Phenytoin follows zero-order kinetics at therapeutic doses -- the most frequently tested pharmacokinetic concept. Gingival hyperplasia is the most asked side effect. Remember: it is a CYP inducer (like carbamazepine, rifampicin, phenobarbital -- the 'P450 inducers' mnemonic). Fetal hydantoin syndrome and HLA-B*15:02 association with SJS/TEN are high-yield.
Clinical overview
Phenytoin is one of the oldest and most extensively studied antiepileptic drugs, introduced in 1938 by Merritt and Putnam. It remains widely used in India for generalised tonic-clonic seizures and focal (partial) seizures, and is a critical second-line agent in status epilepticus after initial benzodiazepine therapy. Phenytoin exhibits zero-order (saturation) kinetics at therapeutic doses -- a small increase in dose can produce a disproportionately large rise in plasma concentration, making toxicity a constant clinical concern. The therapeutic range is narrow (10-20 mcg/mL), and plasma level monitoring is essential. It is highly protein-bound (approximately 90% to albumin), and conditions that lower albumin (nephrotic syndrome, hepatic failure, pregnancy) increase the free fraction, raising toxicity risk even when total levels appear normal. Phenytoin is a potent inducer of CYP enzymes (CYP3A4, CYP2C9), leading to numerous drug interactions including reduced efficacy of oral contraceptives, warfarin, and dexamethasone. Its well-known cosmetic side effects -- gingival hyperplasia, hirsutism, and coarsening of facial features -- make it less preferred in young women. Fosphenytoin, a water-soluble prodrug, is preferred for IV loading as it avoids the propylene glycol vehicle that causes hypotension and cardiac arrhythmias with rapid IV phenytoin infusion.
Pharmacological class
Phenytoin belongs to the Hydantoin anticonvulsant (antiepileptic drug) class. Phenytoin blocks voltage-gated sodium channels in their inactivated state, prolonging the inactivated state and reducing the ability of neurons to fire at high frequency. This use-dependent blockade selectively suppresses abnormal repetitive firing without affecting normal neuronal activity. It also has minor effects on calcium channels and may modulate GABA metabolism at high concentrations.
Indian brand names and formulations
Available as: Eptoin (Abbott India), Dilantin (Pfizer), Phenytoin Sodium (Various generic manufacturers), Fosphen (Sun Pharma) [fosphenytoin].
Tablets/Capsules (50 mg, 100 mg, 300 mg extended-release), Oral suspension (30 mg/5 mL), Injection (50 mg/mL in 2 mL and 5 mL ampoules), Fosphenytoin injection (75 mg PE/mL)
Regulatory status
Phenytoin is classified under Schedule H in India under the Drugs and Cosmetics Act, 1940. Schedule H drug. Must be dispensed on prescription only. Included in the NLEM 2022. Requires regular therapeutic drug monitoring due to narrow therapeutic index.
Indications
- Generalised tonic-clonic (grand mal) seizures
- Focal (partial) seizures with or without secondary generalisation
- Status epilepticus (second-line, after benzodiazepines)
- Trigeminal neuralgia (second-line after carbamazepine)
- Prophylaxis of post-neurosurgical seizures
- Digitalis-induced cardiac arrhythmias (historical use)
Dosing
Oral maintenance: 300 mg/day in 1-2 divided doses (adults). Loading dose (oral): 15-20 mg/kg divided into 3 doses given 2 hours apart. IV loading (status epilepticus): 15-20 mg/kg at rate not exceeding 50 mg/min (to avoid cardiac toxicity). Fosphenytoin can be infused at 150 mg PE/min. Therapeutic drug monitoring target: 10-20 mcg/mL (total), 1-2 mcg/mL (free). Dose adjustments must account for zero-order kinetics.
Contraindications
- Sinus bradycardia, SA block, second- and third-degree AV block
- Adams-Stokes syndrome
- Known hypersensitivity to hydantoins
- Porphyria (acute intermittent)
- Concurrent use with delavirdine (HIV drug interaction)
Adverse effects
- Gingival hyperplasia (seen in up to 50% of chronic users)
- Hirsutism and coarsening of facial features
- Cerebellar ataxia, nystagmus, diplopia (dose-related neurotoxicity)
- Megaloblastic anaemia (folate antagonism)
- Osteomalacia (increased vitamin D metabolism via enzyme induction)
- Peripheral neuropathy with chronic use
- Stevens-Johnson syndrome / Toxic epidermal necrolysis (idiosyncratic, associated with HLA-B*15:02 in South Asian populations)
- Purple glove syndrome (IV extravasation)
- Fetal hydantoin syndrome (teratogenic)
Drug interactions
- CYP enzyme induction -- reduces levels of oral contraceptives, warfarin, corticosteroids, cyclosporine, and many other drugs
- Valproate -- displaces phenytoin from albumin, increasing free fraction while inhibiting its metabolism
- Isoniazid (INH) -- inhibits phenytoin metabolism (especially in slow acetylators), risk of toxicity
- Carbamazepine -- mutual induction, complex bidirectional interaction
- Antacids and calcium -- reduce phenytoin absorption (separate by 2 hours)
- Chloramphenicol -- inhibits phenytoin metabolism
Pregnancy and lactation
Category D. Fetal hydantoin syndrome: craniofacial anomalies (broad nasal bridge, cleft lip/palate), digital hypoplasia, IUGR, and intellectual disability. Risk is approximately 5-10% with monotherapy. Folate supplementation (5 mg/day) is essential before and during pregnancy. Vitamin K (10 mg/day in the last month) prevents neonatal hemorrhagic disease caused by phenytoin-induced reduction of vitamin K-dependent clotting factors.
Exam-style clinical scenario
A 22-year-old woman on phenytoin for epilepsy presents with gum swelling, excessive facial hair, and an unplanned pregnancy despite using oral contraceptive pills. What explains these findings? Answer: Gingival hyperplasia and hirsutism are well-known chronic side effects of phenytoin. The contraceptive failure is due to phenytoin being a potent CYP3A4 inducer, which accelerates the metabolism of ethinyl estradiol, reducing OCP efficacy. She should be counselled about fetal hydantoin syndrome risk and switched to a safer antiepileptic (lamotrigine or levetiracetam) with high-dose folate supplementation.
Cost in India
INR 10-25 per strip of 10 tablets (100 mg); INR 50-100 per vial (250 mg/5 mL injection)
Clinical governance
Author: MedNext Editorial Team. Clinical reviewer: Awaiting clinical review. Jurisdiction: India (Drugs and Cosmetics Act, 1940). Sources: CIMS India, Indian Pharmacopoeia. Publication state: Awaiting clinical review. Correction: Report errors at support@mednext.academy.
Frequently Asked Questions
Why does phenytoin cause gingival hyperplasia?
Phenytoin stimulates fibroblast proliferation and increases collagen synthesis in gingival tissue. It also impairs collagenase activity, reducing collagen breakdown. The effect is worsened by poor oral hygiene and is dose-related. Meticulous dental care can reduce severity. Switching to an alternative antiepileptic (like levetiracetam or valproate) is definitive management.
What does zero-order kinetics mean clinically for phenytoin dosing?
At therapeutic concentrations, the hepatic enzymes metabolising phenytoin become saturated. Further dose increases cause disproportionately large rises in plasma levels -- a 10% dose increase may cause a 50% or greater increase in blood levels. This makes phenytoin dosing unpredictable and necessitates therapeutic drug monitoring. Small dose adjustments (25-50 mg) should be made at intervals of 7-10 days.
Why is HLA-B*15:02 testing relevant before starting phenytoin?
The HLA-B*15:02 allele is strongly associated with phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. This allele is prevalent in South and Southeast Asian populations (8-15% prevalence in India). USFDA and Indian pharmacovigilance guidelines recommend screening before initiating phenytoin or carbamazepine in at-risk populations.
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