INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
EPANUTIN FORTE SUSPENSION

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

EPANUTIN FORTE SUSPENSION
125 mg/5 mL

COMPOSITION:
Each 5 mL medicine measure contains:

	Phenytoin	125 mg
	Alcohol	0,48% v/v
	Preservative: Sodium benzoate	0,5% m/v

PHARMACOLOGICAL CLASSIFICATION:
A: 2.5 Anticonvulsants, including anti-epileptics.

PHARMACOLOGICAL ACTION:
Phenytoin is an anticonvulsant. The primary site of action appears to be the motor cortex where the spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilise the threshold against hyper-excitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centres responsible for the tonic phase of grand mal seizures.
Pharmacokinetics:
The plasma elimination half-life of phenytoin in humans averages 22 hours, with the range varying from 6 to 42 hours.
Phenytoin is approximately 90% plasma protein bound; substantially less binding may occur in patients with renal or hepatic disease and may give rise to significantly elevated concentrations of unbound phenytoin.
The liver is the major organ of elimination for phenytoin. Because this elimination route is readily saturable, small increases in dosage may produce substantial increases in plasma phenytoin concentrations (as little as a 10% increase in daily dose may double or triple the steady state plasma phenytoin concentration).
In therapeutic doses, approximately 2% of phenytoin is excreted unchanged via the kidneys.
Wide variability in pharmacokinetic handling of phenytoin underscores the advisability of appropriate monitoring of plasma phenytoin levels to assist in establishing the optimal dose and dosing interval in individual patients.

INDICATIONS:
Epanutin is indicated for the control of grand mal and psychomotor seizures.

CONTRA-INDICATIONS:
Epanutin is contra-indicated in those patients with a history of hypersensitivity to hydantoin products. Epanutin is contra-indicated in porphyrics.

WARNINGS:
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 antiepileptic 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 antiepileptic drug not belonging to the hydantoin chemical class.
Women of childbearing age:
Epanutin has been associated with teratogenicity when given to women in the first trimester of pregnancy. Its use should be avoided in pregnant women and women likely to become pregnant unless its continued use is considered essential by the doctor. Women who have been exposed to Epanutin in the first trimester of pregnancy should be informed of the risk and should be offered prenatal counselling.
Usage in Pregnancy:
Safe usage during pregnancy has not been established.
Reports in recent years indicate a higher incidence of congenital abnormalities in children whose mothers used anticonvulsant medication during pregnancy. Reported abnormalities include cleft lip/palate, heart malformations, and the fetal hydantoin syndrome (consisting of craniofacial abnormalities, nail and digital hypoplasia, prenatal growth deficiency, microcephaly and mental deficiency associated with intrauterine development during therapy). There is good evidence of a genetic predisposition to congenital abnormalities induced by phenytoin.
There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
Usage should not be discontinued if the medicine is administered to prevent major seizures because of the possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
Because of altered absorption, increased protein binding, and/or increased metabolic clearance of hydantoin anticonvulsants during pregnancy, pregnant women receiving hydantoins may experience an increased incidence of seizures. Serum hydantoin concentrations must be monitored and doses increased accordingly. A gradual resumption of the patient's usual dosage may be necessary after delivery.
Exposure to hydantoin anticonvulsants prior to delivery may lead to an increased risk of life-threatening haemorrhage in the neonate, usually within 24 hours of birth. Hydantoins may also produce a deficiency of vitamin K in the mother, causing increased maternal bleeding during delivery. The risk of maternal and infant bleeding may be reduced by administering water-soluble vitamin K to the mother during delivery and to the neonate, intramuscularly or subcutaneously immediately after birth.
Some patients may experience a rapid reduction in maternal hepatic phenytoin metabolism at the time of delivery, requiring the dosage to be reduced within 12 hours postpartum.
Usage in Lactation:
Not recommended as phenytoin is excreted in breast milk; significant amounts may be ingested by the infant.

DOSAGE AND DIRECTIONS FOR USE:
Dosage should be individualised to provide maximum benefit. In some cases, serum level determinations may be necessary for optimal dosage adjustments - the clinically effective serum level is usually 40 to 80 micromol/L (10 to 20 micrograms/mL). With recommended dosage, a period of 7 to 10 days may be required to achieve therapeutic blood levels with Epanutin.
The dosages below are approximate guides only. Individual requirements vary in different patients, and the dosage should be increased gradually until a therapeutic blood level is reached.
Adult Dosage:
Patients who have received no previous treatment may be started on 5 mL three times daily, and the dosage is then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dose will be 300 - 400 mg daily with a maximum daily dose of 600 mg.
Loading dose: The dosage may be calculated as 12 to 15 mg/kg divided into 2 or 3 doses given over about 6 hours. Maintenance doses are commenced 24 hours later. Alternatively parenteral Epanutin may be used.
Paediatric Dosage:
Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualised to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually in the range of 4 to 8 mg/kg.
Children over 6 years old may require the minimal adult dosage (300 mg/day).
Alternate Dosage:
Once-a-day dosage for adults may be considered if seizure control is established with divided doses. Studies comparing divided doses of 100 mg three times daily with a single, daily dose of 300 mg indicated that absorption, peak plasma levels, biologic half-life, difference between peak and minimum values, and urine recovery were equivalent. Once-a-day dosage offers a convenience to the patient and is intended to be used only for patients who demonstrate adequate control on a once-a-day dosage. A major problem in motivating noncompliant patients may be lessened also when the patient can take all of the medication once a day. However, patients should be cautioned not to miss a dose.
Shake the suspension well before use.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects of phenytoin include nausea, vomiting, constipation, ataxia, slurred speech, blurred vision, diplopia, nystagmus, mental confusion and hallucinations together with headache, dizziness, transient nervousness, motor twitching, toxic hepatitis, liver damage periarteritis nodosa and insomnia. Some of these effects may disappear with continued treatment at reduced dosage.
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. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Tenderness and hyperplasia of the gums is a frequent occurrence particularly in younger patients; hirsutism is a less frequent effect, but is most noticeable in young females.
Coarsening of the facial features, enlargement of the lips, and Peyronie's Disease.
There have been a number of reports of rickets, reduced bone density, and osteomalacia in patients taking phenytoin, probably due to the induction of phenytoin by liver enzymes involved in the metabolism of vitamin D.
Leukopenia, thrombocytopenia, granulocytopenia, agranulocytosis and pancytopenia have been reported. Macrocytosis and megaloblastic anaemia following prolonged use usually responds to treatment with folic acid.
Hypersensitivity syndrome (which may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, immunoglobulin abnormalities.
Phenytoin may cause raised serum levels of glucose, alkaline phosphatase and gamma glutamyl transpeptidase.
Skin rashes have occurred; an incidence of 5 to 10% has been reported. More serious skin reactions include lupus erythematosus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, the occurrence of bullous, exfoliative or purpuric rash, and are an indication for withdrawing phenytoin.
Lymphadenopathy may occur with or without symptoms and signs resembling serum sickness e.g. fever, rash and liver involvement.
Precautions:
Use with caution in patients with hepatic disease.
Vitamin D supplements may be necessary with long-term therapy.
Phenytoin should be discontinued if a skin rash appears. If the rash is exfoliative, purpuric or bullous or if lupus erythematosus, Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. 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 contra-indicated.
Interactions:

1.	Medicines which may increase phenytoin serum levels include: tolbutamide, chloramphenicol, dicoumarol, disulfiram, isoniazid, phenylbutazone, acute alcohol intake, aminosalicylic acid, chlordiazepoxide, phenothiazines, diazepam, oestrogens, succinimides, halothane, methylphenidate, cimetidine, ranitidine, sulphonamides, sulthiame, trazodone, clofibrate, amiodarone, propoxyphene, nifedipine, verapamil, azapropazone, imipramine, warfarin, omeprazole, viloxazine, antifungal agents, (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole).
2.	Medicines which may decrease phenytoin serum levels include: carbamazepine, chronic alcohol abuse, reserpine, folic acid, theophylline, rifampicin, sucralfate and vigabatrin. Molindone hydrochloride contains calcium ions which interfere with the absorption of phenytoin. Ingestion times of phenytoin and antacid preparations containing calcium should be staggered to prevent absorption problems.
3.	Medicines which may either increase or decrease phenytoin serum levels include: antineoplastic agents, phenobarbitone, valproic acid, and sodium valproate. Similarly, the effect of phenytoin on phenobarbitone, valproic acid and sodium valproate serum levels is unpredictable.
	Serum level determinations may be helpful when such interactions are suspected.
4.	Although not a true medicine interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.
5.	Medicines whose efficacy is impaired by phenytoin include: antifungal agents, antineoplastic agents, clozapine, corticosteroids, coumarin anticoagulants, oral contraceptives, quinidine, vitamin D, digitoxin, doxycycline, theophyllines, oestrogens, furosemide, tricyclic antidepressants, rifampicin, paroxetine.
6.	Medicines whose efficacy may be enhanced by phenytoin include warfarin, dicoumarol, alcohol and other central nervous system depressants. Phenytoin may increase lithium levels and may produce toxicity.
7.	Phenytoin may destabilise thyroxine therapy due to displacement from its protein binding sites.

Laboratory Test Interactions
Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The mean lethal dose in adults is estimated to be 2 to 5 grams.
The cardinal initial symptoms are nystagmus, ataxia, dysarthria. Other signs include tremor, hypereflexia, lethargy, slurred speech, nausea and vomiting. The patient then becomes comatose, the pupils are unresponsive, and hypotension occurs. This may be followed by respiratory depression and apnoea.
Treatment:
There is no known antidote. Treatment is supportive and symptomatic. Ventilatory and cardiovascular support may be necessary. Peritoneal dialysis and haemodialysis reduce phenytoin plasma levels rapidly. Total exchange transfusion has been utilised in the treatment of severe intoxication in children.

IDENTIFICATION:
A pleasant orange/vanilla/banana flavoured, opaque orange coloured suspension.

PRESENTATION:
Bottles of 237 mL.

STORAGE INSTRUCTIONS:
Store in cool (below 25°C), dry place. KEEP OUT OF REACH OF CHILDREN.

REFERENCE NUMBER:
B555 (Act 101/1965)

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
SANDTON, 2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
1 July 1986.         Revised: JUNE98

ZIMBABWE DETAILS: 92/13.1/2738        PP 10

Updated on this site: April 2002
Current: January 2005
Source: Pharmaceutical Industry
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