Phenytoin Injection BP

Each ml of the solution for injection contains 50 mg of phenytoin sodium.

Each 5 ml vial contains 250 mg of phenytoin sodium.

For excipients see 6.1.

Solution for Injection

Ampoule containing a clear, colourless solution.

Control of status epilepticus and the prevention of seizures occurring during or following neurosurgery.

Treatment of certain cardiac dysrhythmias, particularly those unresponsive to conventional antidysrhythmic agents or to cardioversion.

Phenytoin Injection BP should be injected slowly and directly into a large vein through a large-gauge needle or intravenous catheter. It 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/mm. Each injection should be followed by an injection of 0.9% sodium chloride through the same needle or catheter to avoid local venous irritation due to the alkalinity of the solution.

Continuous monitoring of the electrocardiogram and blood pressure is essential. Cardiac resuscitative equipment should be available. The patient should be observed for signs of respiratory depression. If administration of intravenous Phenytoin Injection BP does not terminate seizures, the use of other measures, including general anaesthesia, should be considered.

For the control of status epilepticus, 150 to 250 mg should be given by slow intravenous injection at a rate not exceeding 50 mg/minute to avoid hypotension. This dose can be repeated if necessary after 30 minutes. A previously untreated adult may require 10-15 mg/kg. The loading dose is then followed by a maintenance dose of 100 mg given orally or intravenously every 6-8 hours. In geriatric patients with heart disease, it has been recommended that the drug be given at a rate of 50 mg over 2-3 minutes. Dosage for children is usually determined according to weight. Paediatric dosage may also be calculated on the basis of 250 mg/m² of body surface area or 15-20 mg/kg administered in 2 or 3 equally divided doses. Subsequent dosage should be adjusted carefully and slowly according to the patient's requirements. Maintenance dosage for children usually ranges from 4-8 mg/kg daily.

Determination of phenytoin serum levels is advised when using Phenytoin Injection BP in the management of status epilepticus and in the subsequent establishing of maintenance dosage. The clinically effective level is usually 10-20 mg/l although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

In a patient who has not previously received the drug, Phenytoin Injection BP, 100 mg-200 mg (2-4 ml), may be given intramuscularly at approximately 4 hourly intervals prophylactically during neurosurgery and continued during the postoperative period for 48-72 hours. The dosage should then be reduced to a maintenance dose of 300 mg and adjusted according to serum level estimations.

When given by intramuscular injection, phenytoin precipitates out at the injection site and is absorbed slowly and erratically. This route is not, therefore, recommended for treating status epilepticus. If phenytoin is administered by intramuscular injection to patients unable to take the drug orally, the dose should be increased by 50% over the previously established oral dose. To avoid drug accumulation resulting from eventual absorption from intramuscular injection sites, it is recommended that for the first week back on oral therapy the dose is reduced to one-half the original dose. Monitoring of serum concentrations is also recommended. Intramuscular therapy should generally be limited to 1 week.

Phenytoin sodium can be useful in ventricular arrhythmias, particularly those due to digitalis. The recommended dosage is one intravenous injection of Phenytoin Injection BP 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.

WARNINGS

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.

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 risk association in other ethnicities is currently not available.

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 with other Medicaments and other forms of Interaction').

Rapid administration may result in hypotension. 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.

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.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When it is necessary to reduce the dose of phenytoin, 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.

Subcutaneous or perivascular injection should be avoided because of the highly alkaline nature of the solution. Such injection may cause irritation of the tissues varying from slight tenderness to extensive necrosis, sloughing and in rare instances has led to amputation.

The intramuscular route is not recommended for the treatment of status epilepticus because of slow absorption. Serum levels of phenytoin in the therapeutic range cannot be rapidly achieved by this method.

PRECAUTIONS

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.

Patients with renal function impairment should also be carefully observed when prescribing phenytoin, as excretion and protein binding may be altered.

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.

Phenytoin should be used with caution in diabetic patients as hyperglycaemia may be potentiated.

Measurement of serum phenytoin levels is recommended when using phenytoin in the management of status epilepticus and in establishing a maintenance dose. The usually accepted therapeutic level is 10-20 mg/l, although some patients with tonic-clonic seizures can be controlled with lower serum levels.

Phenytoin is not effective for petit mal seizures. Therefore, combined therapy is required if both grand mal and petit mal seizures are present.

Drugs which may increase serum levels of phenytoin include: chloramphenicol, coumarin anticoagulants, disulfiram, phenylbutazone, isoniazid, salicylates, chlordiazepoxide, phenothiazines, diazepam, oestrogens, ethosuximide, sulthiame, halothane, methylphenidate, trimethadione, mephenytoin, sulphonamides, cimetidine, trazodone, ranitidine, fluconazole, ketoconazole, miconazole.

Drugs which may decrease serum levels of phenytoin include: carbamazepine, reserpine, bleomycin, carboplatin, carmustine, cisplatin, methotrexate, vinblastine, folic acid, calcium folinate, rifampicin. The serum levels of phenytoin can also be reduced by concomitant use of the herbal remedy St. John's wort (Hypericum perforatum).

Drugs which may either increase or decrease serum levels of phenytoin and vice versa include: barbiturates, valproic acid and sodium valproate, ciprofloxacin, primidone.

Acute alcohol intake may increase serum levels of phenytoin while chronic alcohol use may decrease them.

Tricyclic antidepressants, haloperidol, monoamine oxidase inhibitors and thioxanthenes may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

Phenytoin 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 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 intravenous phenytoin in patients maintained on dopamine may produce sudden hypotension and bradycardia. This appears to be dose-dependent. If anticonvulsant therapy is necessary during administration of dopamine, an alternative to phenytoin should be considered.

Concurrent use of intravenous phenytoin with lignocaine or beta-blockers may produce additive cardiac depressant effects. Phenytoin may also increase the metabolism of lignocaine.

Use in Pregnancy:

Adverse effects on the foetus of status epilepticus, specifically hypoxia, make it imperative to control the condition. However, phenytoin readily crosses the placenta and about 10% of exposed foetuses have been noted to show minor craniofacial and digital abnormalities - the so-called foetal hydrantoin syndrome. Common features include broad lower nasal bridge, epicanthic folds, hypertelorism, malformed ears, wide mouth and hypoplasia of the distal phalanges and nails. A few of these babies have microencephaly and are retarded. Facial clefts and congenital heart disease are also seen more commonly than might be expected. Overall, however, 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.

The adverse effects on the foetus of status epilepticus, specifically hypoxia, make it imperative to control the condition in the shortest possible time.

The pharmacokinetics of phenytoin are altered in pregnancy. A fall in plasma albumin together with more efficient hepatic metabolism act to reduce total and unbound plasma phenytoin concentrations. 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.

Use in Lactation:

Phenytoin concentrations in breast milk are 20 to 25% of simultaneous maternal plasma levels. If maternal plasma levels are within the therapeutic range, and considering the daily volume of milk taken by the infant, it is unlikely that the infant will be exposed to clinically significant phenytoin concentrations. Breast feeding is not, therefore, contraindicated.

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 most notable signs of toxicity are cardiovascular collapse and/or depression of the central nervous system. Hypotension can occur when the drug is administered rapidly by intravenous injection. 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).

Central Nervous System:

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 phenothiazines and other neuroleptic drugs. These may be due to sudden intravenous administration for status epilepticus. The effect usually lasts for 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 measle-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. 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), therapy may be resumed when the rash has completely disappeared. However, in the case of the rash recurring upon reinstitution of therapy, further phenytoin medication is contraindicated.

Haemopoietic:

Some fatal haemopoietic complications have occasionally been reported in association with the use of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. Although macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy. 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 indicates the need to differentiate such a condition 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.

Injection Site:

Soft tissue irritation and inflammation has occurred at the site of the 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. Subcutaneous or perivascular injection should be avoided because of the highly alkaline nature of the solution.

Others:

Gingival hyperplasia is common with long-term therapy. 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, liver damage, and immunoglobulin abnormalities may occur.

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.

Symptoms:

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:

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.

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 hyperbilirubinemic 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 microgram/ml. In renal failure or hypoalbuminaemia, 5 to 12 microgram/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.

There are no preclinical data of relevance to the prescriber additional to the data presented in other sections of this summary.

Propylene glycol, ethanol and Water for Injections.

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%.

As packaged for sale: 24 months

After dilution: Use immediately, complete infusion within 1 hour.

As packaged for sale: Do not store above 25°C. Keep container in the outer carton.

After dlution: See 6.3

250 mg/5 ml clear Type 1 glass ampoule, in packs of 5 ampoules.

For single use. Discard any unused contents.

The product should be visually inspected for particulate matter and discolouration prior to administration.

Phenytoin Injection BP is suitable for use as long as it remains free of haziness and precipitate. A precipitate might form if the product has been kept in a refrigerator or freezer. This precipitate will dissolve if allowed to stand at room temperature. The product will then be suitable for use.

For infusion administration, the parenteral phenytoin should be diluted in 50 – 100 ml of normal saline, with the final concentration of phenytoin in the solution not exceeding 10 mg/ml. Administration should commence immediately after the mixture has been prepared and must be completed within one hour (the infusion mixture should not be refrigerated). An in-line filter (0.22 – 0.50 microns) should be used. The diluted form is suitable for use as long as it remains free of haziness and precipitate.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

PL 04515/0083

7^th April 1995

22/03/2010