This information is intended for use by health professionals

1. Name of the medicinal product

Phenytoin Hikma 50 mg / ml solution for injection

2. Qualitative and quantitative composition

Each ml of solution contains 50 mg phenytoin sodium, equivalent to 46 mg phenytoin.

One 5 ml ampoule contains 250 mg phenytoin sodium, equivalent to 230 mg phenytoin.

Excipients with known effect:

Each 5 ml ampoule contains:

Ethanol (394 mg)

Propylene glycol (2072 mg)

Sodium (0.517 mg - 0.776 mg)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection

Clear and colourless solution with pH range of 11.5 - 12.1.

4. Clinical particulars
4.1 Therapeutic indications

- Status epilepticus and series of seizures

- Prophylaxis of seizures occurring in connection with neurosurgery.

N.B.

Phenytoin is not effective in absence status epilepticus or in the prophylaxis and treatment of febrile convulsions.

4.2 Posology and method of administration

Dosage instructions

The therapeutic range for plasma concentration is generally between 10 and 20 micrograms/ml phenytoin; concentrations over 25 micrograms/ml phenytoin may be in the toxic range.

Status epilepticus and series of seizures

Continuous monitoring of ECG, blood pressure and neurological status and regular determination of plasma phenytoin concentrations is essential. In addition, resuscitation facilities should be readily available.

Adults and adolescents over 12 years of age

The initial dose is 1 ampoule of Phenytoin (equivalent to 230 mg phenytoin), administered at a maximum rate of 0.5 ml/min (equivalent to 23 mg phenytoin per minute). If the seizures do not stop after 20 to 30 minutes, the dose can be repeated.

If the seizures stop, a dose of 1 ampoule Phenytoin (equivalent to 230 mg phenytoin) can be given every 1.5 to 6 hours up to a maximum daily dose of 17 mg/kg bodyweight (or 6 ampoules - equivalent to 1380 mg phenytoin), to achieve rapid saturation.

At a maximum daily dose of 17 mg/kg bodyweight, this is equivalent to

Bodyweight

Ampoules

Phenytoin

41 kg

3

690 mg

54 kg

4

920 mg

68 kg

5

1150 mg

81 kg

6

1380 mg

Children up to 12 years of age

On day 1 the maximum daily dose is 30 mg/kg bodyweight, on day 2 20 mg/kg bodyweight, on day 3 10 mg/kg bodyweight. The maximum injection rate is 1 mg/kg bodyweight per minute.

Day 1

At a maximum daily dose of 30 mg/kg bodyweight, this is equivalent to

Bodyweight

Ampoules

Phenytoin

8 kg

1

230 mg

15 kg

2

460 mg

23 kg

3

690 mg

31 kg

4

920 mg

38•kg

5

1150 mg

46 kg

6

1380 mg

Day 2

At a maximum daily dose of 20 mg/kg bodyweight, this is equivalent to

Bodyweight

Ampoules

Phenytoin

12 kg

1

230 mg

23 kg

2

460 mg

35 kg

3

690 mg

46 kg

4

920 mg

Day 3

At a maximum daily dose of 10 mg/kg bodyweight, this is equivalent to

Bodyweight

Ampoules

Phenytoin

23 kg

1

230 mg

46 kg

2

460 mg

Prophylaxis of seizures

Adults and adolescents over 12 years of age receive 1 to 2 ampoules of Phenytoin (equivalent to 230 to 460 mg phenytoin) daily at a maximum rate of injection of 0.5 ml/min (equivalent to 23 mg phenytoin per minute).

Children up to 12 years of age receive 5 to 6 mg/kg bodyweight. Rate of injection is reduced according to the weight/age of the child.

At a daily dose of 5 mg/kg bodyweight, this is equivalent to

Bodyweight

ml

Phenytoin

9 kg

1

46 mg

18 kg

2

92 mg

28 kg

3

138 mg

37 kg

4

184 mg

46 kg

5

230 mg

At a daily dose of 6 mg/kg bodyweight, this is equivalent to

Bodyweight

ml

Phenytoin

8 kg

1

46 mg

15 kg

2

92 mg

23 kg

3

138 mg

31 kg

4

184 mg

38 kg

5

230 mg

46 kg

6

276 mg

Duration of administration

Duration of administration is dependent on the underlying disease and the course of the illness. If the medicinal product is well-tolerated, it can be used indefinitely.

Switching preparations

Due to the relatively narrow therapeutic range and the varying bioavailability of the numerous pharmaceutical preparations, when changing from one preparation to another containing phenytoin, the phenytoin-plasma concentrations must be monitored closely. If the dose is kept the same, steady state (constant plasma concentration) can be expected after 5 to 14 days.

After switching to an oral formulation, treatment should be monitored monthly during the first three months, and then six-monthly. Phenytoin-plasma concentration, blood count, liver enzymes (GOT, GPT, gamma-GT), alkaline phosphatase and additionally in children thyroid function should be monitored.

Therefore the dose (if possible) should be reduced slowly and the new antiepileptic medicinal product started at a low dose and gradually increased. Abrupt withdrawal of Phenytoin may increase seizure frequency or lead to status epilepticus.

Additional information on special populations

Patients with renal/hepatic impairment:

There is no reference for dosage adjustment for this special group; however, caution should be taken in patients with renal and hepatic disease (see section 4.4). Impaired renal and hepatic functions require careful monitoring.

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 1-3 mg/kg/min at dose of 15-20 mg/kg. This will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range of 10-20 mg/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.

Method of administration

The solution for injection is for intravenous use only as absorption is delayed and unreliable after intramuscular administration. Phenytoin should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter. Subcutaneous or venous perivascular or intra-arterial injection should be avoided, as the alkaline phenytoin solution for injection can cause tissue necrosis. The solution for injection must not be mixed with other solutions, as phenytoin can crystallise out.

Before use, the ampoules should be checked for precipitation and discolouration.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

Phenytoin 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.

Only a clear solution should be administered. A slight yellow discolouration has no effect on the efficacy of this solution.

For single use only.

Once it has been broken open, Phenytoin should be used immediately.

Because of the risk of local toxicity, intravenous phenytoin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral phenytoin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution (see 4.4. Special warnings and precautions for use, Local Toxicity (including Purple Glove Syndrome)).

4.3 Contraindications

Phenytoin should not be administered:

- if the patient is hypersensitive to phenytoin, other hydantoins or to any of the excipients

- if the patient already has severe damage to the blood cells and bone marrow

- in grade II and grade III AV block or Stokes-Adams syndrome due to its effect on ventricular automaticity

- if the patient suffers from sick sinus syndrome, sinus bradycardia, - sino-artrial block-

- within the first three months after myocardial infarction and in case of cardiac output failure (left ventricular ejection fraction < 35%).

- subcutaneously or intra-arterial due to the high pH of the preparation.

4.4 Special warnings and precautions for use

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.

Phenytoin should not be used in case of:

- heart failure

- severely impaired pulmonary function

- severe hypotension (systolic blood pressure less than 90 mm Hg)

- grade I AV block

- atrial fibrillation and atrial flutter

Hyperglycaemia can be potentiated in diabetic patients.

- 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 or TEN is within the first weeks of treatment. (Adoption to individual drug if such data are available)

- If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Phenytoin 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, Phenytoin must not be re-started in this patient at any time.

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

Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis

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.

Important information regarding treatment

Patients who suffer from genetically determined slow hydroxylation may develop signs of overdose even at moderate doses. The dose should be reduced and phenytoin-plasma concentrations checked.

After switching to an oral formulation, treatment should be monitored monthly during the first three months, and then six-monthly. Phenytoin-plasma concentration, blood count, liver enzymes (GOT, GPT, gamma-GT), alkaline phosphatase and additionally in children thyroid function should be monitored (see section 4.2).

A blood count showing moderate, stable leukopenia and an isolated increase in gamma-GT should not normally necessitate withdrawal of treatment.

Administration in patients with renal or hepatic disease

Phenytoin should be used with particular caution in patients with renal or hepatic disease. Regular follow-up checks should be performed.

Phenytoin should be used with caution in patients with hypoproteinaemia, as reduced plasma protein binding may lead to an increase in the free phenytoin fraction (without increasing the total serum concentration of phenytoin). Increase in the free phenytoin fraction may enhance the risk of nervous system disorders.

Abrupt withdrawal of Phenytoin may increase seizure frequency or lead to status epilepticus.

Phenytoin contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially “sodium-free”.

Phenytoin contains propylene glycol which may cause alcohol-like symptoms.

This medicinal product contains 10 vol % ethanol (alcohol), i.e. up to 394 mg per dose, equivalent to 10 ml beer, 4.17 ml wine per dose.

Harmful to those suffering form alcoholism.

To be taken into account in pregnant of 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

A number of medicinal products can increase or decrease serum phenytoin levels, and phenytoin can alter the serum levels of other medicinal products. If interactions are suspected, it is sensible to determine serum phenytoin levels. The most common interactions are:

Substances that can increase serum phenytoin levels:

Acute alcohol consumption, oral anticoagulants (e.g. dicumarol), benzodiazepines (e.g. chlorodiazepoxide, diazepam, trazodone), anaesthetics (e.g. halothane), antiepileptics (e.g. sulthiame, valproate, ethosuximide, mesuximide, felbamate, oxcarbazepine, eslicarbazepine acetate), non-steroidal antirheumatics (e.g. salicylate, azapropazone, phenylbutazone), antibiotics (e.g. chloramphenicol, erythromycin, isoniazide, sulfonamide), antimycotics (e.g. amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole), calcium channel inhibitors (amiodarone, diltiazem, nifedipine), hormones (e.g. oestrogen), disulfiram, methylphenidate, omeprazole, ticlopidine, viloxazine, cimetidine, ranitidine, cycloserine, PAS, tricyclic psychotropic drugs, fluoxetine, tolbutamide.

Topiramate may increase plasma concentrations of phenytoin in individual patients'.

Substances that can decrease serum phenytoin levels:

Antibiotics (e.g. ciprofloxacin, rifampicine); antiepileptics (e.g. carbamazepine, vigabatrine, phenobarbital, primidone), reserpine, sucralfate, diazoxide, theophylline, chronic alcohol abuse, nelfinavir (oral co-administration may lead to a decrease in phenytoin plasma concentrations; therefore phenytoin plasma concentrations should be monitored if such co-administration occurs).

Substances that can increase or decrease serum phenytoin levels:

Antiepileptics (e.g. carbamazepine, sodium valproate, valproic acid, phenobarbital), chlorodiazepoxide, diazepam.

Additional administration of valproic acid or increasing the dose of valproic acid can increase the amount of free phenytoin (concentration of non protein-bound portion) without increasing the serum level of total phenytoin. This can increase the risk of undesirable effects, especially brain damage (see section 4.8).

Phenytoin can alter the concentration of active substance or the effect of the following medicinal products:

Clozapine, corticosteroids, oral anticoagulants (e.g. dicumarol), doxycycline, praziquantel, rifampicine, tetracycline, azole derivatives (e.g. itraconazole), antiepileptics (e.g. lamotrigine, carbamazepine, valproate, felbamate), oral contraceptives (the contraceptive effect can be unreliable), oestrogen, alcuronium, pancuronium, vecuronium, cyclosporine, diazoxide, furosemide, paroxetine, sertraline, theophylline, digitoxin, nicardipine, nimodipine, chinidine, verapamil, tricyclic psychotropic drugs, methadone, chloropropamide, glyburide, tolbutamide, vitamin D, teniposide.

Phenytoin can lower the plasma concentration of topiramate, zonisamide or tiagabine and the plasma concentration of the active metabolite of oxcarbazepine (i.e. MHD) and eslicarbacepine acetate (i.e. eslicarbacepine), respectively.

Patients on anticoagulants are advised to have regular checks of blood coagulation time (INR). The toxicity of methotrexate can be increased. The effect of phenytoin can be reduced by simultaneous intake of folic acid.

Phenytoin (hydantoin) may increase the potential hepatotoxicity of paracetamol and decrease its pharmacological effects. The mechanism may be related to induction of paracetamol metabolismmetabolisn with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of paracetamol overdose.

Herbal preparations containing St.John's wort (Hypericum perforatum) should not be used while taking phenytoin dues to the risk of decrease plasma concentration and reduced clinical effects of phenytoin.

4.6 Fertility, pregnancy and lactation

Pregnancy

Risks associated with epilepsy and antiepileptics in general:

- Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential.

- The need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant.

- The risk of birth defects is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects.

- Multiple antiepileptic therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible.

- No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both mother and child.

Risks associated with phenytoin:

- An abnormality typical of phenytoin is hypoplasia of the nails or entire ungual phalanx.

- Craniofacial dysmorphia (hypoplasia of the middle part of the face), cardiac abnormalities, microcephaly, retarded growth and restricted cognitive development have been frequently seen following monotherapy with phenytoin.

- 12 cases of neuroectodermal tumours have been described in children who were exposed to phenytoin prenatally. Six of these children had neuroblastoma. Even if the number of cases is too small to prove a causal connection, a risk of transplacental carcinogenesis cannot be ruled out.

- In infants who were exposed to phenytoin prenatally, a decrease in vitamin K-dependent coagulation factors must be anticipated in the first 24 hours of life. Haemorrhages have been described in newborn infants.

In view of this data, the following should be considered:

- Women who are likely to become pregnant or who are of childbearing potential must be notified by a specialist of the necessity of planning and monitoring any pregnancy and informed of the 2-3 fold risk of abnormalities under antiepileptic treatment. One should be aware that the efficacy of oral contraceptives may be reduced (see section 4.5).

- If a woman is pregnant or plans to become pregnant, the need for antiepileptic treatment should be reassessed. Phenytoin must only be used in pregnancy after a careful risk-benefit assessment has been carried out.

- Phenytoin should be prescribed as monotherapy during pregnancy if possible.

- Antiepileptic treatment should not be abruptly withdrawn during pregnancy as this may lead to breakthrough seizures which can be harmful to both mother and unborn child.

- During organogenesis, in particular between gestational day 20 and 40, the lowest dose necessary to control seizures should be used because the incidence of malformations is obviously dose-dependent. Phenytoin plasma concentrations fall during pregnancy and increase after delivery to pre-pregnancy levels. Regular checks of phenytoin plasma levels are therefore advisable throughout pregnancy and following delivery.

- To prevent bleeding complications in newborn infants, vitamin K1 should be administered prophylactically during the last weeks of pregnancy to the mother and subsequently to the newborn infant.

- Folic acid prophylaxis is recommended.

- A high-resolution ultrasound diagnosis should be offered to pregnant women.

Lactation:

Breast-feeding during phenytoin treatment is not recommended as small amounts of the active substance pass into the breast milk. The concentration of phenytoin in breast milk is approximately one third of that in the mother's plasma. Nevertheless, if a mother should wish to breast-feed, the infant should be monitored for failure of gaining weight and increased need to sleep.

4.7 Effects on ability to drive and use machines

Phenytoin has major influence on the ability to drive and use machines.

At the start of phenytoin treatment, at high doses and/or when combined with medicinal products that affect the central nervous system, ability to react may be altered to such an extent that, regardless of the effect of the underlying condition being treated, the ability to drive or operate machinery is impaired. This is particular true when phenytoin is taken together with alcohol.

4.8 Undesirable effects

The assessment of undesirable effects is based on the following frequency data:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1 000 to <1/100)

Rare (≥1/10 000 to <1/1 000)

Very rare (<1/10 000)

Not known (cannot be estimated from the available data)

• Blood and the lymphatic system disorders

Rare - changes in blood count (e.g. leukopenia) may occur, if they do develop, it is recommended that phenytoin is withdrawn. The symptoms may also gradually subside if the dose is reduced.

Therefore, when phenytoin is taken long-term, blood count should be checked at regular intervals (several weeks). A blood count showing moderate, stable leukopenia or an isolated increase in gamma-GT should not normally necessitate withdrawal of treatment; swollen lymph glands; impaired haematopoietic organs and bone marrow disorders have been reported. Megaloblastic anaemia has been described, usually due to folic acid deficiency. There is evidence in the literature that phenytoin can trigger attacks of porphyria.

• Immune system disorders

Rare - anaphylactoide reactions and anaphylaxis have 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)

Very rare – systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities may occur.

• Endocrine disorders

Rare - Laboratory tests should be performed every six months, especially in children, owing to possible impairment of thyroid function.

• Nervous system disorders

Very common - nystagmus, movement coordination disorders (ataxia), paraesthesia, mental confusion, dizziness, vertigo, insomnia, headache, increasing irritability, high-frequency tremor at rest, bulbar speech disorders, exhaustion, memorising disturbances and intellectual capacity disorders.

Common - apathy and sedation, perception disorders and clouding of consciousness, or even coma, have been reported for long-term treated patients

Uncommon - polyneuropathy may develop in the context of long-term therapy. There is evidence that during long-term treatment with plasma concentrations in excess of 25 µg/ml and clinical signs of intoxication – even when standard recommended doses are maintained – irreversible cerebellar atrophy may occur.

Rare – dyskinesia, chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Predominantly sensory peripheral polyneuropathy have been observed in patients receiving long-term treatment with phenytoin, also tonic seizures have been reported.

• Eye disorders

Very common - double vision (diplopia)

• Cardiac disorders

Uncommon - severe general changes on the ECG have been reported for patients undergoing long-term treatment with phenytoin.

Rare - asystole due to inhibition of the sinus node, conduction blockade and suppression of the ventricular escape rhythm in patients with total AV block, especially when phenytoin is administered intravenously. Proarrhythmic effects in the form of changes or increases in cardiac arrhythmias can occur which can lead to severe impairment of cardiac activity or even cardiac arrest. With intravenous administration in particular, decreased blood pressure, deterioration in existing heart and respiratory failure can occur. In isolated cases ventricular fibrillation has been triggered. Atrial fibrillation and flutter is not cured by phenytoin. However, as AV node refractory time can be shortened, acceleration in ventricular rate is possible.

• Gastrointestinal disorders

Common - transient symptoms such as dizziness, vomiting and dry mouth can develop if intravenous administration is too fast, which generally subside within 60 minutes unless the patient has received a medication containing phenytoin before. Loss of appetite, nausea, vomiting, weight loss, constipation, have also been reported for long-term treated patients.

• Hepato-biliary disorders

Rare - liver function disorders, possibly with involvement of other organs, if developed, it is recommended to discontinue phenytoin treatment. The symptoms may also gradually subside if the dose is reduced. Therefore, when phenytoin is taken long-term, liver enzyme activity should be checked at regular intervals (several weeks).

• Skin and subcutaneous tissue disorders

Common – morbiliform rash (measles-like)

Rare - allergic rashes (exanthema); severe allergic reactions e.g. skin inflammation with exfoliative dermatitis.

Very rare - excessive growth of gum tissue (gingival hyperplasia), skin changes e.g. excessive pigmentation (chloasma) and hair growth (hypertrichosis, hirsutism), have been reported. Dupuytren's contracture, Stevens-Johnson and Lyell's syndrome, have also been reported.

Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

Not known – Purple Glove Syndrome has been reported.

• Musculoskeletal, connective tissue and bone disorders

Rare - osteomalacia may develop in susceptible patients or patients with a calcium metabolism disorder (increased alkaline phosphatase). This normally responds well to administration of vitamin D. Alkaline phosphatase should therefore be checked regularly.

Very rare - muscle weakness (myasthenic syndrome) which subside after phenytoin is withdrawn.

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.

• General disorders and administration site conditions

Rare – fever (together with rash). Local irritation, inflammation and tenderness have been reported. Necrosis and sloughing have been reported after subcutaneous or perivascular injection, which are not recommended administration routes. Soft tissue irritation and inflammation have occurred at the site of injection with and without extravasation of phenytoin given intravenously.

4.9 Overdose

Symptoms of an overdose

Signs of overdose can develop in individuals who have different phenytoin plasma levels. Early symptoms include nystagmus, cerebellar ataxia and dysarthria. Additional symptoms may include: tremor, hyperreflexia, somnolence, exhaustion, lethargy, slurred speech, diplopia, dizziness, nausea, vomiting. The patient may fall into a coma, the pupillary reflex may disappear, and blood pressure can fall. Death can result e.g. from central respiratory depression or circulatory failure. The mean lethal (acute) dose is estimated to be 2-5 g phenytoin in adults. The lethal dose for paediatric patients is unknown. Overdose can lead to irreversible degenerative cerebellar changes.

Treatment of intoxication

Initial treatment must include gastric lavage, administration of activated charcoal and monitoring on intensive care. Haemodialysis, forced diuresis and peritoneal dialysis are less effective. Experience on the efficacy of haematogenic charcoal perfusion, complete plasma substitution and transfusion is inadequate. For this reason, intensive internal treatment without special detoxification procedures should be performed, but phenytoin plasma levels should be checked.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptic, hydantoin derivative

ATC-Code: N03AB02

Phenytoin belongs to the group of hydantoins with potent anticonvulsive action. Through hyperpolarisation it stabilises the membranes of the central and peripheral nerves, thereby inhibiting the spread of convulsive potential in the cerebral cortex. The increase in inhibitory impulses in the cerebellum contributes to the anticonvulsive effect.

In contrast to local anaesthetics, phenytoin has no effect on conductivity in nerve fibres. The stimulus threshold and the normal excitatory course are also not altered. However, phenytoin stabilises the membrane of the neurone against the influence of repetitive stimuli.

5.2 Pharmacokinetic properties

Following oral administration phenytoin is primarily absorbed from the small intestine. Phenytoin is principally bound to serum albumin (83% to 94%). Protein-binding is reduced in newborn infants. Following a single dose, the maximum plasma level is generally achieved after 4 to 6 hours (range 3 to 12 hours). Bioavailability is subject to large inter- and intraindividual fluctuations. Since phenytoin obeys saturation kinetics, the half-life is dependent on the plasma level. Plasma half-life is between 20 and 60 hours; it is normally shorter in children; a prolonged half-life can be expected in premature and newborn babies as well as with toxic dosages. The therapeutic range for plasma concentration is generally between 10 and 20 µg/ml; concentrations above 25 µg/ml may lie in the toxic range.

Phenytoin passes through the placenta and reaches similar concentrations in the fetal plasma as in the mother. Phenytoin accumulates in the liver of the foetus.

95% of phenytoin is biotransformed. The main metabolite is the glucuronide of the p-hydroxy-di-phenyl-hydantoin, which circulates in the enterohepatic circulation.

Biotransformation of phenytoin in the liver is effected by oxidative metabolism. The main degradation path is 4-hydroxylation, which accounts for 80% of the metabolised products. CYP2C9 is the decisive contributor to the metabolism of phenytoin (90% of intrinsic net clearance), while the contribution of CYP2C19 to this process is only minimal (10% of intrinsic net clearance). However, the minor influence of CYP2C19 on the metabolism of phenytoin may slightly increase at higher phenytoin concentrations.

Because phenytoin is hydroxylated in the liver by a cytochrome system which is saturable at high plasma levels, additional phenytoin doses may increase the half-life and produce very substantial increases in serum levels when these are in or above the upper therapeutic range. The steady state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

CYP2C9 inhibitors, such as phenylbutazone and sulfaphenazole, have been shown to interfere with hepatic phenytoin clearance. This phenomenon was also observed in patients who were given CYP2C19 inhibitors, e.g. ticlopidine.

5.3 Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered 3-4 times in excess of the maximum human exposure indicating limited relevance to clinical use (see also 4.8 and 4.9).

Apart from a number of negative findings on mutagenicity, there is evidence that phenytoin induces chromosome mutations. It was not possible to make any further evaluation from these studies owing to their poor quality. Malignant and benign proliferative changes of the lymphatic system have been observed in long-term studies in mice. The significance of this observation in humans is unclear.

Phenytoin is teratogenic in a variety of species including humans (see also 4.6).

6. Pharmaceutical particulars
6.1 List of excipients

Propylene glycol

Ethanol (96%)

Sodium hydroxide (for pH-adjustment)

Water for injection.

6.2 Incompatibilities

Phenytoin must not be mixed with other medicinal products as the phenytoin acid precipitates out.

6.3 Shelf life

2 years

After first opening: Phenytoin should be used immediately.

Before use, the ampoules should be checked for precipitation and discolouration.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

Phenytoin 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.

Only a clear solution should be administered. A slight yellow discolouration has no effect on the efficacy of this solution.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Transparent breakable ampoules made from type I glass.

Pack sizes: 5 ampoules or 50 (10x5) ampoules.

6.6 Special precautions for disposal and other handling

Before use, the ampoules should be checked for precipitation and discolouration.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

Phenytoin 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.

Only a clear solution should be administered. A slight yellow discolorationdiscolouration has no effect on the efficacy of this solution.

For single use only. Any unused product should be discarded.

7. Marketing authorisation holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó n.° 8, 8A e 8B – Fervença

2705-906 Terrugem SNT

Portugal

Tel.: ++351-21 960 84 10

Fax: ++351-21 961 51 02

8. Marketing authorisation number(s)

PL 15413/0019

9. Date of first authorisation/renewal of the authorisation

03/03/2012

10. Date of revision of the text

06/05/2014