4.1. Therapeutic indications

Control of tonic-clonic seizures (grand mal epilepsy), partial seizures (focal including temporal lobe) or a combination of these, and for the prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury. Epanutin has also been employed in the treatment of trigeminal neuralgia but it should only be used as second line therapy if carbamazepine is ineffective or patients are intolerant to carbamazepine.

4.2. Posology and method of administration

For oral administration only.

Dosage:

Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage. Epanutin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases, serum level determinations may be necessary for optimal dosage adjustments - the clinically effective level is usually 10 mcg/ml - 20 mcg/ml (40‑80 micromoles/l) although some cases of tonic‑clonic seizures may be controlled with lower serum levels of phenytoin. With recommended dosage a period of 7 to 10 days may be required to achieve steady state serum levels with Epanutin and changes in dosage should not be carried out at intervals shorter than 7 to 10 days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Epanutin Capsules, Oral Suspension and Infatabs:

Epanutin Capsules contain phenytoin sodium whereas Epanutin Oral Suspension and Epanutin Infatabs contain phenytoin. Although 100 mg of phenytoin sodium is equivalent to 92 mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Posology

Adult dosage for seizures:

Initially 3 to 4 mg/kg/day with subsequent dosage adjustment if necessary. For most adults a satisfactory maintenance dose will be 200 mg to 500 mg daily in single or divided doses. Exceptionally, a daily dose outside this range may be indicated. Dosage should normally be adjusted according to serum levels where assay facilities exist.

Dosing in Special Populations

Patients with renal or hepatic disease:

See section 4.4.

Adult dosage for trigeminal neuralgia:

The clinically effective dose has not been established in clinical trials. In adults, 300-500 mg daily given in divided doses has been reported in the literature. Dosing should be adjusted based on clinical response. Determination of serum phenytoin levels is advised. Levels of total phenytoin should not exceed 20 mcg/ml

Elderly (over 65 years)

Phenytoin clearance may be decreased in elderly patients and lower or less frequent dosing may be required (see section 5.2 Special Populations – Age). As with adults the dosage of Epanutin should be titrated to the patient's individual requirements using the same guidelines. As older people tend to receive multiple drug therapies, the possibility of drug interactions should be borne in mind.

Paediatric population dosage for seizures:

Initially, 5 mg/kg/day in two divided doses, with subsequent dosage individualised to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 mg/kg ‑ 8 mg/kg.

Neonates:

The absorption of phenytoin following oral administration in neonates is unpredictable. Furthermore, the metabolism of phenytoin may be depressed. It is therefore especially important to monitor serum levels in the neonate.

4.3. Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin, or to any of the excipients listed in section 6.1, or other hydantoins.

Co-administration of phenytoin is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non‑nucleoside reverse transcriptase inhibitors.

4.4. Special warnings and precautions for use

General

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence seizures are present together, combined drug therapy is needed.

Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anti‑epileptic drug not belonging to the hydantoin chemical class.

Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures.

Acute alcohol intake may increase phenytoin serum levels while chronic alcoholism may decrease serum levels.

Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total plasma phenytoin concentrations should be made with caution. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinemia. Unbound phenytoin concentrations may be more useful in these patient populations.Herbal preparations containing St. John's wort (Hypericum perforatum) should not be used while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical effects of phenytoin (see section 4.5).

Suicide

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti‑epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for phenytoin.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Cardiac Effects

Cases of bradycardia and asystole/cardiac arrest have been reported, most commonly in association with phenytoin toxicity (see section 4.9), but also at recommended phenytoin doses and levels.

Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)

Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin. Some of these events have been fatal or life threatening.

HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leucocytosis, and eosinophilia. The interval between the first drug exposure and symptoms is usually 2 to 4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Patients at higher risk for developing HSS/DRESS include black patients, patients who have experienced this syndrome in the past (with phenytoin or other anticonvulsant drugs), patients who have a family history of this syndrome and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals.

Serious Cutaneous Adverse Reactions

Epanutin can cause severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and DRESS, which can be fatal (see section 4.8 Skin and subcutaneous tissue disorders). Although serious skin reactions may occur without warning, patients should be advised of the signs and symptoms of HSS/DRESS (see section 4.4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)), occurrence of rash and should be monitored closely for skin reactions. Patients should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Epanutin treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Epanutin, Epanutin must not be re-started in this patient at any time.

If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. The risk of serious skin reactions and other hypersensitivity reactions to phenytoin may be higher in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of human leukocyte antigen HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

HLA-B* 1502 may be associated with an increased risk of developing SJS in individuals of Thai and Han Chinese Origin when treated with phenytoin. If these patients are known to be positive for HLA-B*1502, the use of phenytoin should only be considered if the benefits are thought to exceed risks.

In the Caucasian and Japanese population, the frequency of HLA-B*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Case-control, genome-wide association studies in Taiwanese, Japanese, Malaysian and Thai patients have identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant.

CYP2C9 metabolism

Phenytoin is metabolised by the CYP450 CYP2C9 enzyme. Patients who are carriers of the decreased function CYP2C9*2 or CYP2C9*3 variants (intermediate or poor metabolisers of CYP2C9 substrates) may be at risk of increased phenytoin plasma concentrations and subsequent toxicity. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles, close monitoring of clinical response is advised and monitoring of plasma phenytoin concentrations may be required.

Angioedema

Angioedema has been reported in patients treated with phenytoin and fosphenytoin. Phenytoin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur (see section 4.8 Immune system disorders).

Hepatic Injury

Phenytoin is highly protein bound and extensively metabolised by the liver. Reduced dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10 mcg/ml - 20 mcg/ml (40‑80 micromoles/l).

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with HSS/DRESS (see section 4.4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)). Patients with impaired liver function, older patients or those who are gravely ill may show early signs of toxicity.

The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in black patients.

Haematopoietic System

Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without signs and symptoms resembling HSS/DRESS (see section 4.4). In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Central Nervous System Effect

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium”, “psychosis”, or “encephalopathy”, or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Musculoskeletal Effect

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of vitamin D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

Metabolic Effect

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using the medication in patients suffering from this disease.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported in association with toxic levels.

Women of Childbearing Potential

Phenytoin may cause foetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes (see section 4.6).

Epanutin should not be used in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.

Before the initiation of treatment with phenytoin in a woman of childbearing potential, pregnancy testing should be considered.

Women of childbearing potential should be fully informed of the potential risk to the foetus if they take phenytoin during pregnancy.

Women of childbearing potential should be counselled regarding the need to consult their physician as soon as they are planning pregnancy to discuss switching to alternative treatments prior to conception and before contraception is discontinued (see section 4.6).

Women of childbearing potential should be counselled to contact their doctor immediately if they becomes pregnant or might be pregnant and are taking phenytoin.

Women of childbearing potential should use effective contraception during treatment and for one month after stopping treatment. Due to enzyme induction, Epanutin may result in a failure of the therapeutic effect of hormonal contraceptives, therefore, women of childbearing potential should be counselled regarding the use of other effective contraceptive methods (see sections 4.5 and 4.6).

Information about Excipients

Epanutin contains sodium benzoate, sucrose, ethanol and colouring agents sunset yellow FCF (E110) and carmoisine (E122) (see section 2).

Sodium benzoate

Epanutin contains 25 mg sodium benzoate in each 5 ml which is equivalent to 5 mg/ml. Benzoates may increase unconjugated bilirubin levels by displacing bilirubin from albumin, which may increase neonatal jaundice. Neonatal hyperbilirubinaemia may lead to kernicterus (non-conjugated bilirubin deposits in the brain tissue) and encephalopathy.

Sucrose

A 500 mg dose of Epanutin (see section 4.2) contains 17.44 g of sucrose, which should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. This medicine may be harmful to the teeth.

Ethanol

Epanutin contains 3.975 mg/ml of anhydrous ethanol (see section 2). The amount of ethanol in a 300 mg dose (50 ml volume) of this medicine is equivalent to less than 5 ml beer or 2 ml wine. The amount of ethanol in a 500 mg dose (83.3 ml volume) of this medicine is equivalent to less than 9 ml beer or 4 ml wine. The small amount of ethanol in this medicine will not have any noticeable effects.

Sodium

Epanutin contains less than 1 mmol sodium (23 mg) per 5 ml of oral suspension, that is to say essentially 'sodium-free'. The maximum daily dose of 500 mg (see section 4.2) contains 242.4 mg of sodium, which is equivalent to 12.12% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Colouring agents

Epanutin also contains the colouring agents Sunset yellow FCF (E110) and carmoisine (E122), which may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Drug Interactions

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes and may reduce the levels of drugs metabolized by these enzymes.

There are many drugs that may increase or decrease serum phenytoin levels or that phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

Drugs that may increase phenytoin serum levels

Table 1 summarizes the drug classes that may potentially increase phenytoin serum levels.

Table 1 Drugs that may potentially increase phenytoin serum levels

Drug Classes

Drugs in each Class (such as*)

Alcohol (acute intake)

Analgesic/Anti-inflammatory agents

azapropazone

phenylbutazone

salicylates

Anesthetics

halothane

Antibacterial agents

chloramphenicol

erythromycin

isoniazid

sulfadiazine,

sulfamethizole

sulfamethoxazole-trimethoprim

sulfaphenazole

sulfisoxazole

sulfonamides

Anticonvulsants

felbamate

oxcarbazepine

sodium valproate

succinimides

topiramate

Antifungal agents

amphotericin B

fluconazole

itraconazole

ketoconazole

miconazole

voriconazole

Antineoplastic agents

capecitabine

fluorouracil

Benzodiazepines/Psychotropic agents

chlordiazepoxide

diazepam

disulfiram

methylphenidate

trazodone

viloxazine

Calcium channel blockers/Cardiovascular agents

amiodarone

dicoumarol

diltiazem

nifedipine

ticlopidine

H2-antagonists

cimetidine

HMG-CoA reductase inhibitors

fluvastatin

Hormones

oestrogens

Immunosuppressant drugs

tacrolimus

Oral hypoglycemic agents

tolbutamide

Proton pump inhibitors

omeprazole

Serotonin re-uptake inhibitors

fluoxetine

fluvoxamine

sertraline

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Drugs that may decrease phenytoin serum levels

Table 2 summarizes the drug classes that may potentially decrease phenytoin plasma levels.

Table 2 Drugs that may decrease phenytoin plasma levels

Drug Classes

Drugs in each Class (such as*)

Alcohol (chronic intake)

Antibacterial agents

ciprofloxacin

rifampicin

Anticonvulsants

vigabatrin

Antineoplastic agents

bleomycin

carboplatin

cisplatin

doxorubicin

methotrexate

Antiulcer agents

sucralfate

Antiretrovirals

fosamprenavir

nelfinavir

ritonavir

Bronchodilators

theophylline

Cardiovascular agents

reserpine

Folic acid

folic acid

Hyperglycemic agents

diazoxide

St. John's Wort

St. John's wort

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St. John's wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St. John's wort. Herbal preparations containing St. John's wort should therefore not be combined with phenytoin. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John's wort. If a patient is already taking St. John's wort check the anticonvulsant levels and stop St. John's wort. Anticonvulsant levels may increase on stopping St. John's wort. The dose of anticonvulsant may need adjusting.

Drugs that may either increase or decrease phenytoin serum levels

Table 3 summarizes the drug classes that may either increase or decrease phenytoin serum levels.

Table 3 Drugs that may either increase or decrease phenytoin serum levels

Drug Classes

Drugs in each Class (such as*)

Antibacterial agents

ciprofloxacin

Anticonvulsants

carbamazepine

phenobarbital

sodium valproate

valproic acid

Antineoplastic agents

Psychotropic agents

chlordiazepoxide

diazepam

phenothiazines

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Drugs whose serum levels and/or effects may be altered by phenytoin

Table 4 summarizes the drug classes whose serum levels and/or effects may be altered by phenytoin.

Table 4 Drugs whose serum levels and/or effects may be altered by phenytoin

Drug Classes

Drugs in each Class (such as*)

Antibacterial agents

doxycycline

rifampicin

tetracycline

Anticoagulants

apixaban

dabigatran

edoxaban

rivaroxaban

warfarin

Anticonvulsants

carbamazepine

lacosamide

lamotrigine

phenobarbital

sodium valproate

valproic acid

Antifungal agents

azoles

posaconazole

voriconazole

Antihelminthics

albendazole

praziquantel

Antineoplastic agents

teniposide

Antiplatelets

ticagrelor

Antiretrovirals

delavirdine

efavirenz

fosamprenavir

indinavir

lopinavir/ritonavir

nelfinavir

ritonavir

saquinavir

Bronchodilators

theophylline

Calcium channel blockers/Cardiovascular agents

digitoxin

digoxin

disopyramide

mexiletine

nicardipine

nimodipine

nisoldipine

quinidine

verapamil

Corticosteroids

Cyclosporine

Diuretics

furosemide

HMG-CoA reductase inhibitors

atorvastatin

fluvastatin

simvastatin

Hormones

oestrogens

oral contraceptives

Hyperglycemic agents

diazoxide

Immunosuppressant drugs

Neuromuscular blocking agents

alcuronium

cisatracurium

pancuronium

rocuronium

vecuronium

Opioid analgesics

methadone

Oral hypoglycemic agents

chlorpropamide

glyburide

tolbutamide

Psychotropic agents/Antidepressants

clozapine

paroxetine

quetiapine

sertraline

Vitamin D

vitamin D

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

Hyperammonaemia with Concomitant Use of Valproate

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonaemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonaemia.

Drug-Enteral Feeding/Nutritional Preparations Interaction

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin should not be administered concomitantly with an enteral feeding preparation.

More frequent serum phenytoin level monitoring may be necessary in these patients.

There is some evidence that this effect is reduced if continuous feeding is stopped 2 hours before, and for 2 hours after, phenytoin oral suspension administration. However, it may still be necessary to monitor the serum phenytoin level and increase the dose of phenytoin.

Drug/Laboratory Test Interactions

Phenytoin may cause a slight decrease in serum levels of total and free thyroxine, possibly as a result of enhanced peripheral metabolism. These changes do not lead to clinical hypothyroidism and do not affect the levels of circulating TSH. The latter can therefore be used for diagnosing hypothyroidism in the patient on phenytoin. Phenytoin does not interfere with uptake and suppression tests used in the diagnosis of hypothyroidism. It may, however, produce lower than normal values for dexamethasone or metapyrone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate concentrations be measured at least once every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

4.6. Fertility, pregnancy and lactation

Pregnancy

Risk related to antiepileptic medicinal products in general

When possible, medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant. Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant. In pregnant women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. As a general principle, monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated AEDs.

Risk related to phenytoin

Phenytoin crosses the placenta in humans. Similar concentrations of phenytoin have been reported in the umbilical cord and maternal blood.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Studies have shown phenytoin exposure during pregnancy is associated with an approximate 6% frequency of major malformations, which is higher than the frequency in the general population of 2-3%. Malformations such as orofacial clefts, cardiac defects, craniofacial defects, nail and digit hypoplasia, and growth abnormalities (including microcephaly and prenatal growth deficiency) have been reported either individually or as part of a Fetal Hydantoin Syndrome among children born to women with epilepsy who used phenytoin during pregnancy. Neurodevelopmental disorders have been reported among children born to women with epilepsy who used phenytoin alone or in combination with other AEDs during pregnancy. A small number of studies have found an increase of serious adverse outcomes compated to control subjects including fetal hydantoin syndrome and below avergae IQ. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. However, the respective role of antiepileptic drugs and other factors in the increased risk is not determined.

Epanutin should not be used during pregnancy and in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risks of taking phenytoin during pregnancy.

If based on a careful evaluation of the risks and the benefits, no alternative treatment option is suitable, and treatment with Epanutin is continued, the lowest effective dose of phenytoin should be used. If a woman is planning to become pregnant, all efforts should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If a woman becomes pregnant while taking phenytoin, she should be referred to a specialist to reassess phenytoin treatment and consider alternative treatment options.

An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see section 4.2). However, postpartum restoration of the original dosage will probably be indicated.

Reproductive and development toxicity has been observed in animals (see section 5.3).

Phenytoin is teratogenic in rats, mice and rabbits.

Women of childbearing potential

Epanutin should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risk of potential harm to the foetus if phenytoin is taken during pregnancy and therefore the importance of planning any pregnancy. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with Epanutin.

Women of childbearing potential should use effective contraception during treatment and for one month after stopping treatment. Due to enzyme induction, Epanutin may result in a failure of the therapeutic effect of hormonal contraceptives, therefore, women of childbearing potential should be counselled regarding the use of other effective contraceptive methods (see section 4.5). At least one effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, involving the patient in the discussion, when choosing the contraception method.

Women planning to become pregnant and in pregnant women

In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible. Epanutin should not be discontinued prior to reassessment of the treatment. When possible, patients should be informed of the potential harm to the foetus. If based on a careful evaluation of the risks and the benefits, Epanutin treatment is continued during the pregnancy, it is recommended to use the lowest effective dose and to institute specialized prenatal monitoring, oriented on the possible occurrence of the described malformations.

In neonates

Haemorrhagic syndrome has been reported in neonates born from epileptic mothers receiving phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother during the last gestational month and to the neonate after birth.

Post-natal monitoring/children

In case of exposure during pregnancy, children should be closely monitored in relation to neurodevelopmental disorders in order to provide specialized care as soon as possible, if necessary.

Breast-feeding

Following administration of oral phenytoin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast feeding is not recommended for women receiving Epanutin.

Fertility

In animal studies, phenytoin had no direct effect on fertility.

4.7. Effects on ability to drive and use machines

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machines) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness (see section 4.8).

4.8. Undesirable effects

In the table below all adverse reactions with phenytoin are listed by class and frequency Not Known (cannot be estimated from available data).

MedDRA System organ class

Frequency

Undesirable Effects

Blood and lymphatic system disorders

Not Known

Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, and aplastic anaemia. While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease (see section 4.4).

Frequent blood counts should be carried out during treatment with phenytoin.

Pure red cell aplasia has also been reported.

Immune system disorders

Not Known

Anaphylactoid reaction, anaphylactic reaction, immunoglobulin abnormalities may occur, angioedema (see section 4.4).

Metabolism and nutrition disorders

Not Known

Hypocalcaemia, hypophosphataemia in chronically treated epileptic patients.

Psychiatric disorders

Not Known

Insomnia, transient nervousness.

Nervous system disorders

Not Known

Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, dysarthria, decreased coordination and mental confusion. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use (see section 4.4). Dizziness, motor twitchings, headache, paraesthesia, somnolence and dysgeusia have also been observed.

There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. There are occasional reports of irreversible cerebellar dysfunction associated with severe phenytoin overdosage.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Ear and labyrinth disorders

Not Known

Vertigo

Vascular disorders

Not Known

Polyarteritis nodosa may occur.

Respiratory, thoracic and mediastinal disorders

Not Known

Pneumonitis.

Gastrointestinal disorders

Not Known

Vomiting, nausea, gingival hyperplasia constipation (see section 4.4).

Hepatobiliary disorders

Not Known

Acute hepatic failure, hepatitis toxic, liver injury.

Skin and subcutaneous tissue disorders

Not Known

Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash is the most common; dermatitis is seen more rarely. Other more serious and rare forms have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, hirsutism, hypertrichosis, Peyronie's Disease and Dupuytren's contracture may occur rarely, coarsening of the facial features, enlargement of the lips, Severe cutaneous adverse reactions (SCARs): acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported very rarely (see section 4.4). Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4) has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgia, eosinophilia, pyrexia, hepatic function abnormal, lymphadenopathy or rash). Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients. Urticaria has been reported.

Musculoskeletal and connective tissue disorders

Not Known

Systemic lupus erythematosus, arthropathy. There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with phenytoin. The mechanism by which phenytoin affects bone metabolism has not been identified. However, phenytoin has been shown to induce the CYP450 enzyme, which can affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, osteoporosis.

Renal and urinary disorders

Not Known

Tubulointerstitial nephritis.

Injury, poisoning and procedural complications

Not Known

Fractures.

Investigations

Not Known

Thyroid function test abnormal.

Paediatric population

The adverse event profile of phenytoin is generally similar between children and adults. Gingival hyperplasia occurs more frequently in paediatric patients and in patients with poor oral hygiene.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The lethal dose in children is not known. The mean lethal dose for adults is estimated to be 2g to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperreflexia, somnolence, drowsiness, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient then becomes comatose, the pupils are unresponsive and hypotension occurs followed by respiratory depression and apnoea. Bradycardia and asystole/cardiac arrest have been reported (see section 4.4). Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20 mg/l, and ataxia at 30 mg/l, dysarthria and lethargy appear when the serum concentration is greater than 40 mg/l, but a concentration as high as 50 mg/l has been reported without evidence of toxicity.

As much as 25 times therapeutic dose has been taken to result in serum concentration over 100 mg/l (400 micromoles/l) with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment:

Treatment is non-specific since there is no known antidote. If ingested within the previous 4 hours the stomach should be emptied. If the gag reflex is absent, the airway should be supported. Oxygen, and assisted ventilation may be necessary for central nervous system, respiratory and cardiovascular depression. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been utilised in the treatment of severe intoxication in children.

In acute overdosage the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.