WARNINGS

Effects of Abrupt Withdrawal Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus.

When, in the judgment 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.

Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Dilantin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Dilantin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Lymphadenopathy There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) 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.

Effects of Alcohol Use on Phenytoin Serum Levels Acute alcoholic intake may increase phenytoin serum levels, while chronic alcohol use may decrease serum levels.

Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Usage In Pregnancy Clinical A.

Risks to Mother.

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 (see PRECAUTIONS, Laboratory Tests ).

However, postpartum restoration of the original dosage will probably be indicated.

B.

Risks to the Fetus.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes.

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.

There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population.

However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.

Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.

C.

Postpartum Period.

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero .

This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m 2 basis) to pregnant rabbits.

Skin reactions Dilantin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

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 hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms.

The physician should advise the patient to discontinue treatment if the rash appears (see section regarding drug discontinuation).

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 Dilantin medication is contraindicated.

Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome 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 another anticonvulsive drug.

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 Dilantin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

Anticonvulsant Hypersensitivity Syndrome Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication.

It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic.

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.

Although up to 1 in 5 patients on Dilantin may develop cutaneous eruptions, only a small proportion will progress to AHS.

Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients.

The syndrome is more severe in previously sensitized individuals.

If a patient is diagnosed with AHS, discontinue the Dilantin and provide appropriate supportive measures.