This information is intended for use by health professionals

1. Name of the medicinal product

Phenytoin Sodium 50mg/ml Solution for Injection

2. Qualitative and quantitative composition

Each 5ml of solution contains Phenytoin Sodium 250mg.

Excipient(s) with known effect

Each 5ml of solution also contains 395.75 mg of Ethanol and not more than 23mg of Sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for Injection.

A clear colourless particle free solution.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

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

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.

Determination of phenytoin serum levels is advised during use in the management of status epilepticus and subsequently whilst establishing maintenance dosage. The clinically effective range is usually 10- 20mg/1 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 peak plasma levels may not be reached for up to 24 hours.

Other clinical conditions: It is not possible to provide a universally applicable dosage schedule.

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

Although absorption of phenytoin is slow following i.m. injection, such use may be appropriate in 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, Phenytoin Injection 100 - 200mg (2 - 4ml) may be given intramuscularly at approximately 4-hour 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 300mg and adjusted according to serum level estimations.

If possible, intramuscular injections of phenytoin should not be continued for more than one week; after this, alternative routes such as naso-gastric intubation should be considered. For time periods less than one week, the patient switched from intramuscular administration should receive 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): Phenytoin clearance may be decreased in elderly patients. Lower or less frequent dosing may be required (see section 5.2). It should be noted that complications may occur more readily in elderly patients.

Paediatric population

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

Infants and children: Children tend to metabolize phenytoin more rapidly than adults. This should be considered when determining dosage regimens; monitoring serum levels is therefore particularly beneficial in such cases.

Method of administration: Intravenous. Intramuscular.

Solutions for parenteral administration should be inspected visually for particulate matter and discoloration prior to use. Only a clear solution should be used and the product should be discarded if a precipitate or haziness develops in the solution. On refrigeration or freezing, a precipitate might form, but this will dissolve when 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 discoloration may develop, but this does not affect the potency of the 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 can most often be achieved with serum levels in the range 10 - 20mg/1 (40 - 80 micromoles/1).

Because of the risk of local toxicity, intravenous phenytoin 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 administration by intravenous infusion phenytoin injection should be diluted in 50 - 100 ml of normal saline, and the final concentration of phenytoin in the solution should not exceed 10 mg/ml, the infusion mixture should not be refrigerated. 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.

Phenytoin should neither be mixed with other drugs nor be added to dextrose or dextrose-containing solutions due to the potential for precipitation of phenytoin acid.

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

4.3 Contraindications

Hypersensitivity to the active substance, other hydantoins or to any of the excipients listed in section 6.1

Because of its effect on ventricular automaticity, it is also contra-indicated in sinus bradycardia, sino-atrial block, and second and third degree A-V block, and patients with Adams-Stokes syndrome. Intra-arterial injection must be avoided because of the high pH of the solution.

Co-administration of phenytoin is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

4.4 Special warnings and precautions for use

General

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

Hypotension usually occurs with rapid administration of phenytoin by the intravenous route. Irritation and inflammation of soft tissue has occurred at the injection site 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.

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

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including 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.

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

Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures.

Because phenytoin is highly protein bound and extensively metabolised by the liver, reduced maintenance dosage may be required in patients with impaired liver function to prevent accumulation and toxicity. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, as the pharmacologically active free drug concentration is unlikely to be altered, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range 10 - 20mg/l.

Dosage should not exceed the minimum necessary to control convulsions.

Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total plasma phenytoin concentrations should be made with caution. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinemia. Unbound phenytoin concentrations may be more useful in these patient populations.

Cardiovascular Effect

The most significant signs of toxicity with the intravenous use of phenytoin 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.

Anticonvulsant Hypersensitivity Syndrome/ Drug Reaction with Eosinophilia and Systemic Symptoms (AHS/DRESS):

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug-induced, multiorgan syndrome that is potentially fatal and occurs in some patients taking anticonvulsant medication, including phenytoin. AHS/DRESS typically, although not exclusively is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leucocytosis, and eosinophilia. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2-4 weeks, but has been reported in individuals receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative aetiology for the signs and symptoms cannot be established. Drug rash with eosinophilia and systemic symptoms (DRESS) reflects a serious hypersensitivity reaction to drugs, characterized by skin rash, fever, lymph node enlargement, and internal organ involvement. Cases of DRESS have been noted in patients taking phenytoin.

Patients at higher risk for developing AHS/DRESS include black patients, patients who have a family history of or who have experienced this syndrome in the past (with phenytoin or other anticonvulsant drugs), and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the phenytoin and provide appropriate supportive measures.

Serious skin reactions:

Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Phenytoin.

Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS and TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Phenytoin sodium treatment should be discontinued.

The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

If the patient has developed SJS or TEN with the use of Phenytoin and it must not be re-started in this patient at any time.

The physician should advise the patient to discontinue treatment if the rash appears. 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 contraindicated.

Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms.

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.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

Literature reports suggest that the combination of phenytoin, cranial irradiation, and the gradual reduction of corticosteroids may be associated with the development of erythema multiforme and/or SJS and/or TEN.

Local Toxicity (including Purple Glove Syndrome)

Soft tissue irritation and inflammation have occurred at the site of injection with and without extravasation of intravenous phenytoin.

Oedema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing of skin. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting and in rare cases, amputation.

Improper administration including subcutaneous or perivascular injection should be avoided.

Intramuscular phenytoin administration may cause pain, necrosis, and abscess formation at the injection site (see section 4.2).

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.

Central Nervous System Effect

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 and/or cerebellar atrophy. 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)

Hepatic Injury

Biotransformation of phenytoin occurs mainly in the liver.

Toxic hepatitis and liver damage have been reported and may, in rare cases, be fatal.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with AHS/DRESS (see section 4.4).

Patients with impaired hepatic function, the elderly, or those who are gravely ill may show early signs of toxicity.

The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered.

The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in black patients.

Haematopoietic System

Haematopoietic 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.

Metabolic Effect

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. Caution is advised when treating patients with diabetes.

There are isolated reports associating phenytoin with exacerbation of porphyria, therefore, caution should be exercised when using phenytoin in patients with porphyria.

Suicide

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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.

Laboratory tests: It may be necessary to measure serum phenytoin levels to achieve optimal dosage adjustments.

This product contains a number of excipients known to have a recognized action or effect. These are:

• Sodium: This medicinal product contains less than 1mmol sodium (23mg) per dose i.e. essentially 'sodium-free'

• Ethanol (395.75 mg/5 ml):- This may be harmful for those suffering from alcoholism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

4.5 Interaction with other medicinal products and other forms of interaction

Drug Interactions

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Sucralfate may decrease phenytoin serum levels.

A pharmacokinetic interaction study between nelfinavir and phenytoin both administered orally showed that nelfinavir reduced AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively. Therefore, phenytoin concentration should be monitored during co-administration with nelfinavir, as nelfinavir may reduce phenytoin plasma concentration.

Certain antacids may either increase or decrease phenytoin serum levels.

Phenytoin increases the clearance of quetiapine and thus impairing the effect of it. Neurotoxicity has been reported during concomitant use of phenytoin and lithium.

Drugs whose effect is impaired by phenytoin include: antifungal agents e.g. antifungals, antineoplastic agents, calcium channel blockers, clozapine, corticosteroids, ciclosporin, dicoumarol, digitoxin, doxycycline, furosemide, lamotrigine, methadone, neuromuscular blockers, oestrogens, oral contraceptives, paroxetine, quinidine, rifampicin, theophylline, vitamin D, amprenavir, disopyramide, felodipine, haloperidol, levodopa, methoxsalen, mexiletine, and thyroxine.

Drugs whose effect may be enhanced by phenytoin include warfarin. 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.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes and may reduce the levels of drugs metabolized by these enzymes.

There are many drugs which may increase or decrease serum phenytoin levels or which phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

The most commonly occurring drug interactions are listed below.

Drugs which may increase Phenytoin serum levels

Table 1 summarizes the drug classes which may potentially increase Phenytoin serum levels.

Table 1. Drugs which may increase Phenytoin Serum Levels

Drug Classes

Drugs in each Class (such as)

Alcohol (acute intake)

Analgesic/Anti-inflammatory agents

azapropazone

phenylbutazone

salicylates

Anesthetics

halothane

Antibacterial agents

chloramphenicol

erythromycin

isoniazid

sulfadiazine

sulfamethizole

sulfamethoxazole-trimethoprim

sulfaphenazole

sulfisoxazole

sulfonamides

Anticonvulsants

felbamate

oxcarbazepine

sodium valproate

succinimides

topiramate

Antifungal agents

amphotericin B

fluconazole

itraconazole

ketoconazole

miconazole

voriconazole

Antineoplastic agents

fluorouracil

capecitabine

Benzodiazepines/Psychotropic agents

chlordiazepoxide

diazepam

disulfiram

methylphenidate

trazodone

viloxazine

Calcium channel blockers/Cardiovascular agents

amiodarone

dicumarol

diltiazem

nifedipine

ticlopidine

H2-antagonists

cimetidine

HMG-CoA reductase inhibitors

fluvastatin

Hormones

oestrogens

Immunosuppressant drugs

tacrolimus

Oral hypoglycemic agents

tolbutamide

Proton pump inhibitors

omeprazole

Serotonin re-uptake inhibitors

fluoxetine

fluvoxamine

sertraline

Drugs which may decrease Phenytoin serum levels

Table 2 summarizes the drug classes which may potentially decrease Phenytoin serum levels.

Table 2. Drugs which may decrease Phenytoin Serum Levels

Drug Classes

Drugs in each Class (such as)

Alcohol (chronic intake)

Antibacterial agents

rifampin

ciprofloxacin

Anticonvulsants

vigabatrin

Antineoplastic agents

bleomycin

carboplatin

cisplatin

doxorubicin

methotrexate

Antiretrovirals

fosamprenavir

nelfinavir

ritonavir

Bronchodilators

theophylline

Cardiovascular agents

reserpine

Folic Acid

folic acid

Hyperglycemic agents

diazoxide

Sucralfate

Sucralfate

St. John's wort

St. John's wort

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St. John's wort (Hypericum perforatum).

This is due to induction of drug metabolising enzymes by St. John's wort. 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 increase or decrease Phenytoin serum levels

Table 3 summarizes the drug classes which may either increase or decrease Phenytoin serum levels.

Table 3. Drugs which may increase or decrease Phenytoin Serum

Drug Classes

Drugs in each Class (such as)

Antacids

Antacids

Antibacterial agents

ciprofloxacin

Anticonvulsants

carbamazepine

phenobarbital

sodium valproate

valproic acid

Antineoplastic agents

Psychotropic agents

chlordiazepoxide

diazepam

phenothiazines

Drugs whose serum levels and/or effects may be altered by phenytoin

Table 4 summarizes the drug classes whose serum levels and/or effects may be altered by Phenytoin.

Table 4. Drugs whose serum levels and/or effects may be altered by Phenytoin

Drug Classes

Drugs in each Class (such as)

Antibacterial agents

doxycycline

rifampin

tetracycline

Anticonvulsants

carbamazepine

lamotrigine

phenobarbital

sodium valproate

valproic acid

Antifungal agents

azoles

posaconazole

voriconazole

Antihelmintics

albendazole

praziquantel

Antineoplastic agents

teniposide

Antiretrovirals

delavirdine

efavirenz

fosamprenavir

indinavir

lopinavir/ritonavir

nelfinavir

ritonavir

saquinavir

Bronchodilators

theophylline

Calcium channel blockers/Cardiovascular agents

digitoxin

digoxin

mexiletine

nicardipine

nimodipine

nisoldipine

quinidine

verapamil

Corticosteroids

Coumarin anticoagulants

warfarin

Cyclosporine

Diuretics

furosemide

HMG-CoA reductase inhibitors

atorvastatin

fluvastatin

simvastatin

Hormones

oestrogens

oral contraceptives

Hyperglycemic agents

diazoxide

Neuromuscular blocking agents

alcuronium

cisatracurium

pancuronium

rocuronium

vecuronium

Opioid analgesics

methadone

Oral hypoglycemic agents

chlorpropamide

glyburide

tolbutamide

Psychotropic agents/Antidepressants

clozapine

paroxetine

quetiapine

sertraline

Vitamin D

vitamin D

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

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.

Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also 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. Phenytoin may affect blood sugar metabolism tests.

It is recommended that serum folate concentrations be measured at least every 6 months, and folic acid supplements given if necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy

The following information should be taken into account when considering the intravenous use of phenytoin in the management of status epilepticus in pregnancy. It is essential to control the condition as quickly as possible in order to reduce the potential adverse effects, specifically hypoxia, of status epilepticus upon the foetus.

There are intrinsic methodologic problems in obtaining meaningful data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in the development of birth defects. Most mothers on anticonvulsant therapy deliver normal infants. In patients receiving an anticonvulsant drug to prevent major seizures, it is important that the drug should not be discontinued because of the strong possibility of precipitating status epilepticus and attendant hypoxia and threat to life if the drug was withdrawn. In individual cases, where the frequency and severity of the seizure disorder are such that cessation of therapy does not pose a serious risk to the patient, discontinuation of the drug may be considered prior to and during pregnancy. However, it cannot be stated with certainty 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 patients with epilepsy. Therefore, phenytoin should not be used as a first-line drug during pregnancy, especially in early pregnancy, unless the physician considers that the potential benefits outweigh the risk.

In addition to the reports of increased incidence of congenital malformations such as cleft lip/palate and cardiac malformations in children of women who received phenytoin and other antiepileptic agents, there have been reports of foetal hydantoin syndrome. The syndrome consists of prenatal growth deficiency, microencephaly and mental deficiency in the children of women who received phenytoin, alcohol, barbiturates or trimethadione. However, all of these features are interrelated and are frequently associated with intrauterine growth retardation due to other causes.

There are isolated reports of malignancies, including neuroblastoma, in the children of women who 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, postpartum 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.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness (see Section 4.8).

4.8 Undesirable effects

In the table below all adverse reactions with phenytoin are listed by class and frequency Not Known (cannot be estimated from the available data).

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

MedDRA System organ Class

Frequency

Undesirable Effects

Blood and lymphatic system disorders

Not Known

Haematopoietic 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.

Immune system disorders

Rare

Not Known

Hypersensitivity syndrome

Anaphylactoid reaction, anaphylactic reaction, periarteritis nodosa, immunoglobulin abnormalities may occur.

Psychiatric disorders

Not Known

Insomnia, transient nervousness, confusion.

Nervous system disorders

Rare

Not Known

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.

Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, dysarthria and decreased coordination. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use (see section 4.4). Dizziness, motor twitchings, headache, paraesthesia, somnolence, drowsiness and dysgeusia have also been observed.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Tonic convulsions have also been reported.

Peripheral sensory neuropathy.

Ear and labyrinth disorders

Not Known

Vertigo

Cardiac disorders

Not Known

Hypotension may occur. Arrhythmias including bradycardia, atrial and ventricular depression and ventricular fibrillation can occur and these have, in some cases, resulted in asystole/ cardiac arrest and death. Severe complications are most commonly encountered in older people or gravely ill patients.

Respiratory, thoracic and mediastinal disorders

Not Known

Pneumonitis, alterations in respiratory function including respiratory arrest may occur.

Gastrointestinal disorders

Not Known

Vomiting, nausea, gingival hyperplasia, constipation.

Hepatobiliary disorders

Not Known

Acute hepatic failure, hepatitis toxic, liver injury, hepatotoxicity, hepatic function abnormal

Skin and subcutaneous tissue disorders

Rare

Not Known

Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4) has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgia, eosinophilia, pyrexia, hepatic function abnormal, lymphadenopathy or rash). 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.

Dermatological manifestations 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 and rare forms which may be fatal have bullous, exfoliative or purpuric dermatitis, lupus erythematosus, hirsutism, hypertrichosis, coarsening of the facial features and enlargement of the lips, Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported very rarely (see section 4.4). Skin exfoliation.

Musculoskeletal and connective tissue disorders

Not Known

Systemic lupus erythematosus, arthropathy. 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. Discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported (see section 4.4). Dupuytren's contracture. Arthralgia.

Renal and urinary disorders

Not Known

Tubulointerstitial nephritis, Peyronie's Disease.

General disorders and administration site conditions

Not Known

Local irritation, inflammation, tenderness, necrosis and oedema have been reported with or without extravasation of intravenous phenytoin. Fever.

Investigations

Not Known

Thyroid function test abnormal

Paediatric population

The adverse event profile of phenytoin is generally similar between children and adults. Gingival hyperplasia occurs more frequently in paediatric patients and in patients with poor oral hygiene.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The mean lethal dose in adults is estimated to be 2 to 5 grams. The lethal dose in children is not known. The initial signs are nystagmus, diplopia, 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 above 40mg/l, although a serum 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. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment: There is no known antidote and treatment is symptomatic and supportive. Particular attention should be paid to circulatory and respiratory function 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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.

Phenytoin is an anticonvulsant which appears to stabilise rather than elevate the seizure threshold and to limit the spread of seizure activity rather than abolish the primary focus of seizure discharge. Phenytoin exerts a stabilising effect on excitable membranes of a variety of cells, including neurons and cardiac myocytes.

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.

5.2 Pharmacokinetic properties

Absorption

After injection phenytoin is distributed into body fluids including CSF.

Distribution

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.

Biotransformation

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.

Elimination

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.

Special Populations

Patients with Renal or Hepatic Disease: see section 4.4.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see section 4.2).

5.3 Preclinical safety data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical particulars
6.1 List of excipients

Propylene Glycol

Ethanol

Sodium Hydroxide

Water for Injections

6.2 Incompatibilities

Phenytoin has a pH in the range of 10 - 12.3. It will only stay in solution when the pH is considerably alkaline (about 10 - 12). The mixing of phenytoin sodium injection with other drugs is not recommended.

Phenytoin should neither be mixed with other drugs nor be added to dextrose or dextrose-containing solutions due to the potential for precipitation of phenytoin acid.

6.3 Shelf life

3 years.

If only part used, discard the remaining solution.

6.4 Special precautions for storage

Do not store above 30°C.

Keep the ampoule in the outer carton in order to protect from light.

6.5 Nature and contents of container

5ml, clear glass ampoules, glass type I, Ph. Eur. packed in cardboard cartons to contain 10 x 5ml ampoules.

6.6 Special precautions for disposal and other handling

For I.V. and I.M. administration.

Use as directed by the physician.

Solutions in which a haziness or precipitate develops should not be used.

Do not mix with other drugs because of precipitation of phenytoin acid.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Mercury Pharmaceuticals Ltd,

Capital House, 85 King William Street,

London EC4N 7BL, UK

8. Marketing authorisation number(s)

PL 12762/0597

9. Date of first authorisation/renewal of the authorisation

Date of first authorization: 29/11/91.

10. Date of revision of the text

January 2019