Phenytoin (Epanutin): Side Effects and Monitoring Explained

In short: Phenytoin, known in the UK by the brand name Epanutin, is an anti-seizure medication (ASM) with a narrow margin between an effective blood level and a level that causes side effects. Small dose changes can produce large changes in blood level, which is why phenytoin levels are monitored and why staying on the same manufacturer’s product matters. Most phenytoin side effects are manageable and dose related, but a small number of reactions need urgent medical attention. No one should stop or change an ASM without medical advice.

What is phenytoin used for?

Phenytoin is used in two quite different ways in the UK: as a long-term oral treatment to reduce seizures, and as an emergency intravenous treatment in hospital for prolonged convulsive seizures.

For everyday treatment, NICE guideline NG217 places phenytoin as a later option rather than a first choice, for example as a third-line add-on treatment for focal seizures. Many people currently taking it have been stable on it for years, and long-standing treatment that is working well is not usually changed without good reason.

In hospital, injectable phenytoin is licensed for the control of status epilepticus of the tonic-clonic type and for seizures during or after neurosurgery or severe head injury, according to the UK Summary of Product Characteristics for phenytoin injection. It is given slowly with continuous ECG and blood pressure monitoring. This hospital role is separate from tablets, capsules or suspension taken at home, and it is not something that happens in a community setting. If you support someone at risk of prolonged seizures, see our guidance on recognising and responding to status epilepticus.

Phenytoin is also used for trigeminal neuralgia, which is outside the scope of this article.

Why do small dose changes matter so much?

Phenytoin is cleared by the body in a non-linear way, so once the enzymes that break it down become saturated, a small increase in dose can cause a disproportionately large rise in the blood level.

The UK Summary of Product Characteristics for phenytoin sodium capsules states plainly that “small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations”. Combined with a narrow therapeutic index, this is the single most important thing to understand about phenytoin.

Two practical consequences follow:

• Dose changes are made in small steps and are usually followed by a blood test.
• Anything that alters absorption or metabolism matters, including a change of product, a new medicine, or an illness affecting the liver.

What are the common phenytoin side effects?

Many people take phenytoin without troublesome effects. Where effects do occur, they most often relate to the nervous system, the gums, and the skin or hair.

An important point about frequency: the UK SmPCs for phenytoin list adverse reactions with a frequency of “not known”, meaning the frequency cannot be estimated from the available data. For that reason, this article does not attach percentages to individual phenytoin side effects. Anyone wanting product-specific detail should read the patient information leaflet supplied with their medicine or the electronic Medicines Compendium entry for Epanutin oral suspension.

Effects reported with phenytoin include:

• Unsteadiness, dizziness and poor coordination
• Slurred or slowed speech
• Involuntary flickering eye movements (nystagmus)
• Drowsiness, confusion or mental slowing
• Headache, nausea, vomiting or constipation
• Rash
• Tremor and nervousness
• Sleep disturbance

Effects that appear or worsen shortly after a dose change are worth reporting promptly, because they may reflect the blood level rather than an unavoidable feature of the medicine.

Signs that the level may be too high

Unsteadiness, slurred speech, flickering eye movements and new confusion are the classic signs of a phenytoin level above the intended range. The SmPC notes that nystagmus on lateral gaze usually appears at around 20 mg/L and ataxia, meaning unsteadiness of movement, at around 30 mg/L.

If any of these appear, contact the prescriber, epilepsy specialist nurse or GP the same day. Do not reduce or skip doses independently. A blood test and a prescriber-led dose review are the correct response.

Gum overgrowth and oral hygiene

Phenytoin can cause the gums to thicken and grow over the teeth, known as gingival hyperplasia. Good oral hygiene reduces the risk and the severity.

The SmPC records that gingival hyperplasia occurs more frequently in children and in people with poor oral hygiene. Practical steps include:

• Brushing twice daily and cleaning between the teeth
• Regular dental appointments, telling the dental team that phenytoin is prescribed
• Early reporting of bleeding, swollen or overgrown gums

For people who need support with personal care, oral hygiene should be written into the support plan rather than left to chance. Our article on the importance of care planning covers how to record this properly.

What are the longer-term effects?

Long-term phenytoin treatment is associated with a small number of recognised effects that build slowly and are easy to miss without review.

• Changes in appearance: coarsening of the facial features, enlargement of the lips, excess hair growth (hirsutism or hypertrichosis).
• Peripheral neuropathy: a mainly sensory nerve effect, often numbness or altered sensation in the feet and hands, reported with long-term use.
• Bone health: phenytoin increases the breakdown of vitamin D, which the SmPC links to vitamin D deficiency and a raised risk of osteomalacia, osteoporosis and fractures. NG217 lists phenytoin among ASMs associated with reduced bone mineral density. Vitamin D may be checked periodically, and our article on epilepsy and osteoporosis explains why this matters over time.
• Mood: suicidal thoughts and behaviour have been reported with ASMs as a class. Any new or worsening low mood or thoughts of self-harm should be raised with a healthcare professional without delay.

None of these mean phenytoin is the wrong medicine. They are reasons for planned review rather than reasons to stop.

Rare but serious reactions

A small number of reactions are serious and need urgent assessment. They are uncommon, and knowing what to look for is the point of describing them.

• DRESS (drug reaction with eosinophilia and systemic symptoms): typically fever, rash and swollen glands with involvement of other organs, most often in the first weeks of treatment.
• Severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis, which usually begin within the first weeks and may start with a spreading rash, blistering, or sores in the mouth, eyes or genitals.
• Liver injury: toxic hepatitis and liver damage have been reported, usually within the first two months.
• Blood disorders: including low white cells and low platelets, which may show as unexplained fever, sore throat, mouth ulcers, bruising or bleeding.

The HLA-B*1502 consideration

People of Han Chinese or Thai family background may be tested for the HLA-B*1502 gene variant before phenytoin is started. The SmPC states that HLA-B*1502 may be associated with an increased risk of Stevens-Johnson syndrome in people of Thai and Han Chinese origin treated with phenytoin, and NHS Specialist Pharmacy Service guidance on phenytoin monitoring lists this as a baseline test for those groups. Where the test is positive, an alternative ASM is usually considered.

Why does the manufacturer’s product need to stay the same?

Phenytoin is a Category 1 medicine under MHRA guidance on switching between different manufacturers’ products of anti-seizure medications, which means people should be kept on one specific manufacturer’s product.

The MHRA guidance places phenytoin, carbamazepine, phenobarbital and primidone in Category 1 and advises prescribers to ensure the patient is maintained on a specific manufacturer’s product. With a narrow therapeutic index, a change in product can shift the blood level enough to affect seizure control or cause side effects.

There is a further phenytoin-specific point. Epanutin capsules contain phenytoin sodium, while Epanutin oral suspension and Infatabs contain phenytoin base. The SmPC notes these are not necessarily biologically equivalent, so a change of formulation is a clinical decision, not a like-for-like substitution.

What this means in practice: check that each new supply matches the previous one, and query any change with the pharmacy before it is taken. Our article on generic versus brand prescriptions explains how to raise this.

Which medicines interact with phenytoin?

Phenytoin interacts with a long list of medicines, both by having its own level changed and by changing the levels of others.

Examples given in the SmPC include medicines that can raise phenytoin levels, such as fluconazole and other azole antifungals, omeprazole, amiodarone, isoniazid and some antidepressants, and medicines that can lower them, such as rifampicin and St John’s wort. Phenytoin can in turn reduce the effect of warfarin, hormonal contraceptives, corticosteroids and others.

Always tell a pharmacist or prescriber that phenytoin is prescribed before starting anything new, including over-the-counter products and herbal supplements.

Pregnancy and contraception

Decisions about ASMs in pregnancy must be specialist-led, and no one should stop or change medication on their own.

The SmPC states that phenytoin may result in failure of the therapeutic effect of hormonal contraceptives, so an alternative or additional method is needed during treatment and for a period after stopping. Our article on contraception and epilepsy covers this in more detail.

The MHRA’s safety review of ASMs in pregnancy identified an increased risk of major congenital malformations with phenytoin and advised urgent specialist referral for women planning pregnancy, alongside the clear message: do not stop taking these medicines without discussing it with your doctor. The review is published in the January 2021 Drug Safety Update. Phenytoin levels can also change during pregnancy, so monitoring may be increased.

What does phenytoin monitoring involve?

Monitoring means blood tests to check the phenytoin level, alongside periodic checks of other markers such as vitamin D, liver function and blood counts.

The generally quoted therapeutic serum level is 10 to 20 mg/L (40 to 80 micromol/L), a figure given both in the SmPC and by NHS Specialist Pharmacy Service. Detailed dosing and monitoring requirements are set out in the BNF entry for phenytoin.

Levels are not usually checked routinely for the sake of it. They are more useful when there is a specific question: a recent dose change, unexplained loss of seizure control, suspected toxicity, a possible interaction, or a query about adherence.

The limits are worth understanding. The range is a guide, not a target to chase. Some people do well below it, particularly in pregnancy, in older adults and where protein binding is altered, and a level inside the range does not rule out side effects. The clinical picture always sits alongside the number.

When to seek urgent medical attention

Call 999 or go to A&E immediately if a person taking phenytoin has:

• A seizure lasting five minutes or longer, or repeated seizures without recovery in between
• A widespread or blistering rash, peeling skin, or sores in the mouth, eyes or genitals
• Swelling of the face, lips, mouth or throat, or difficulty breathing
• Fever with a rash and swollen glands
• Yellowing of the skin or eyes, or severe abdominal pain with vomiting

Our guidance on when to call 999 sets out the criteria in full.

Contact a GP, epilepsy specialist nurse or NHS 111 the same day if there is:

• New unsteadiness, slurred speech, flickering eye movements or confusion
• Unexplained fever, sore throat, mouth ulcers, bruising or bleeding
• New or worsening low mood, or thoughts of self-harm
• A supply that does not match the usual manufacturer’s product

Raise at the next routine appointment: gum changes, hair growth, numbness or tingling in the feet or hands, and any change in appearance.

Never stop or change the dose of an ASM without medical advice. Abrupt withdrawal of phenytoin can precipitate status epilepticus.

Frequently asked questions

Is Epanutin the same as phenytoin?
Epanutin is a UK brand name for phenytoin. The capsules contain phenytoin sodium, while the oral suspension and Infatabs contain phenytoin base, and these forms are not automatically interchangeable.

Are Epanutin side effects different from those of other phenytoin products?
The recognised effects are those of phenytoin itself. What differs between products is how the medicine is absorbed, which is why MHRA guidance advises staying on one manufacturer’s product.

Do phenytoin levels need checking every few months?
Not necessarily. Testing is generally driven by a clinical question such as a dose change, suspected toxicity, a new interacting medicine or loss of seizure control, rather than a fixed schedule. The prescriber decides.

Can gum overgrowth be reversed?
It often improves with thorough oral hygiene and dental treatment, and the dental team can advise on management. Report gum changes early rather than waiting.

What should care staff record?
The exact product and manufacturer supplied, the times and doses given, any missed doses, and any new unsteadiness, speech changes, rash or gum changes. Written escalation steps should sit in the support plan. Our guidance on caring for someone with epilepsy covers what good recording looks like.

This article is general information about phenytoin and is not a substitute for advice from a qualified healthcare professional. Anyone with questions about their own medicine should speak to their prescriber, epilepsy specialist nurse, GP or pharmacist.