Chemical formula: C₁₅H₁₂N₂O₂ Molecular mass: 252.268 g/mol PubChem compound: 1775
Phenytoin interacts in the following cases:
Drugs that may potentially increase phenytoin serum levels.
Drugs that may either increase or decrease phenytoin serum levels.
Drugs that may decrease phenytoin plasma levels.
Drugs whose serum levels and/or effects may be altered by phenytoin.
The effect of phenytoin on warfarin is variable and prothrombin times should be determined when these two factors are combined.
When possible, medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant. Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant. In pregnant women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. As a general principle, monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated AEDs.
Phenytoin crosses the placenta in humans. Similar concentrations of phenytoin have been reported in the umbilical cord and maternal blood.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. In humans, phenytoin exposure during pregnancy is associated with a frequency of major malformations 2 to 3 times higher than that of the general population, which has a frequency of 2-3%. Malformations such as orofacial clefts, cardiac defects, dysmorphic facial features, nail and digit hypoplasia, and growth abnormalities (including microcephaly) have been reported among children born to women with epilepsy who took phenytoin during pregnancy. Neurodevelopmental disorder has been reported among children born to women with epilepsy who took phenytoin alone or in combination with other AEDs during pregnancy. Studies related to neurodevelopmental risk in children exposed to phenytoin during pregnancy are contradictory and a risk cannot be excluded. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. However, the respective role of antiepileptic drugs and other factors in the increased risk is not determined.
Phenytoin should not be used in women of childbearing potential, women planning pregnancy, and pregnant women, except where there is a clinical need and when possible, the woman is made aware of the risks of taking phenytoin during pregnancy.
An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
Phenytoin should not be used in women of childbearing potential unless other antiepileptic drugs are ineffective or not tolerated and when possible, the woman is made aware of the risk of potential harm to the foetus and the importance of planning pregnancy. Women of childbearing potential should use effective contraception during treatment. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with phenytoin.
Phenytoin may result in a failure of hormonal contraceptives, hence women of childbearing potential should be counselled regarding the use of other effective contraceptive methods.
In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible. Phenytoin should not be discontinued prior to reassessment of the treatment. When possible, patients should be informed of the potential harm to the foetus. If based on a careful evaluation of the risks and the benefits, phenytoin treatment is continued during the pregnancy, it is recommended to use the lowest effective dose and to institute specialized prenatal monitoring, oriented on the possible occurrence of the described malformations.
Haemorrhagic syndrome has been reported in neonates born from epileptic mothers receiving phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother during the last gestational month and to the neonate after birth.
In case of exposure during pregnancy, children should be closely monitored in relation to neurodevelopmental disorders in order to provide specialized care as soon as possible, if necessary.
Following administration of oral phenytoin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast feeding is not recommended for women receiving phenytoin.
Phenytoin is teratogenic in rats, mice and rabbits.
In animal studies, phenytoin had no direct effect on fertility.
Caution is recommended in patients performing skilled tasks (e.g. driving or operating machines) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness.
In the list below all adverse reactions with phenytoin are listed by class and frequency Not Known (cannot be estimated from available data).
Signs of toxicity are associated with cardiovascular and central nervous system depression.
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 signs and symptoms 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.
Not Known: Anaphylactoid reaction, anaphylactic reaction, periarteritis nodosa, immunoglobulin abnormalities may occur.
Not Known: Hypocalcaemia, hypophosphataemia in chronically treated epileptic patients.
Not Known: Insomnia, transient nervousness
Not Known: Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, dysarthria, decreased coordination and mental confusion. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use. Dizziness, motor twitchings, headache, paraesthesia somnolence, drowsiness and dysgeusia have also been observed.
There have also been rare reports of phenytoin-induced dyskinesia, including chorea, dystonia, tremor, and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Tonic convulsions have also been reported.
Not Known: Vertigo
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.
Not Known: Polyarteritis nodosa may occur.
Not Known: Pneumonitis, Alterations in respiratory function including respiratory arrest may occur.
Not Known: Vomiting, nausea, gingival hyperplasia constipation.
Not Known: Acute hepatic failure, hepatitis toxic, liver injury
Not Known: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash is the most common; dermatitis is seen more rarely. Other more serious and rare forms have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, hirsutism, hypertrichosis, Peyronie’s Disease and Dupuytren’s contracture may occur rarely, coarsening of the facial features, enlargement of the lips, Severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported very rarely. Drug reaction with eosinophilia and systemic symptoms (DRESS) 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.
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.
However, phenytoin has been shown to induce the CYP450 enzyme, which can affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, osteoporosis.
Discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported .
Not Known: Tubulointerstitial nephritis
Not Known: Local irritation, inflammation, tenderness, necrosis, oedema and skin exfoliation have been reported with or without extravasation of intravenous phenytoin.
Not Known: Fractures.
Not Known: Thyroid function test abnormal
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.
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