Mesantoin Description

Active Ingredient: mephenytoin, USP

Inactive Ingredients: D&C Red #7 Calcium Lake, gelatin, lactose, starch, stearic acid, and sucrose.

Mesantoin® (mephenytoin) is available in speckled, pale pink 100 mg tablets for oral administration.

Mesantoin - Clinical Pharmacology

Mephenytoin exhibits pharmacologic effects similar to both phenytoin and the barbiturates in antagonizing experimental seizures in laboratory animals. Mephenytoin produces behavioral and electroencephalographic effects in people which are similar to those produced by barbiturates.

The absorption of mephenytoin given orally as a solution of the racemic drug is rapid. Mephenytoin is metabolized stereoselectively. The S-enantiomer is preferentially hydroxylated to give 5-ethyl-3-methyl-5-(4-hydroxyphenyl)-2,4-imidazolidinedione (S-4´-hydroxymephenytoin). The R-enantiomer is primarily N-demethylated to give 5-ethyl-5-phenyl-2,4-imidazolidinedione (R-phenylethylhydantoin) [R-PEH], the active metabolite. Following simultaneous administration of 14C-S-mephenytoin and 3H-R-mephenytoin, 95±3% of the administered 14C radioactivity was recovered in the urine 24 hours after dosing in the form of S-4´-hydroxymephenytoin, while in the same period, only 3% of the administered 3H radioactivity was found in the urine.

R-mephenytoin reaches peak concentration in about 1.5 hours. Both R-mephenytoin and its active metabolite R-PEH displayed linear kinetics in the dose range of 50-200 mg. The steady state volume of distribution for R-mephenytoin is about 1.4 L/kg. The mean elimination half-life of R-mephenytoin is 73±30 hours and for the metabolite R-PEH is 127±31 hours. The relative bioavailability of R-mephenytoin (Tablet/Solution) is 104%.

In several populations, a genetic impairment which decreases the efficiency of aromatic hydroxylation of S-mephenytoin, but not the N-demethylation of R-mephenytoin, has been established. Poor metabolizers occur with a frequency of 2%-5% in the Caucasian population and 18%-23% in Japanese subjects.

Indications and Usage for Mesantoin

For the control of grand mal, focal, Jacksonian, and psychomotor seizures in those patients who have been refractory to less toxic anticonvulsants.

Contraindications

Mesantoin® (mephenytoin) is contraindicated in patients who have previously shown hypersensitivity to hydantoin products.

Warnings

Mesantoin® (mephenytoin) should be used only after safer anticonvulsants have been given an adequate trial and have failed.

As with all anticonvulsants, dose reduction must be gradual so as to minimize the risk of precipitating seizures.

Patients should be cautioned about possible additive effects of alcohol and other central nervous system depressants. Acute alcohol intoxication may increase the anticonvulsant effect due to decreased metabolic breakdown. Chronic alcohol abuse may result in decreased anticonvulsant effect due to enzyme induction.

Usage in Pregnancy

The effects of Mesantoin® (mephenytoin) in human pregnancy and on nursing infants have not been systematically investigated.

Reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and an elevated incidence of birth defects in children born to these women. Data are more extensive with respect to diphenylhydantoin and phenobarbital, but these are also the most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

The reports suggesting an elevated incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodological problems in obtaining adequate data on drug teratogenicity in humans; the possibility also exists that other factors, e.g., genetic factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazards to the developing embryo or fetus.

Hydantoins can cause fetal harm when administered to a pregnant woman. There have been two cases in which the following have been associated with the use of Mesantoin® (mephenytoin): neonatal patent ductus arteriosus, coarctation of the aorta, ventricular septal defect, atrial septal defect, downslanting palpebral fissures, hypoplastic maxilla, big nose, and facial hemangiomas. In both these cases concomitant drugs (i.e. alcohol and primidone) were used.

The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential. If Mesantoin® (mephenytoin) is used during pregnancy, or if the patient becomes pregnant while taking Mesantoin® (mephenytoin), the patient should be apprised of the potential hazard to the fetus.