EPINOTIN Phenytoin Injection USP

250 mg/5 ml


For the use of a Registered Medical Practitioner or a Hospital or a Institution only. 

Certain cardiac arrhythmias
Prevention of seizures occurring during or following neurosurgery
Control of status epilepticus of the grand mal type

EPINOTIN  (Phenytoin sodium) is a hydantoin derivative anticonvulsant. The chemical name is 2,4- Imidazolidinedione,5,5-diphenyl-, monosodium salt. The molecular formula is C15H11N2NaO2 and molecular weight is 274.3.

Its structural formula is :

Phenytoin Injection USP


EPINOTIN is a clear, colourless solution filled in suitable size amber ampoule.

Each ml contains :
Phenytoin Sodium I.P.   50 mg
Propylene Glycol I.P.      40 % v/v
Ethanol I.P. 10 % v/v
Water for Injections I.P.       q.s.

Phenytoin sodium inhibits the spread of seizure activity in the motor cortex. It appears that by promoting sodium efflux from neurons, phenytoin sodium tends to stabilise the threshold against hyperexcitability caused by environmental changes or excessive stimulation capable of reducing membrane sodium gradient. This includes the reduction of post tetanic potentiation of synapses. Loss of post tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin thereby reduces the over-activity of brain stem centres responsible for the tonic phase of grand mal seizures. Phenytoin sodium’s antiarrhythmic action may be attributed to the normalization of influx of sodium and calcium to cardiac Purkinje fibres. Abnormal ventricular automaticity and membrane responsiveness are decreased. It also shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential. Hydantoins induce production of liver microsomal enzymes, thereby accelerating the metabolism of concomitantly administered drugs.

The onset of action after an intravenous dose is 30 to 60 minutes and the effect persists up to 24 hours. Phenytoin is about 90 % protein bound. Protein binding may be lower in neonates and hyperbilirubinaemic infants; also altered in patients with hypoalbuminaemia, uraemia or acute trauma, and in pregnancy. Optimum control without clinical signs of toxicity occurs most often with  serum  levels  between 10  and  20 µg/ml.  In  renal  failure  or  hypoalbuminaemia, 5  to 12 µg/ml or even less may be therapeutic. Phenytoin is metabolised in the liver, the major inactive metabolite is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The rate of metabolism is increased in younger children, pregnant women, in women during menses and in patients with acute trauma. The rate decreases with advancing age. Phenytoin may be metabolised slowly in a small number of individuals due to genetic factors, which may cause limited enzyme availability and lack of induction. The plasma half-life is normally from 10 to 15 hours. Because phenytoin exhibits saturable or dose-dependent pharmacokinetics, the apparent half-life of phenytoin changes with dose and serum concentration. At therapeutic concentrations of the drug, the enzyme system responsible for metabolising phenytoin becomes saturated. Thus a constant amount of drug is metabolised, and small increases in dose may cause disproportionately large increases in serum concentrations and apparent half-life, possibly causing unexpected toxicity.

For the control of status epilepticus of the grand mal type and the prevention of seizures occurring during or following neurosurgery. It has also been used in the treatment of certain cardiac arrhythmias, particularly in those patients who do not respond to conventional antiarrhythmic agents or to cardioversion.


Administration :
EPINOTIN  must  be  administered  slowly Intravenous administration  should not exceed 50 mg/minute in adults. In neonates the drug should be administered at a rate not exceeding 1 to 3 mg/kg/min. Dilution of EPINOTIN into intravenous infusion is not recommended due to lack of solubility and resultant precipitation. EPINOTIN should be injected slowly and directly into a large vein through a large-gauge needle or intravenous catheter. Each injection should be followed by an injection of sodium chloride intravenous infusion 0.9 % through the same needle or catheter to avoid local venous irritation due to the alkalinity of the solution. Continuous infusion should be avoided.

The ampoule used in this product is equipped with O.P.C (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.

Dosage :
For the control of status epilepticus in adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg/minute. The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours. For neonates and children a loading dose of 10 to 20 mg/kg intravenously will usually provide a plasma concentration of phenytoin within the generally accepted therapeutic range (10 to 20 micrograms/ml). The drug should be administered intravenously at a rate not exceeding 1 to 3 mg/kg/min. In the treatment of status epilepticus an intravenous benzodiazepine such as diazepam is usually given initially for the rapid control of seizures and is then followed by the slow intravenous administration of phenytoin. Intramuscular administration of phenytoin is unsuitable for the emergency treatment of status epilepticus due to very slow and erratic absorption from the intramuscular site. For the prevention of seizures during or following neurosurgery, cautious intravenous administration of 250 mg every six to twelve hours is recommended until oral dosage is possible. Plasma levels should be monitored to ensure optimal efficacy and to minimise toxicity. Phenytoin should not be given by intramuscular injection for the prevention of seizures following neurosurgery.
Phenytoin sodium can be useful in ventricular arrhythmias. Although not a cardiac depressant, it has a positive inotropic effect and enhances conduction, though it generally decreases automaticity.  The  recommended  dosage  is  one intravenous  injection  of EPINOTIN of  3  to 5 mg/kg bodyweight initially, repeating if necessary.

1. Patients with a known hypersensitivity to phenytoin or other hydantoins. 
2. Patients with sinus bradycardia, sino-atrial block, second and third degree AV block or Adams-Stokes syndrome. 
3. Intra-arterial administration must be avoided in view of the high pH of the preparation.

This drug must be administered slowly, at a rate not exceeding 50 mg/minute in adults. In neonates, the drug should be administered at a rate not exceeding 1-3 mg/kg/min. The response to phenytoin may be significantly altered by the concomitant use of other drugs (see Interactions). In patients with cardiovascular disease, parenteral administration may result in atrial and ventricular conduction depression, ventricular fibrillation or reduced cardiac output. Severe complications are most commonly encountered in elderly or gravely ill patients. In these patients, the drug should be administered at a rate not exceeding 25 mg/minute, and if necessary, at a slow rate of 5 to 10 mg/minute. The intramuscular administration of phenytoin sodium is not recommended due to erratic absorption and local tissue reactions when given by this route. Phenytoin should be used with caution in diabetic patients, as hyperglycaemia may be potentiated. Patients with renal function impairment should be carefully observed when prescribing phenytoin, as excretion and protein binding may be altered. Similarly, because phenytoin is metabolised in the liver, dosage reduction may be required in patients with extensive hepatic impairment. Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When the need arises for a dosage reduction of phenytoin, or discontinuation or substitution of alternative anticonvulsant therapy is required, this should be done gradually. In hypersensitivity reactions, where rapid substitution of therapy is warranted, the alternative drug should be one not belonging to the hydantoin class of compounds. Phenytoin should be used with caution in patients with hypotension and severe myocardial insufficiency. Caution should also be used when administering phenytoin to patients suffering from porphyria. There have been isolated reports linking phenytoin to exacerbation of this disease. Hypotension usually occurs when the drug is administered rapidly by the I.V. route.

Soft tissue irritation and inflammation, varying from slight tenderness to extensive necrosis and sloughing, has been noted at the site of injection. Each injection of phenytoin should be followed by an injection of sodium chloride intravenous infusion 0.9 % through the same needle or catheter to avoid the irritation. The liver is the principal site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism appears to be due to limited enzyme availability and lack of induction, which may be genetically determined. There have been a number of reports suggesting a relationship between phenytoin and the development of local or generalised lymphadenopathy, including benign lymph node hyperplasia, lymphoma, pseudolymphoma and Hodgkin’s Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy requires differentiation from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms resembling serum sickness e.g. rash, fever and liver involvement. In all cases of lymphadenopathy, seizure control should be sought 

using alternative antiepileptic drugs and observation of patients for an extended period is recommended. Serum levels of phenytoin sustained above the optimal range may produce encephalopathy, or confusional states (delirium psychosis), or rarely irreversible cerebellar dysfunction. Plasma level determinations are recommended at the first signs of acute toxicity. If plasma levels are excessive, then dosage reduction is indicated. Termination is recommended if symptoms persist (see Warnings). 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, phenytoin should not be resumed. If the rash is mild (measles-like or scarlatiniform), resumption of therapy will depend on a consideration of the risk/benefit ratio by the treating physician. However, in the case of the rash recurring upon reinstitution of therapy, further phenytoin medication is contraindicated. Phenytoin is not effective for petit mal seizures. Therefore, combined therapy is required if both grand mal and petit mal seizures are present. There have been isolated reports of hyperglycaemia occurring in patients receiving phenytoin, resulting from  the drug’s inhibition of insulin secretion. Phenytoin may also raise the serum glucose in diabetic patients.


 Pregnancy : Pregnancy Category D.

Phenytoin sodium taken during pregnancy has been associated with distinctive craniofacial abnormalities, mental and growth deficiency and less frequently, oral clefts and cardiac anomalies. This clinical pattern is sometimes called the ‘foetal hydantoin syndrome’.
Overall, the risk of having an abnormal child as a result of medication is far outweighed by the dangers to the mother and foetus of uncontrolled epilepsy. There is frequently an increase in seizures amongst pregnant patients, due to an increased rate of phenytoin metabolism. Dosage will usually need to be adjusted in pregnant patients, and to that end periodic measurement of serum phenytoin levels is important. The original dose will probably be resumed postpartum. There have been reports of neonatal coagulation defects within the first 24 hours in babies born to mothers receiving phenytoin. Phytomenadione has been shown to correct or prevent this defect and has been recommended to be administered to the mother before delivery and to the baby after birth.
Nursing mothers : 
Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in breast milk.
A number of drugs have been noted to increase or decrease the effects of phenytoin either through an effect on metabolic degradation of phenytoin, interference with protein binding, altered absorption or by unknown mechanisms. Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with capecitabine or its metabolite fluorouracil.  Formal interaction studies between phenytoin and capecitabine have not been conducted, but the mechanism of interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine.  Serum levels of phenytoin sustained above the optimal range may produce encephalopathy, or confusional states (delerium psychosis), or rarely irreversible cerebellar dysfunction.  Therefore, patients taking phenytoin concomitantly with capecitabine or fluorouracil should be regularly monitored for increased phenytoin levels.
Drugs which may increase serum levels of phenytoin sodium include :
chloramphenicol, coumarin anticoagulants, disulfiram, phenylbutazone, isoniazid, salicylates, chlordiazepoxide, phenothiazines, diazepam, oestrogens, ethosuximide, sulthiame, halothane, methylphenidate, trimethiadione, mephenytoin, sulphonamides, cimetidine, trazodone, ranitidine, fluconazole, ketoconazole, miconazole and fluoxetine.
Drugs which may decrease serum levels of phenytoin sodium include :
carbamazepine, reserpine, bleomycin, carboplatin, carmustine, cisplatin, methotrexate, vinblastine, folic acid, calcium folinate, rifampicin, and theophylline.
Drugs which may either increase or decrease serum levels of phenytoin sodium and vice versa include :
barbiturates, valproic acid and sodium valproate, primidone. Acute alcoholic intake may increase serum levels of phenytoin sodium while chronic alcoholic use may decrease them. Tricyclic antidepressants, haloperidol, MAO inhibitors and thioxanthenes may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.
Phenytoin sodium impairs the efficacy of several drugs, including :
anticonvulsants, corticosteroids, coumarin anticoagulants, cyclosporine, dacarbazine, vitamin D, digoxin, disopyramide, doxycycline, frusemide, L-dopa, mexiletine, oestrogens, oral contraceptives, quinidine, succinimide and xanthines. Caution is advised when nifedipine or verapamil are used concurrently with phenytoin. All are highly protein bound medications and therefore changes in serum concentrations of the free, unbound medications may occur. Phenytoin Sodium, especially in large doses, may increase serum glucose levels and therefore dosage adjustments for insulin or oral antidiabetic agents may be necessary. Concurrent use of phenytoin and oral diazoxide may decrease the efficacy of phenytoin and the hyperglycaemic effect of diazoxide and is not recommended. Use of I.V. phenytoin in patients maintained on dopamine may produce sudden hypotension and bradycardia. This appears to be dose-rate dependent. If anticonvulsant therapy is necessary during administration of dopamine, an alternative to phenytoin should be considered.
Concurrent use of I.V. phenytoin with lignocaine or β-blockers may produce additive cardiac depressant effects. Phenytoin may also increase metabolism of lignocaine. Concomitant use of fluoxetine in patients stabilised on phenytoin has resulted in elevated plasma phenytoin concentrations and signs and symptoms of phenytoin toxicity. Plasma phenytoin concentrations should be monitored closely during concomitant use of fluoxetine, and the dose of phenytoin adjusted if necessary.
Laboratory Test Interactions :
Phenytoin increases blood glucose levels due to inhibition of insulin secretion. Raised serum levels of alkaline phosphatase, hypocalcaemia and osteomalacia have been linked with altered vitamin D metabolism. Elevated serum levels of gamma glutamyl transpeptidase (GGT) may be related to hepatic enzyme induction. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone.
Incompatible with amikacin sulphate, cephapirin sodium, clindamycin phosphate, and many other drugs. It is recommended that phenytoin sodium not be mixed with other drugs or with any infusion solution other than sodium chloride 0.9 %.
The most notable signs of toxicity are cardiovascular collapse and/or CNS depression. Nystagmus is the most frequently reported clinical finding of toxicity and tends to occur when the serum phenytoin concentration exceeds 20 mg/L. Hypotension does occur when the drug is administered rapidly by the I.V. route. Toxicity should be minimised by following the appropriate directions (see Dosage and Administration).
Cardiovascular :
Severe cardiotoxic reactions and fatalities have been reported, most commonly in gravely ill patients or the elderly (see Warnings).
These are the most common reactions encountered with phenytoin and include nystagmus, ataxia, slurred speech, decreased coordination and mental confusion. Cases of dizziness, insomnia, transient nervousness, motor twitchings and headaches have also been reported. These side effects are usually dose related. 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. These may be due to sudden administration of I.V. phenytoin for status epilepticus. The effect usually lasts 24-48 hours after discontinuation. A predominantly sensory peripheral polyneuropathy has been reported for patients on long-term phenytoin therapy.
Gastrointestinal : Nausea, vomiting and constipation.
Dermatological : A measles-like rash is the most common dermatological manifestation. Rashes are sometimes accompanied by fever, and are generally more common in children and young adults. Other types of rashes are more rare, and more serious forms which may be fatal include bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome and toxic epidermal necrolysis (see Precautions).
Haemopoietic : Some fatal haemopoietic complications have occasionally been reported in association with the use of phenytoin. These have included thrombocytopaenia, leukopaenia, granulocytopaenia, agranulocytosis, and pancytopaenia with or without bone marrow suppression. Although macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy has also been reported (see Precautions).
Other : Gingival hyperplasia occurs frequently. Its incidence may be reduced by maintaining good oral hygiene such as frequent brushing, gum massage and appropriate dental care. Coarsening of the facial features, enlargement of the lips, hypertrichosis, Peyronie’s Disease, systemic lupus erythematosus, periarteritis nodosa, toxic hepatitis, immunoglobulin abnormalities, osteomalacia and liver damage may occur. Liver damage may be a manifestation of hypersensitivity to the drug. Local irritation, inflammation, tenderness, necrosis and sloughing at the injection site have been reported with or without extravasation of I.V. phenytoin. Rare reports of pulmonary infiltrates or fibrosis, with symptoms including fever, troubled or quick, shallow breathing, unusual tiredness or weakness, loss of appetite and weight and chest discomfort, have also occurred.
Phenytoin in appropriate doses may as such impair driving skills but epilepsy itself dictates the practice of driving. Patients affected by drowsiness should not drive or operate machinery.
The lethal dose in adults is considered to be 2 to 5 grams. The lethal dose in children is not known. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperflexia, lethargy, slurred speech, nausea and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.
Treatment is nonspecific since there is no known antidote. (If ingestion has taken place, 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.
The product should be visually inspected for particulate matter and discolouration prior to administration. Do not use the injection if it is hazy or contains a precipitate. EPINOTIN SHOULD NOT BE REFRIGERATED as this causes precipitation of crystals. These crystals usually do not redissolve  when solution temperature is brought to room temperature. 
Stored below 30°C (86°F), protected from light.
Do not refrigerate.
24 months from the date of manufacture.
EPINOTIN is supplied as per below table :
Phenytoin Injection USP
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.
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