EPANUTIN Oral suspension Ref.[7331] Active ingredients: Phenytoin

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 Skin Reactions

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Epanutin. Although serious skin reactions may occur without warning, patients should be advised of the signs and symptoms of HSS/DRESS (see section 4.4-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.

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 – 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

Epanutin 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).

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:

* 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:

* 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:

* 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:

* 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.

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.

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. In humans, phenytoin exposure during pregnancy is associated with a frequency of major malformations 2 to 3 times higher than that of the general population, which has a frequency of 2-3%. Malformations such as orofacial clefts, cardiac defects, dysmorphic facial features, nail and digit hypoplasia, and growth abnormalities (including microcephaly) have been reported among children born to women with epilepsy who took phenytoin during pregnancy. Neurodevelopmental disorder has been reported among children born to women with epilepsy who took phenytoin alone or in combination with other AEDs during pregnancy. Studies related to neurodevelopmental risk in children exposed to phenytoin during pregnancy are contradictory and a risk cannot be excluded. 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 in women of childbearing potential, women planning pregnancy, and pregnant women, except where there is a clinical need and when possible, the woman is made aware of the risks of taking phenytoin during pregnancy.

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.

In women of childbearing potential

Epanutin should not be used in women of childbearing potential unless other antiepileptic drugs are ineffective or not tolerated and when possible, the woman is made aware of the risk of potential harm to the foetus and the importance of planning pregnancy. Women of childbearing potential should use effective contraception during treatment. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with Epanutin.

Epanutin may result in a failure of hormonal contraceptives, hence women of childbearing potential should be counselled regarding the use of other effective contraceptive methods (see section 4.5).

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.

Phenytoin is teratogenic in rats, mice and rabbits.

Fertility

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

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).

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

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.

Immune system disorders

Not Known: Anaphylactoid reaction, anaphylactic reaction, immunoglobulin abnormalities may occur.

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): 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.

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.

Refer to Enteral feeding/Nutritional Preparations Interaction in section 4.5.