1 NAME OF THE MEDICINAL PRODUCT

Phenytoin Wockhardt 100mg Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Phenytoin Sodium 100mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

White, circular, sugar coated, biconvex tablets coded or uncoded.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Epilepsy: control of tonic-clonic (grand mal) seizures and partial seizures (focal including temporal lobe) or a combination of these.

Treatment of seizures occurring during or following neurosurgery and/or severe head injury.

Treatment of trigeminal neuralgia but only as a second line therapy if carbamazepine is ineffective or patients are intolerant of carbamazepine.

4.2 Posology and method of administration

Posolosv 92mg of phenytoin is equivalent to 100mg of phenytoin sodium.

Dosage should be individually titrated as there may be wide variability in phenytoin serum levels with equivalent dosage. Phenytoin should be introduced in small doses with gradual increments until control is achieved or until toxic effects appear. The clinically effective plasma phenytoin concentration is 10-20pg/ml (40-80pmol/1) but some patients are satisfactorily controlled at concentrations outside this range.

Adults: Initially 3 to 4mg/kg/day with subsequent dosage adjustment as necessary. The usual maintenance dose is 200 to 500mg daily in single or divided doses.

Children and Infants: Initially 5mg/kg/day in 2 or 3 divided doses. A suggested maintenance dose is 4 to 8mg/kg daily in divided doses. Maximum dosage is 300mg daily.

Neonates: In neonates the absorption of phenytoin following oral administration is variable and the metabolism of phenytoin may be depressed. It is therefore very important to monitor serum levels in the neonate.

Administration in liver disorders: A reduced dose should be used to avoid toxicity.

Elderly: The usual adult dose unless serum albumin is low or hepatic or renal dysfunction is present.

If it is necessary to transfer a patient from phenytoin to other anticonvulsant therapy, this is best effected over a period of one week with gradual withdrawal of phenytoin.

Method of administration Oral

4.3    Contraindications

Hypersensitivity to phenytoin, other hydantoins, or any of the excipients.

Acute intermittent porphyria.

4.4    Special warnings and precautions for use

Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures.

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 sodium.

Therefore patients should be monitored for sings 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.

Care should be taken in treating patients with phenytoin if they have alcoholism, diabetes mellitus, blood dyscrasias, hepatic, renal or thyroid function impairment or febrile illness with a temperature above 38°C for more than 24 hours.

Patients or their carers should be told how to recognise signs of blood or skin disorders, and are advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, bruising or bleeding develop. If a rash occurs treatment should be discontinued: if the rash is mild re-introduce cautiously but discontinue immediately

if recurrence. Leucopenia, which is severe, progressive or associated with clinical symptoms, requires withdrawal (if necessary under cover of a suitable alternative).

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. Protein binding may be reduced in certain disease states such as uraemia, and in certain patient populations such as neonates and the elderly. The resulting elevation of free phenytoin may not necessarily require a change in dosage of phenytoin although relatively lower total plasma phenytoin concentrations will be found to be effective since there is less bound phenytoin available for measurement. Patients with impaired liver function, the elderly or gravely ill may show early signs of toxicity.

Patients with renal abnormalities or hypoalbuminaemia associated with AIDS may have an increased risk of elevated free phenytoin concentrations and subsequent toxicity.

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 may affect glucose metabolism and inhibit insulin release.

Hyperglycaemia has been reported in association with toxic levels. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes.

Plasma levels of phenytoin sustained above the optimal range may produce confusional states. At the first sign of acute toxicity, plasma drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Phenytoin therapy may interfere with Vitamin D metabolism (see section 4.5). In the absence of an adequate dietary intake of Vitamin D or exposure to sunlight, osteomalacia, hypocalcaemia or rickets may develop. Phenytoin induces the CYP450 enzyme which affects bone metabolism indirectly by increasing metabolism of vitamin D₃. Increased metabolism of vitamin D₃, induced by phenytoin, may lead to vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis and hypophosphataemia in chronically treated epileptic patients.

Phenytoin should be used with caution in patients with porphyria as it may exacerbate the disease. (Refer to section 4.3 regarding acute intermittent porphyria).

Patients should be monitored whilst being treated with phenytoin. Complete blood cell and platelet counts and serum biochemistry including liver function tests should be performed periodically. Dental examinations are recommended at regular intervals for teeth cleaning and reinforcement of patient's plaque control for inhibition of gingivial hyperplasia. EEGs, serum phenytoin and folate levels and physical examination paying special attention to the lymph glands and skin should also be undertaken periodically. Thyroid function determinations are recommended during the first few months of treatment to detect symptoms of hypothyroidism which may be unmasked by phenytoin.

Dosage reduction, discontinuation or substitution of an alternative antiepileptic should be done gradually. Gradual withdrawal is recommended as abrupt discontinuation in a responsive epileptic patient may result in convulsions and possibly status epilepticus. If treatment with phenytoin has to be withdrawn abruptly, the changeover to another anticonvulsant agent should, if necessary, be effected under the cover of benzodiazepines. 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.

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Phenytoin. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. 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, phenytoin treatment should be discontinued. Patients should be alert for signs and symptoms of hypersensitivity such as itching; and should seek immediate medical advice on observing them. 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 Phenytoin, Phenytoin must not be re-started in this patient at any time.

If a rash is of the milder type (measles-like or scarlatiniform), phenytoin therapy may be resumed after the rash has completely disappeared. If the rash recurs further phenytoin medication is contraindicated. Black patients may be at increased risk of hypersensitivity reactions (including skin rash, SJS, TEN and hepatotoxicity).

HLA-B*1502 may be associated with an increased risk of developing Stevens Johnson syndrome (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 the HLA-B*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about the risk association in other ethnicities is currently not available.

Antiepileptic Hypersensitivity Syndrome (AHS):

Antiepileptic Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2-4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals in whom the reaction may occur within one day of re-challenge. If a patient is diagnosed with AHS, discontinue the phenytoin and provide appropriate supportive measures.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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

Alcohol or Opioid Dependence Drugs: concomitant administration of phenytoin with disulfiram may result in increased plasma phenytoin levels. Also chronic phenytoin medication may increase methadone metabolism and may precipitate withdrawal symptoms in patients being treated for opioid dependence.

Anaesthetics: chronic use of phenytoin prior to anaesthesia may increase the metabolism of the anaesthetics enflurane, halothane and methoxyflurane.

Analgesics: aspirin, phenylbutazone and possibly other NSAIDS increase plasma phenytoin concentrations. The metabolism of paracetamol may be increased in patients taking phenytoin which may reduce the therapeutic effect of paracetamol. Isolated reports of unexpected paracetamol hepatotoxicity have been described in patients taking phenytoin. The concomitant use of azapropazone should be avoided.

Antacids: may reduce phenytoin absorption, phenytoin plasma levels, and seizure control. Concurrent use need not be avoided but separation of the dosages by two to three hours may minimise such effects. Concurrent use of phenytoin with any dosage forms containing calcium may decrease the bioavailability of both and should be taken one to three hours apart.

Anthelmintics: phenytoin may reduce plasma mebendazole concentration and significantly reduce plasma praziquantel concentration.

Antiarrhythmics: the therapeutic effect of disopyramide, mexiletine and quinidine is decreased by concurrent phenytoin administration. Concomitant administration of amiodarone may result in increased plasma phenytoin levels.

Antibacterials: plasma phenytoin concentration is increased by isoniazid (in slow acetylators), chloramphenicol, clarithromycin, and may be increased by metronidazole. Co-trimoxazole, trimethoprim and possibly other sulphonamides increase the plasma phenytoin concentration and antifolate effect, while rifamycins decrease the plasma phenytoin concentration. Plasma phenytoin concentration may be increased or decreased by ciprofloxacin. The plasma concentration of doxycycline is reduced by phenytoin. Plasma chloramphenicol concentration may be increased or decreased by phenytoin. Phenytoin may impair the effect of rifampicin.

Anticoagulants: concomitant administration of phenytoin with anticoagulants (coumarin or indanedione derivatives^ may result in increased plasma phenytoin levels. Phenytoin may impair the effect of dicoumarol. The metabolism of nicoumalone is accelerated with a possibility of reduced anticoagulant effect but enhancement has also been reported. The effect of phenytoin on warfarin is variable, and prothrombin times should be determined.

Antidepressants: treatment with tricyclic antidepressants, monoamine oxidase inhibitors (MAOI), or maprotiline may lower the seizure threshold and decrease the anticonvulsant effects of phenytoin, also CNS depression may be enhanced. Because the seizure threshold is lowered the dosage of phenytoin may need to be adjusted. Fluoxetine, sertraline, fluvoxamine, trazodone and viloxazine may increase plasma phenytoin concentrations. Phenytoin may also impair the effect of sertraline. Phenytoin may reduce the plasma concentrations of mianserin and paroxetine. 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.

Antidiabetics: concurrent use of phenytoin with oral antidiabetics may result in increased serum glucose concentration with the possibility of hyperglycaemia. Tolbutamide increases the plasma phenytoin concentration transiently, possibly increasing toxicity. Phenytoin possibly reduces the plasma concentration of repaglinide (avoid concomitant use).

Antiepileptics affected by phenytoin: phenytoin often lowers the plasma concentrations of clonazepam, carbamazepine, lamotrigine, tiagabine, topiramate and valproate, sometimes lowers the plasma concentration of ethosuximide and primidone and often raises the plasma concentration of phenobarbital.

Antiepileptics which have an effect on phenytoin: Carbamazepine, phenobarbitol, primidone and sodium valproate may either increase or decrease phenytoin plasma concentrations. Vigabatrin often decreases the plasma concentration of phenytoin. Ethosuximide and topimarate sometimes raise the plasma concentration of phenytoin. High doses of oxcarbazepine may increase plasma phenytoin concentration. Concomitant administration of two or more antiepileptics may enhance toxicity without a corresponding increase in antiepileptic effect. Interactions between individual antiepileptics can complicate monitoring of treatment and cause enhanced effects, increased sedation, and decreased plasma concentrations. These interactions are highly variable and unpredictable. Plasma monitoring is therefore often advisable with combination therapy.

Antifungals: concomitant administration of phenytoin and miconazole, Amphotericin B or fluconazole may result in an increase in the plasma phenytoin concentration. The plasma concentration of itraconazole can be reduced by phenytoin. Concurrent use of ketoconazole with phenytoin may result in altered metabolism of either drug. Phenytoin has been reported to reduce voriconazole levels and voriconazole to increase phenytoin levels; dose adjustments may be necessary.

Antihypertensives: diazoxide may decrease the plasma phenytoin concentration. Caution is advised when diltiazem, nifedipine or verapamil are used concurrently with phenytoin, as these are highly protein bound medications and changes in serum concentrations of the free unbound medication may occur. Phenytoin can reduce the effect of felodipine, isradipine, nisoldipine and probably nicardipine, nifedipine and other dihydropyridines, diltiazem and verapamil.

Antimalarials: produce antagonism of anticonvulsant effect. An increased risk of antifolate effect is seen with pyrimethamine.

Antiplatelet drugs: ticlopidine increases the plasma phenytoin concentration with risk of toxicity.

Antipsychotics: phenytoin accelerates the metabolism of clozapine, quetiapine and sertindole, reducing plasma concentrations. Treatment with haloperidol, phenothiazines, thioxanthines and loxapine may lower the seizure threshold and decrease the anticonvulsant effects of phenytoin.

Antivirals: plasma concentrations of indinavir, nelfinavir, lopinavir and saquinavir are possibly reduced by phenytoin. Nelfinavir may reduce plasma phenytoin concentrations; phenytoin concentration should therefore be monitored during co-administration. Zidovudine may increase or decrease plasma phenytoin concentrations.

Anxiolytics and Hypnotics: diazepam, chlordiazepoxide, clonazepam and possibly other benzodiazepines increase decrease or may not affect plasma phenytoin concentrations.

Phenytoin may reduce plasma concentrations of benzodiazepines.

Bupropion: phenytoin may reduce plasma concentration of bupropion.

Cardiac Glycosides: the therapeutic effect of cardiac glycosides such as digoxin and digitoxin is decreased by concurrent phenytoin administration.

CNS Stimulants: concomitant administration of phenytoin with methylphenidate or modafinil may result in increased plasma phenytoin level.

Corticosteroids: metabolism of corticosteroids is accelerated (reduced effect). The therapeutic effects of fludrocortisone, dexamethasone, methylprednisolone, prednisolone, prednisone and probably other glucocorticoids can be markedly reduced by the concurrent use of phenytoin. Serum phenytoin levels may be changed by dexamethasone.

Cytotoxics: cause reduced absorption of phenytoin. The therapeutic effect of phenytoin may be reduced when used concomitantly with bleomycin, cisplatin, and vinblastine. Plasma phenytoin may be increased by capecitabine, fluorouracil, and levamisole. Phenytoin may reduce plasma concentrations of busulfan, etoposide and imatinib. There is an increased antifolate effect with methotrexate.

Enteral and Parenteral Nutrition: therapeutic plasma concentrations of phenytoin may be difficult to achieve in patients receiving some enteral foods (phenytoin absorption reduced) or parenteral nutrition.

Diuretics: Acetazolamide may increase plasma phenytoin concentrations. Osteopenia and severe osteomalacia induced by phenytoin may be enhanced by treatment with carbonic anhydrase inhibitors such as acetazolamide. Phenytoin , when used alone or in combination with other anticonvulsants, has the potential to reduce the diuretic effect of furosemide.

Folinic and Folic Acid: plasma phenytoin concentrations may be reduced by folic acid and folinic acid.

Hormone Antagonists: phenytoin may reduce serum levels of toremifene. High dose tamoxifen can elevate plasma levels of phenytoin, causing toxicity.

Immunosuppresants: Leflunomide may increase plasma phenytoin concentrations Phenytoin may reduce plasma ciclosporin concentrations.

Levodopa: the therapeutic effect of levodopa is decreased by concurrent phenytoin administration.

Lithium: neurotoxicity may occur without an increased plasma lithium concentration.

Muscle relaxants: effect of non-depolarising muscle relaxants antagonised (recovery from neuromuscular blockade accelerated).

Oestrogens and Progestogens: the effect of oral contraceptives can be considerably decreased by concurrent phenytoin administration. The metabolism of gestrinone and tibolone are accelerated.

Thyroid Hormones: concomitant administration of laevothyroxine and phenytoin reduces the serum protein binding of laevothyroxine and reduces serum T₄ by 15-25%, however most patients remain euthyroid.

Ulcer healing Drugs: concomitant administration of phenytoin with cimetidine, omeprazole or esomeprazole may result in an increased plasma phenytoin level. Sucralfate reduces the absorption of phenytoin.

Uricosuric Agents: concomitant administration of phenytoin with sulfinpyrazone may result in an increased plasma phenytoin level.

Vaccines: concomitant administration of phenytoin with influenza virus vaccine may result in increased plasma phenytoin levels.

Vitamins: the therapeutic effect of Vitamin D is decreased by concurrent phenytoin administration (see section 4.4).

Xanthines: metabolism of theophylline is accelerated causing reduced plasma theophylline concentration. Xanthines may decrease plasma concentrations of phenytoin.

Interference with laboratory tests: phenytoin may interfere with a number of laboratory test values including raised plasma alkaline phosphatase, raised gamma glutamyl transpeptidase and raised glucose concentration. Phenytoin treatment also interferes with the following diagnostic tests: Schilling test (due to a reversible malabsorption of vitamin B₁₂), thyroid function tests (T₄ levels are decreased) and gallium citrate Ga⁶⁷ imaging (phenytoin stimulates a benign alteration in lymphoid tissue). The presence of phenytoin may result in lower than normal values for dexamethasone and metyrapone suppression tests. Phenytoin may cause lowered serum levels of folic acid. Serum folate concentrations should be measured at least once every 6 months and a folic acid supplement given if necessary. Phenytoin may affect blood sugar metabolism tests

4.6 Fertility, pregnancy and lactation

Pregnancy

Specialist advice should be given to women who are of childbearing potential. If pregnancy is planned, the risks of phenytoin must be compared to the risk of discontinuing treatment. Phenytoin crosses the placenta.

In view of the increased risk of neural tube defects and other congenital malformations associated with phenytoin, women taking antiepileptic drugs who intend to become pregnant or become pregnant should be counselled and offered antenatal screening. To counteract the risk of neural tube defects, adequate folate supplements are advised for women before and during the first trimester.

Other reported congenital abnormalities include the fetal hydantoin syndrome symptoms of which include intrauterine growth retardation, microcephaly, underdeveloped nails on fingers and toes, developmental delay and craniofacial abnormalities). Congenital heart defects, urogenital defects, cleft lip and/or palate have also been reported. The features of foetal hydantoin syndrome are all interrelated and are frequently associated with intrauterine growth retardation from other causes. Phenytoin should only be used during pregnancy, especially early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk.

The frequency of seizures may increase during pregnancy in some women. This may be due to altered phenytoin absorption or metabolism. During pregnancy, caution is needed in interpreting plasma concentrations as total plasma concentrations of phenytoin may fall, particularly in the later stages, but free plasma concentrations may remain the same or even rise. Periodic measurement of serum phenytoin levels is valuable in the management of a pregnant epileptic patient as a guide to adjustment of dose. However, postpartum restoration of the original dose will probably be indicated.

Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorders are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or foetus.

Exposure to phenytoin prior to delivery may lead to an increased risk of haemorrhage in the neonate, usually within 24 hours of the birth. Phenytoin may also produce a deficiency of vitamin K in the mother causing increased maternal bleeding during delivery. Risk of maternal and infant bleeding may be reduced by administration of vitamin K prophylactically to the mother one month prior to and during delivery and to the neonate intravenously immediately after birth.

Neuroblastoma as well as other neuroectodermal and non-ectodermal tumours have been seen in neonates and children exposed to phenytoin prenatally. It is possible that there is an increased risk of neuroblastoma in children with fetal hydantoin syndrome.

Breast-feeding

Phenytoin is excreted in breast milk. Infant breast-feeding is not recommended. The benefits of breast-feeding should be weighed against the possibility of an adverse effect occurring in the infant.

4.7    Effects an ability to drive and to use machines

Phenytoin causes dizziness and drowsiness. Patients should not drive or operate machinery if affected. Driving by patients with epilepsy is legally regulated and restricted to those whose seizures are adequately controlled.

4.8    Undesirable effects

Side effects are fairly frequent in patients receiving phenytoin but some disappear with dose reduction or continued administration.

Blood and lymphatic system disorders:

Fatal haematopoietic complications have occasionally been reported in association with phenytoin administration. Haematological reactions include eosinophilia, thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression and aplastic anaemia. Macrocytosis and megaloblastic anaemia have occurred but these conditions usually respond to folate therapy. A relationship has been suggested between phenytoin treatment and development of lymphadenopathy including benign lymph node enlargement, pseudolymphoma, lymphoma and Hodgkin’s disease. The occurrence of lymphadenopathy (local and generalised) indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g. fever, rash and liver involvement. 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.

Immune system disorders: anaphylactoid reactions and anaphylaxis.

Antiepileptic Hypersensitivity Syndrome (AHS): a rare drug induced, multiorgan syndrome which is potentially fatal, comprising serum sickness (fever, rash, lymphadenopathy, arthralgia and urticaria) and less commonly lymphocytosis, and liver and other organ involvement such as renal failure, has been associated with some antiepileptic drugs including phenytoin. Clinical manifestations include interstitial nephritis, anaemia, interstitial pulmonary infiltrates, pneumonitis, thrombocytopenia, eosinophilia, myopathy, polyarteritis nodosa and diffuse intravascular coagulation, The syndrome occurs most frequently on first exposure to the drug, with initial symptoms starting anywhere between 1 and 8 weeks after exposure (see Section 4.4).

Hypersensitivity reactions include hepatic necrosis. Possible increased incidence of hypersensitivity reactions (including skin rash and hepatotoxicity) in black patients.

Nervous system disorders

Common side effects include headache, dizziness, transient nervousness, and insomnia.

The most common undesirable effects encountered with phenytoin are related to the central nervous system as a syndrome of cerebellar, vestibular and ocular effects, notably nystagmus, diplopia and ataxia, and may be asscociated with exacerbation of seizure frequency and reversible hyperglycaemia. CNS side effects are usually dose related and also slurred speech, mental confusion,-motor twitching, paraesthesia, somnolence and drowsiness. There are also rare reports of phenytoin induced dyskinesias including chorea, dystonia, tremor and asterixis. Occasionally irreversible cerebellar dysfunction and peripheral neuropathy have been reported. Prolonged therapy may produce subtle effects on mental function and cognition, especially in children. A predominantly sensory polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Gastrointestinal disorders:

Common side effects include lack of appetite, nausea, vomiting or constipation. Tenderness and hyperplasia of the gums often occurs, particularly in younger patients. Rarely, salivary gland enlargement.

Hepatobiliary disorders:

Hepatitis, liver damage.

Skin and subcutaneous tissue disorders:

Dermatological side effects are sometimes accompanied by fever and include acne, scarlatiniform or morbilliform rashes. Bullous, exfoliative or purpuric dermatitis, lupus eyrthematosus, and erythema multiforme are rare events. Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely. (see section 4.4)

Musculoskeletal and connective tissue disorders:

Polyarthropathy. 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.

Connective tissue side effects include coarsening of the facial features, enlargement of lips Peyronie's disease and Dupuytren's contracture.

Reproductive system and breast disorders:

Gynaecomastia. Hirsutism.

Investigations:

Plasma calcium may be lowered which can lead to rickets or osteomalacia. Phenytoin can also cause significant reduction in 25-hydroxycholecalciferol concentrations and elevated alkaline phosphatase. Phenytoin may increase high-density lipoprotein (HDL) cholesterol and plasma triglyceride concentrations.

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.

4.9 Overdose

a)    Symptoms

The lethal dose in children is not known. The mean lethal dose in adults is estimated to be 2 to 5g. Initial symptoms and signs of overdose include blurred vision, nystagmus, ataxia, dysarthria and seizures. Coma, fixed dilatation of pupils hypotension and apnoea then follow. Death is due to respiratory and circulatory depression. Reports of irreversible cerebellar dysfunction are associated with severe overdose of phenytoin. Hyperglycaemia has also been reported with toxic levels of phenytoin.

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

b)    Treatment

There is no specific antidote. Maintain a clear airway and ensure adequate ventilation. The benefit of gastric decontamination is uncertain. Consider activated charcoal if the patient presents within 1 hour of ingestion of 20mg/kg or more phenytoin, provided the airway can be protected. Consider repeated doses of oral activated charcoal, provided the patient is not vomiting and the airway can be protected. Treatment should then be supportive and symptomatic, fluid, cardiorespiratory, hepatic, renal and blood glucose statuses should be monitored. Oxygen and assisted ventilation may be necessary for central nervous system (CNS), respiratory and cardiovascular depression.

Haemodialysis and haemoperfusion are of doubtful clinical efficacy. Peritoneal dialysis is not effective. 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 bourne in mind.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptic, hydantoin derivative, ATC Code: N03AB02

Phenytoin is a hydantoin anticonvulsant structurally related to the barbiturates but having a five membered ring. The mechanism of anticonvulsant action is not completely understood but it is thought to be due to a neuronal membrane stabilising effect at the cell body, axon and synapse. In neurones phenytoin decreases sodium and calcium ion influx, in non-neuronal cell types it increases sodium ion efflux and potassium uptake and at the synapse it decreases post tetanic potentiation and repetitive after-discharge. Phenytoin has an excitatory effect on the cerebellum activating inhibitory cerebellar pathways, this may reduce the seizure activity that is associated with an increased cerebellar discharge.

The antineuralgic action of phenytoin is also not understood but it is thought that phenytoin may act in the CNS to decrease synaptic transmission leading to neuronal discharge. Phenytoin raises the threshold of facial pain and shortens the duration of attacks by diminishing self maintenance of excitation and repetitive firing.

5.2 Pharmacokinetic properties

Phenytoin is slowly and irregularly absorbed from the gastro-intestinal tract. Absorption is poor in neonates. Phenytoin is metabolised in the liver. The rate is increased in young children, pregnant or menstruating women and after trauma. The rate decreases with age.

The major inactive metabolite of phenytoin is 5 (p-hydroxyphenyl)-5-phenylhydantoin. Phenytoin is primarily eliminated in the urine as metabolites, but is also excreted in faeces, breast milk and in small quantities in the saliva. Phenytoin excretion is enhanced by alkaline urine. Phenytoin is highly protein bound (90%) this may be lower in neonates (84%) and in hyperbilirubinaemic infants (80%), and is also altered in patients with hypoalbuminaemia and in uraemic patients.

The therapeutic serum concentration of phenytoin is usually within the range 10-20pg/ml, this is usually achieved after 5-10 days of daily oral dosage of 300mg phenytoin. Higher concentrations (23 pg/ml or more) may be needed to control simple or complex partial seizures with or without tonic-clonic seizures than are necessary for control of tonic-clonic seizures alone. The time to peak plasma concentration after a single oral phenytoin dose is 1% to 3 hours. The half life of phenytoin is about 22 hours but with wide inter-individual variation (range 7 to 42 hours).

5.3 Preclinical safety data

There is some controversy as to whether chronic phenytoin overdosage in experimental animals and humans causes cerebellar Purkinje cell degeneration. Overdosage in humans has been reported to cause computerised topographic appearances of cerebellar atrophy. There is no evidence of significant mutagenicity from phenytoin given to rats and mice between the 10th and the 14th day of pregnancy causes an increased incidence of fetal malformation (fetal resorption, cleft lip and cleft palate, hydronephrosis, hydrocephalus and abdominal haemorrhages). In humans phenytoin very occasionally causes a reversible pseudolymphoma syndrome in which the enlarged lymph nodes have a histological appearance resembling that of Hodgkin’s disease. There have been suggestions that the drug may occasionally be responsible for the development of malignant lymphomas and leukaemia. However, one study found no association between phenytoin intake and neoplasia in humans.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Icing sugar

Calcium hydrogen phosphate (Caliment)

Sucrose Purified water Magnesium stearate Byco - C (Gelatin)

Titanium dioxide

Sucrose

Talc

Opaglos 6000P (IMS74 OP, shellac USNF/DAB, beeswax-white. carnauba wax-yellow)

6.2 Incompatibilities

None.

Shelf life

24 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original container in order to protect from moisture. Place 2 desiccants on top of tablets

6.5    Nature and contents of container

Polypropylene or polyethylene containers containing 28, 100, 250, 500, 1000 or 5000 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 29831/0176

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 October 1990 / 29 November 1995

DATE OF REVISION OF THE TEXT

15/04/2016