Phenytoin 250mg/5ml Solution for Injection

Each 5 ml ampoule contains 250 mg phenytoin sodium.

For excipients, see 6.1

Solution for injection.

Clear, colourless, sterile, solution.

Phenytoin Solution for Injection is indicated for

The control of status epilepticus of the tonic-clonic (grand mal type) and the prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury.

Phenytoin is also used in the treatment of cardiac arrhythmias where first line therapy is not effective. It is of particular value when these are digitalis induced.

For intravenous administration.

Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Phenytoin Solution for Injection is suitable for use as long as it remains clear and free of 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 this solution.

There is a relatively small margin between full therapeutic effect and minimally toxic doses of this drug. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20mg/l (40-80 micromoles/l).

Phenytoin Solution for Injection should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter.

Each injection or infusion of intravenous phenytoin should be preceded and followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to alkalinity of the solution. (See section 4.4.)

For infusion administration the phenytoin solution should be diluted in 50-100ml of normal saline, with the final concentration of phenytoin not exceeding 10mg/ml, the infusion mixture should not be refrigerated. Administration should begin immediately after the infusion mixture has been prepared and must be completed within one hour. An in-line filter (0.22-0.50 microns) should be used.

The diluted form is suitable for use as long as it remains clear and free of precipitate.

It is essential that both electrocardiogram and blood pressure of the patient be continuously monitored. Cardiac resuscitative equipment should be available. The patient should be observed for signs of respiratory depression. If administration of intravenous phenytoin does not terminate seizures, the use of other measures, including general anaesthesia, should be considered.

Use in Status Epilepticus:

In a patient having continuous seizure activity, as compared to the more common rapidly recurring seizures, i.e. serial epilepsy, injection of intravenous diazepam or a short acting barbiturate is recommended because of their rapid onset of action, prior to administration of phenytoin.

Following the use of diazepam in patients having continuous seizures and in the initial management of serial epilepsy a loading dose of phenytoin 10-15mg/kg should be injected slowly intravenously, at a rate not exceeding 50mg per minute in adults (this will require approximately 20 minutes in a 70kg patient). The loading dose should be followed by maintenance doses of 100mg orally or intravenously every 6 to 8 hours.

In neonates, it has been shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15-20mg/kg of phenytoin intravenously will usually produce serum concentrations of 10–20 mg/l phenytoin which is within the generally accepted therapeutic range. The drug should be injected slowly intravenously at a rate of 1-3mg/kg/min.

It is advised that the serum levels of phenytoin are determined in the management of status epilepticus and to establish a maintenance dose. The clinically effective level is usually 10-20mg/l although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.

Use in Cardiac Arrhythmias:

3.5-5mg per kg of bodyweight intravenously initially, repeated once if necessary. The solution should be injected slowly, intravenously and at a uniform rate which should not exceed 1ml (50mg) per minute.

Other clinical conditions:

The intravenous route of administration is preferred. Dosage and dosing interval will, of necessity, be determined by the needs of the individual patient. Factors such as previous antiepileptic therapy, seizure control, age and general medical condition must be considered.

Phenytoin is slowly absorbed when administered intramuscularly; this may be appropriate for the treatment of certain conditions.

When short-term intramuscular administration is necessary for a patient previously stabilised orally, compensating dosage adjustments are essential to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose, for the same period of time the patient received phenytoin intramuscularly. This is to prevent excessive serum levels due to continued release from intramuscular tissue sites

Neurosurgery:

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

If the patient requires more than a week of intramuscular phenytoin, alternative routes should be explored such as gastric intubation. For time periods less than one week, the patient switched from intramuscular administration should receive one half the original oral dose for the same period of time the patient received phenytoin intramuscularly. Measurement of serum levels is of value as a guide to an appropriate adjustment of dosage.

Elderly (over 65 years):

As for adults. However, complications may occur more readily in elderly patients.

Neonates:

In neonates it has been shown that absorption of phenytoin is unreliable after oral administration. Phenytoin should be injected slowly intravenously at a rate of 1-3mg/kg/min at a dose of 15-20mg/kg. This will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range of 10-20mg/l.

Infants and children:

As for adults. Children tend to metabolise phenytoin more rapidly than adults. This should be considered when determining dosage regimens; monitoring serum levels is therefore particularly beneficial in such cases.

Phenytoin is contra-indicated in patients who are hypersensitive to phenytoin or other hydantoins. Intra-arterial administration must be avoided in view of the high pH of the preparation.

Because of its effect on ventricular automaticity, phenytoin is contra-indicated in sinus bradycardia, sino-atrial block, and second and third degree A-V block, and patients with Adams-Stokes syndrome.

In adults, intravenous administration should not exceed 50mg per minute. In neonates, the drug should be administered at a rate of 1-3mg/kg/min.

The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Severe cardiotoxic reactions and fatalities due to depression of atrial and ventricular conduction and ventricular fibrillation, respiratory arrest and tonic seizures have been reported particularly in elderly or gravely ill patients, if the preparation is given too rapidly or in excess.

When the drug is administered rapidly by the intravenous route hypotension usually occurs.

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. Subcutaneous or perivascular injection should be avoided because of the highly alkaline nature of the solution.

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.

General:

Intravenous phenytoin should be used with caution in patients with hypotension and severe myocardial insufficiency.

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.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present together, combined drug therapy is needed.

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. 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.

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).

Phenytoin is highly protein bound and extensively metabolised by the liver. In patients with impaired liver function a reduced maintenance dosage may be required to prevent accumulation and toxicity. 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 10-20mg/l. Dosage should not exceed the minimum necessary to control convulsions.

Biotransformation of phenytoin occurs mainly in the liver. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes. Therefore it is advised that caution be taken when treating diabetic patients.

It has been rarely reported that the use of phenytoin exacerbates porphyria, therefore caution should be exercised in using this medication in patients suffering from this disease.

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 behaviours emerge.

Laboratory Tests:

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

Drugs which may increase phenytoin serum levels include: amiodarone, antifungal agents (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole), chloramphenicol, chlordiazepoxide, diazepam, dicoumarol, diltiazem, disulfiram, oestrogens, fluoxetine, H2-antagonists, halothane, isoniazid, methylphenidate, nifedipine, omeprazole, phenothiazines, phenylbutazone, salicylates, succinimides, sulphonamides, tolbutamide, trazodone, and viloxazine.

Drugs, which may decrease phenytoin serum levels, include folic acid, reserpine, rifampicin, sucralfate, theophylline and vigabatrin.

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St John's wort (Hypericum perforatum). St John's wort induces enzymes that metabolise phenytoin. 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, which may either increase or decrease phenytoin serum levels, include carbamazepine, phenobarbital, valproic acid, sodium valproate, antineoplastic agents, certain antacids and ciprofloxacin. Similarly the effect of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.

Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

Phenytoin impairs the effect of the following drugs: antifungal agents, antineoplastic agents, calcium channel blockers, clozapine, corticosteroids, ciclosporin, dicoumarol, digitoxin, doxycycline, frusemide, lamotrigine, methadone, neuromuscular blockers, oestrogens, oral contraceptives, paroxetine, quinidine, rifampicin, theophylline and vitamin D.

The effect of warfarin is enhanced by phenytoin. The effect of phenytoin on warfarin is variable and prothrombin times should be determined when these agents are combined.

Serum level determinations are especially helpful when possible drug interactions are suspected.

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, gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate concentrations be measured at least every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

In considering the use of phenytoin intravenously in the management of status epilepticus in pregnancy, the following information should be weighed in assessing the risks and the benefits. The potential adverse effects upon the foetus of status epilepticus, specifically hypoxia, make it imperative to control the condition in the shortest possible time.

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 and 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.

There is some evidence that phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients, therefore it should not be used as the first drug during pregnancy, especially early pregnancy, unless in the judgement of the physician the potential benefits 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 been recent reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, microencephaly 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, because of 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, post partum 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.

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

None known.

Signs of toxicity are associated with cardiovascular and central nervous system depression.

Central Nervous System:

The most common adverse reactions with phenytoin therapy occur in the central nervous system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, mental confusion, paraesthesia, drowsiness and vertigo. Dizziness, insomnia, transient nervousness, motor twitching, and headache have also been observed. There have also been rare reports of phenytoin-induced dyskinesia, 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. Tonic seizures have also been reported.

Cardiovascular:

Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or gravely ill patients.

Respiratory:

Alterations in respiratory function including respiratory arrest may occur.

Injection Site:

Local irritation, inflammation and tenderness. Necrosis and sloughing have been reported after subcutaneous or perivascular injection. Subcutaneous or perivascular injection should be avoided. Soft tissue irritation and inflammation have occurred at the site of injection with and without extravasation of intravenous phenytoin.

Dermatological System:

Dermatological reactions sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common. Other types of dermatitis are seen more rarely. Other more serious forms, which may be fatal, have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Haemopoietic System:

Haemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, and 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. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or 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 serum sickness, e.g. fever, rash and liver involvement.

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.

Gastrointestinal System:

Nausea, vomiting, constipation, toxic hepatitis, and liver damage.

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.

Immune System:

Hypersensitivity syndrome 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, periarteritis 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.

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.

The lethal dose in children is not known. The mean lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperflexia, lethargy, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

Attempts to relate serum levels of the drug to toxic effects have shown wide interpatient variation. Nystagmus on lateral gaze usually appears at 20mg/l, and ataxia at 30mg/l, dysarthria and lethargy appear when the serum concentration is>40mg/l, but a concentration as high as 50mg/l has been reported without evidence of toxicity.

As much as 25 times the therapeutic dose, which resulted in a serum concentration of 100mg/l, was taken with complete recovery.

Treatment:

Treatment is non-specific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used 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.

Pharmacotherapeutic group: Antiepileptics

ATC code: N03AB 01

Phenytoin is effective in various animal models of generalised convulsive disorders and 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.

After injection phenytoin is distributed into body fluids including 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).

In serum, phenytoin binds rapidly and reversibly to proteins. About 90% of phenytoin in plasma is bound to albumin. The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours.

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

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.

There are no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

Propylene glycol

Ethanol (96%)

Sodium hydroxide

Water for injection.

Phenytoin solution for injection should not be mixed with other drugs because of precipitation of phenytoin acid.

2 years.

Do not store above 25°C.

Store in the original package.

Keep out of sight and reach of children.

The product should not be used if a precipitate or haziness is noticed in the ampoule

Transparent, type I glass ampoules.

Each 5ml ampoule contains 250mg phenytoin sodium.

Packs contain 1 ampoule or 50 ampoules (clinical pack)

Should be used immediately after opening. Discard any unused product once opened.

Refer also to 4.2 above.

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

UK

PL 16853/0129

21 August 2006

April 2012