Phenytoin

Side effects

Possible side effects:

• Ataxia, nystagmus, slurred speech, poor coordination
• Diplopia
• Mental confusion
• Drowsiness, dizziness
• Nausea, vomiting
• Insomnia
• Headache
• Gingival hypertrophy
• Hirsutism
• Dysmorphism
• Decreased bone mineral density
• Rash: hypersensitivity
• Increased liver enzymes

Rare but potentially life-threatening side effects:

• Rash: DRESS Syndrome, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
• Lymphadenopathy: a variety of causes.
• Haematological abnormalities: leucopoenia, anaemia, pancytopenia with or without bone marrow suppression.
• Hepatotoxicity, rare cases may be fatal.

Other notable side effects:

• Peripheral neuropathy
• Choreiform movements
• Cerebellar atrophy
• Systemic Lupus Erythematosus
• All anticonvulsants are potentially teratogenic and this is often dose related (see section: AED Prescribing - Pregnancy)

Dosing

• The below initiation and escalation doses are only a guide and need to be individualised based on patient (age, weight, co-morbidities), disease (seizure type, frequency, duration) and medication (metabolism, interactions, side-effect profile) characteristics.

 

• Situations that require more careful consideration include children with higher weights, polytherapy, or multiple co-morbidities. Consultation with appropriate formularies or a paediatric neurologist may be required in specific circumstances.

Commonly used regime (adapted from MIMS and AMH):

In children:

• Initiate oral therapy at 4-5mg/kg/day in 2 equally divided doses.
• Increase gradually according to clinical response and plasma concentration.
• Maintenance dosage: 4-8mg/kg/day in 2-3 doses. Higher doses may be required in children. Be guided by levels and clinical response. If in doubt, seek neurological advice.
• Average adult maintenance dose is 200-400mgs per day. The upper limit guide for dosage in children is 300mgs daily.
• Dosages per kilogram can only be used up to weights of 30-40kgs.
• Dosage changes are ideally undertaken at intervals > 7-10 days, typically at 3-4 weeks.
• Withdrawal should be done slowly with a gradual taper. When withdrawing phenytoin, the dosage of other drugs may need adjustment due to interactions.

In neonates:

• Oral absorption is unpredictable and phenytoin metabolism is depressed. Monitoring plasma levels is helpful.

Intravenous dosing:

• A common children’s IV dosage for status epilepticus is a loading dose of 20mg/kg. The drug should be administered intravenously at 1mg/kg/min. Maximum Infusion rate 50mg/min. 
• IVI administration should be accompanied by blood pressure, ECG, and respiratory monitoring.
• Parenteral infusions should not be added to drip bottles or mixed with other drugs or glucose solutions, because of the serious risk of precipitation. The use of an infusion pump is recommended. Phenytoin must be run separately and flushed with 0.9% sodium chloride only.

Preparations:

• Capsules: 30mgs, 100mgs
• Infatabs: 50mgs
• Paediatric suspension

Monitoring and Levels:

• Phenytoin has non-linear pharmacokinetics. The non-linearity occurs at different doses for different patients and there is wide variability with similar patient dosages, necessitating plasma levels.
• FBC, LFTs and renal function tests are recommended at baseline and as clinically indicated.
• 25-hydroxy Vit D is recommended as phenytoin can alter vitamin D metabolism and affect bone mineral density.
• In patients on long-term treatment, monitor bone health, and as appropriate, bone mineral density.

Interactions | Precautions

Precautions:

• Carrying the HLA-B 1502 allele is a risk factor for SJS and TEN. Asian ancestry (especially Han Chinese, Thai, and Malay) are more likely to carry the HLA-B 1502 allele, which significantly increases the risk of severe skin reactions.
• There is a cross-reactivity of hypersensitivity drug reactions with carbamazepine and phenytoin. Symptoms of rash should be medically evaluated immediately.
• Good dental care should be maintained to prevent phenytoin from causing enlarged gums.
• Folic acid supplementation may be necessary as phenytoin lowers folic acid blood levels-.
• Phenytoin is contraindicated in Porphyria
• Phenytoin is a potential teratogen. It should not be used in women of childbearing potential without trial of other options and without full consent of the patient regarding risk to the foetus.
• Phenytoin may cause congenital malformations and impaired growth in the foetus (e.g. craniofacial dysmorphism, digital and nail hypoplasia, orofacial clefts).
• Extravasation of intravenous preparation can cause “Purple glove syndrome”.

Interactions:

• Phenytoin is associated with significant pharmacokinetic interactions and is an inducer of hepatic metabolism (See MIMS for a complete list, particularly non-antiepileptic medications).
• Phenytoin may increase the metabolism of levothyroxine, hence levothyroxine doses may need to be increased.
• Acetazolamide, brivaracetam, carbamazepine, clobazam and clonazepam, felbamate, oxcarbazepine, phenobarbital, rufinamide, stiripentol, sulthiame and topiramate can decrease the clearance of phenytoin and increase phenytoin plasma levels (certain interactions are complex and the same drug may either increase or decrease phenytoin levels, e.g. phenobarbitone).
• Phenytoin can decrease plasma levels of brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, lacoseamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, rufinamide, stiripentol, topiramate, valproic acid and zonisamide.
• Phenytoin can increase plasma levels of phenobarbital.
• Phenytoin enhances the metabolism of oral contraceptives and may lead to contraception failure.
• Valproate can increase the free fraction of phenytoin and also inhibit its clearance.
• Hyperammonaemia may occur with the combination of phenytoin and valproate.

Pharmacodynamic interactions:

• When used together, phenytoin and lacosamide can cause neurotoxicity
• When used together, phenytoin and lamotrigine can cause a drug-induced chorea.

Information last reviewed: 24/04/2023.