INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
EPANUTIN READY MIXED PARENTERAL

EPANUTIN
READY MIXED PARENTERAL
(Phenytoin Injection B.P.C.)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

EPANUTIN READY MIXED PARENTERAL
(injection)

COMPOSITION:
Each 5 mL vial contains a ready mixed solution of 250 mg Phenytoin Sodium B.P. equivalent to 230 mg phenytoin, in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection adjusted to pH 12 with sodium hydroxide.

PHARMACOLOGICAL CLASSIFICATION:
A: 2.5 Anti-convulsants, 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 hyperexcitability 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 Ready Mixed Parenteral is indicated for -

(1)	Prevention and treatment of seizures occurring during and after neurosurgery;
(2)	The control of status epilepticus of the grand mal type;
(3)	It is of use in the treatment of certain cardiac arrhythmias, especially when these are digitalis-induced.

CONTRA-INDICATIONS:
Epanutin Ready Mixed Parenteral is contra-indicated in those patients with a history of hypersensitivity to hydantoin products. Epanutin is contraindicated in porphyrics.
Because of its effects on ventricular automaticity, Epanutin Ready Mixed Parenteral is contra-indicated in sinus bradycardia, sino-atrial block, second and third-degree A-V block, and patients with Adams-Stokes syndrome. Fatalities due to cardiac arrest, ventricular fibrillation, tonic seizures and respiratory arrest have been reported following intravenous administration of phenytoin in cases with cardiac arrhythmias. Alterations of cardiac and respiratory function can be produced by too rapid administration of the drug intravenously.

WARNINGS:
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.
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.
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.
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:
The addition of Epanutin Ready Mixed Parenteral solution to intravenous infusions is not recommended due to lack of solubility and resultant precipitation. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
The solution is suitable for use as long as it remains free of haziness and precipitate. Upon refrigeration or freezing, a precipitate might form; this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. Only a clear solution should be used. A faint yellow colouration may develop; however, this has no effect on the potency of the solution.
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).
The rate of administration is very important. It should not exceed 50 mg/min in adults, and should not exceed 1 to 3 mg/kg/min in neonates. At this rate toxicity should be minimized.
Use in Neurosurgery:
For initiating prophylaxis and for the treatment of seizures, an intravenous loading dose followed by maintenance doses (oral if possible) should be administered; see “Use in Status Epilepticus”.
Use in Status Epilepticus:
ADULTS - An initial loading dose of 10 to 15 mg/kg body mass. This initial dose (usually administered over 20 minutes) should be followed by the appropriate maintenance doses. For most adults, the satisfactory maintenance dose will be 300-400 mg daily with a maximum daily dose of 600 mg.
CHILDREN - A loading dose of 10 to 20 mg/kg body mass intravenously at a rate not exceeding 1 to 3 mg/kg/minute. Paediatric dosage may also be calculated on the basis of 250 mg/m² body surface. The appropriate maintenance dosing (oral if possible) should be administered in divided doses; the recommended daily maintenance dosage is usually in the range of 4 to 8 mg/kg.
Determination of phenytoin serum levels is advised, to monitor the adequacy of the dosage administered.
Use in Cardiac Arrhythmias:
3,5 to 5 mg per kg of body mass injected slowly intravenously and at a uniform rate which does not exceed 1 mL (50 mg) per minute. This dose may be repeated once if necessary.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most notable signs of toxicity associated with the intravenous use of this medicine are cardiovascular collapse and/or central nervous system depression. Hypotension is likely when the medicine is administered rapidly by the intravenous route.
Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression, ventricular fibrillation, and reduced cardiac output. Severe complications are most commonly encountered in elderly or gravely ill patients.
Skin rashes have occurred. 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.
Phenytoin should be used with caution in patients with hypotension and severe myocardial insufficiency.
The intramuscular route is not recommended because blood levels of phenytoin in the therapeutic range cannot be readily nor predictably achieved.
Parenteral Epanutin sometimes causes nystagmus, diplopia, ataxia, slurred speech, decreased coordination, mental confusion, circumoral tingling, dizziness, insomnia, transient nervousness, motor twitchings, headaches, nausea, vomiting and constipation. When these effects are observed, the plasma concentration is usually above 80 micromol/L (20 micrograms/mL) which is just above the usual therapeutic plasma concentration. (Usual therapeutic range in plasma: 40 to 80 micromol/L (10 to 20 micrograms/mL)).
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.
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.
Polyarthropathy, fever, hepatitis, periarteritis nodosa, immunoglobulin disturbances, Peyronies disease and lymphadenopathy have been reported rarely.
Phenytoin may cause raised serum levels of glucose, alkaline phosphatase and gamma glutamyl transpeptidase.
Intravenous injections of Epanutin are irritant and may cause phlebitis.
Phenytoin-induced dyskinesias, including chorea, dystonia, tremor, and asterixis, have been reported. A predominantly sensory peripheral neuropathy is a repercussion of prolonged therapy.
Lymphadenopathy may occur with or without symptoms and signs resembling serum sickness e.g. fever, rash and liver involvement.
Precautions:
The addition of Epanutin Ready Mixed Parenteral to intravenous infusion is not recommended due to lack of solubility and resultant precipitation. Epanutin Ready Mixed Parenteral should be injected slowly (not exceeding 50 mg per minute in adults), directly into a large vein through a large gauge needle or intravenous catheter. Each injection of intravenous Epanutin should be followed by an injection of sterile saline thorugh the same needle or intravenous catheter to reduce local nevous irritation due to the alkalinity of the solution. Continuous infusion should be avoided.
Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Soft tissue irritation may vary from slight tenderness to extensive necrosis, sloughing, and in rare instances has led to amputation. Improper administration including subcutaneous or perivascular injection should be avoided to help prevent possibility of the above.
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, halothane, methylphenidate, cimetidine, ranitidine, sulphonamides, sulthiame, trazodone, clofibrate, miconazole, amiodarone, propoxyphene, nifedipine, verapamil, azapropazone, imipramine, warfarin.
2.	Medicines which may decrease phenytoin serum levels include: carbamazepine, chronic alcohol abuse, reserpine, folic acid, theophylline, rifampicin. 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: 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: corticosteroids, coumarin anticoagulants, oral contraceptives, quinidine, vitamin D, digitoxin, doxycycline, theophyllines, oestrogens, furosemide, tricyclic antidepressants.
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 metapyrone tests.

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:
Clear, colourless ready mixed solution containing 50 mg phenytoin sodium per mL in a 5 mL flint glass vial.

PRESENTATION:
5 mL vial containing 250 mg (50 mg/mL) phenytoin sodium B.P.

STORAGE INSTRUCTIONS:
Store at room temperature (below 25°C). Protect from light and excessive heat. Solutions of Epanutin Ready Mixed Parenteral should not be added to intravenous solutions because of precipitation of the acid.
KEEP OUT OF REACH OF CHILDREN.

REFERENCE NUMBERS:
B1624 (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:
2 April 1984

ZIMBABWE DETAILS:         93/13.1/2804 PP

Updated on this site: April 2002
Current: January 2005
Source: Pharmaceutical Industry
SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2005