Summary of Product Characteristics Updated 05-Dec-2014 | Kent Pharmaceuticals Ltd
N.B.Phenytoin is not effective in absence status epilepticus or in the prophylaxis and treatment of febrile convulsions.
Dosage instructionsThe 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 seizuresContinuous 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 ageThe 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
|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 ageOn 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 1At a maximum daily dose of 30 mg/kg bodyweight, this is equivalent to
|8 kg||1||230 mg|
|15 kg||2||460 mg|
|23 kg||3||690 mg|
|31 kg||4||920 mg|
|46 kg||6||1380 mg|
|12 kg||1||230 mg|
|23 kg||2||460 mg|
|35 kg||3||690 mg|
|46 kg||4||920 mg|
|23 kg||1||230 mg|
|46 kg||2||460 mg|
Prophylaxis of seizuresAdults 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
|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|
|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 administrationDuration 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 preparationsDue 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 administrationThe 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)).
Important information regarding treatmentPatients 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 diseasePhenytoin 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.
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.
Blood and the lymphatic system disordersRare - 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 disordersRare - 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 disordersRare - Laboratory tests should be performed every six months, especially in children, owing to possible impairment of thyroid function.
Nervous system disordersVery 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 patientsUncommon - 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 disordersVery common - double vision (diplopia)
Cardiac disordersUncommon - 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 disordersCommon - 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 disordersRare - 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 disordersCommon 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 disordersRare - 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 conditionsRare 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.
Symptoms of an overdoseSigns 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 intoxicationInitial 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.
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