We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we'll assume that you are happy to receive all cookies on the medicines.ie website. Find out more

Pfizer Healthcare Ireland

9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24,
Telephone: +353 1 467 6500
Fax: +353 1 467 6501
Medical Information Direct Line: 1 800 633 363
Medical Information Website: http://www.pfizermedicalinformation.ie


Summary of Product Characteristics last updated on medicines.ie: 19/09/2017
SPC EPANUTIN 100mg Hard Capsules


Go to top of the page
1. NAME OF THE MEDICINAL PRODUCT

EPANUTIN 100 mg Hard Capsules


Go to top of the page
2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains phenytoin sodium 100 mg

Excipients with known effect:

Each capsule contains 96.15 mg lactose monohydrate

For the full list of excipients, see section 6.1


Go to top of the page
3. PHARMACEUTICAL FORM

Capsules, hard

A white powder in a No 3 hard gelatin capsule with a white opaque body and orange cap, radially imprinted 'EPANUTIN 100'.


Go to top of the page
4. CLINICAL PARTICULARS

Go to top of the page
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.


Go to top of the page
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 seven 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 ten days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Epanutin Capsules, Suspension and Infatabs:

Epanutin Capsules contain phenytoin sodium whereas Epanutin 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 mg/kg/day 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.

Adult Dosage for Trigeminal Neuralgia:

The clinically effective dose has not been established in clinical trials. In adults, 300-500 mg given in divided daily 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.

Dosing in Special Populations

Patients with Renal or Hepatic Disease:

See section 4.4.

Elderly:

Phenytoin clearance is decreased slightly 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 to 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.


Go to top of the page
4.3 Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin, or 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.


Go to top of the page
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.

Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures.

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.

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 phenytoin plasma 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.

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 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 HLAB gene, in patients using carbamazepine.

HLA-B*1502 may be associated with increased risk of developing SJS/TEN in patients of Thai and Han Chinese ancestry taking drugs associated with SJS/TEN, including 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 the 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 to 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 within the first 2 months of treatment and may be associated with HSS/DRESS (see section 4.4). Patients with impaired liver function, elderly 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, 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 symptoms and signs 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.

While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy.

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.

Endocrine disorders

There have been reports of secondary hyperparathyroidism associated with phenytoin use.

Information for the Patient using an Oral Formulation of Phenytoin

Phenytoin may cause lowered serum levels of folic acid. It is recommended that serum folate concentrations be measured at least once every 6 months, and folic acid supplements given if necessary.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.


Go to top of the page
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 which may increase or decrease serum phenytoin levels or which phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

The most commonly occurring drug interactions are listed below.

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

Drugs that may decrease phenytoin serum levels

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

Table 2 Drugs that may decrease phenytoin serum levels

Drug Classes

Drugs in each Class (such as)

Alcohol (chronic intake) 42

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

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 which 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

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

Anticonvulsants

carbamazepine

lamotrigine

phenobarbital

sodium valproate

valproic acid

Antifungal agents

azoles

posaconazole

voriconazole

Antihelmintics

albendazole

praziquantel

Antineoplastic agents

teniposide

Antiretrovirals

delavirdine*

efavirenz

fosamprenavir

indinavir

lopinavir/ritonavir

nelfinavir

ritonavir

saquinavir

Bronchodilators

theophylline

Calcium channel blockers/Cardiovascular agents

digitoxin

digoxin

mexiletine

nicardipine

nimodipine

nisoldipine

quinidine

verapamil

Corticosteroids

Coumarin anticoagulants

warfarin

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

* Coadministration of phenytoin is contraindicated with delavirdine due to the potential to decrease delavirdine plasma concentration due to enzyme induction by phenytoin, and for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors (see section 4.3).

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/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

Fertility

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

Pregnancy

Phenytoin crosses the placenta.

There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. 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 disorder 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.

Anticonvulsants including phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients. The exact role of drug therapy in these abnormalities is unclear and genetic factors, in some studies, have also been shown to be important. Epanutin should only be used during pregnancy, especially early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk.

In addition to the reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have more recently been reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, micro-encephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.

There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

An increase in seizure frequency during pregnancy occurs in a proportion of patients, and this may be due to altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.

Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenytoin. Vitamin K has been shown to prevent or correct this defect and may be given to the mother before delivery and to the neonate after birth.

Phenytoin is teratogenic in rats, mice and rabbits.

Breast-feeding

Breast-feeding is not recommended for women taking phenytoin because phenytoin appears to be secreted in low concentrations in human milk.


Go to top of the page
4.7 Effects on ability to drive and use machines

Patients should be advised not to drive a car or operate potentially dangerous machines until it is known that this medication does not affect their ability to engage in these activities.


Go to top of the page
4.8 Undesirable effects

The following adverse reactions have been reported with phenytoin (frequency unknown-cannot be estimated from available data):

Immune system reactions:

Anaphylactoid reaction and anaphylaxis.

Central Nervous System:

Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased co-ordination 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, insomnia, transient nervousness, motor twitchings, taste perversion, headaches paraesthesia, somnolence and vertigo 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.

Gastrointestinal System:

Acute hepatic failure, toxic hepatitis, liver damage, vomiting, nausea, constipation (see section 4.4).

Dermatological System:

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. Severe cutaneous adverse reactions (SCARs): SJS and TEN have been reported very rarely (see section 4.4).

Connective Tissue System:

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's Disease and Dupuytren's contracture may occur rarely.

Haematopoietic System:

Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, 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.

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

Immune System:

Hypersensitivity syndrome/Drug reaction with eosinophilia and systemic symptoms (HSS/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 arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, polyarteritis nodosa, and immunoglobulin abnormalities may occur.

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.

Other:

Polyarthropathy, interstitial nephritis, pneumonitis.

Musculoskeletal System:

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, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

Endocrine Disorders:

Secondary hyperparathyroidism.

Investigations:

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie.


Go to top of the page
4.9 Overdose

The lethal dose in children is not known. The mean lethal dose for adults is estimated to be 2 g to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. The patient then becomes comatose, the pupils are unresponsive and hypotension occurs followed by respiratory depression and apnoea. 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 mcg/ml, and ataxia at 30 mcg/ml, dysarthria and lethargy appear when the serum concentration is greater than 40 mcg/ml, but a concentration as high as 50 mcg/ml has been reported without evidence of toxicity.

As much as 25 times therapeutic dose has been taken to result in serum concentration over 100 mcg/ml (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.


Go to top of the page
5. PHARMACOLOGICAL PROPERTIES

Go to top of the page
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, ATC Code: N03AB02.

Phenytoin is effective in various animal models of generalised convulsive disorders, reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.

It appears to stabilise rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.

The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated however, possible contributory effects include:

1. Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation

2. Post-synaptic action to enhance GABA-mediated inhibition and reduce excitatory synaptic transmission

3. Pre-synaptic actions to reduce calcium entry and block release of neurotransmitter


Go to top of the page
5.2 Pharmacokinetic properties

Absorption

Phenytoin is absorbed from the small intestine after oral administration. Various formulation factors may affect the bioavailability of phenytoin, however, non-linear techniques have estimated absorption to be essentially complete. After absorption it is distributed into body fluid including the cerebrospinal fluid (CSF). Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).

Distribution

The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours. Steady state therapeutic drug levels are achieved at least 7 to 10 days after initiation of therapy.

Biotransformation

Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.

Elimination

The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.

Pharmacokinetic Interaction

Co-administration of nelfinavir tablets (1,250 mg twice a day) with phenytoin capsule (300 mg once a day) did not change the plasma concentration of nelfinavir. However, co-administration of nelfinavir reduced the AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively (see section 4.5).

Special Populations

Patients with Renal or Hepatic Disease: see section 4.4.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see section 4.2 Dosing in Special Populations –Elderly).


Go to top of the page
5.3 Preclinical safety data

Carcinogenesis

In a transplacental and adult carcinogenicity study, phenytoin was administered in diet at 30 to 600 ppm to mice and 240 to 2400 ppm to rats. Hepatocellular tumors were increased at the higher doses in mice and rats. In additional studies, mice received 10 mg/kg, 25 mg/kg, or 45 mg/kg and rats were given 25 mg/kg, 50 mg/kg, or 100 mg/kg in the diet for 2 years. Hepatocellular tumors in mice increased at 45 mg/kg. No increases in tumor incidence were observed in rats. These rodent tumors are of uncertain clinical significance.

Genetic toxicity studies showed that phenytoin was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.


Go to top of the page
6. PHARMACEUTICAL PARTICULARS

Go to top of the page
6.1 List of excipient(s)

Core:

Lactose monohydrate

Magnesium stearate

Shell:

Gelatin

E127 (Erythrosine)

E104 (Quinoline yellow)

E171 (Titanium dioxide)

Sodium laurilsulfate

Printing ink:

Shellac

E172 (black iron oxide)

Propylene glycol

Or

Shellac

Black iron oxide (E172)

Propylene glycol

Potassium Hydroxide


Go to top of the page
6.2 Incompatibilities

Not applicable.


Go to top of the page
6.3 Shelf life

3 years.


Go to top of the page
6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.


Go to top of the page
6.5 Nature and contents of container

White HDPE container with a white polypropylene child resistant cap, containing 84 capsules. An activated silica gel dessicant, within the HDPE canister, is included in each bottle.

Not all pack sizes may be marketed.


Go to top of the page
6.6 Special precautions for disposal and other handling

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


Go to top of the page
7. MARKETING AUTHORISATION HOLDER

Pfizer Healthcare Ireland

9 Riverwalk

National Digital Park

Citywest Business Campus

Dublin 24

Ireland


Go to top of the page
8. MARKETING AUTHORISATION NUMBER(S)

PA 822/11/3


Go to top of the page
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal: 1st April 2009


Go to top of the page
10. DATE OF REVISION OF THE TEXT

09/2017

Ref: EP 31_1



Link to this document from your website:
http://www.medicines.ie/medicine/15473/SPC/EPANUTIN+100mg+Hard+Capsules/

Document Links

 
  Link to this page
  View all medicines
from this company
Print this page
View document history
Bookmark and Share

Active Ingredients

 
   Phenytoin Sodium