Action And Clinical Pharmacology: Methsuximide elevates seizure threshold in the cortex and basal ganglia and reduces synaptic response to low frequency repetitive stimulation. The peroxisomal spike and wave pattern of the EEG, common in petit mal seizure, is suppressed.
Pharmacokinetics: Methsuximide is absorbed from the gastrointestinal tract and peak plasma levels are achieved in 1 to 3 hours. The plasma half-life of methsuximide is slightly less than 3 hours. In one study, mean peak serum levels were 3 µg/mL following a single 600 mg dose and 6 to 7 µg/mL following a single 1.2 g dose of methsuximide.
Limited studies indicate that the drug is metabolized via N-demethylation to N-demethylmethsuximide (NDM). Profound CNS depression following methsuximide overdose has been attributed to this metabolite, and it is probable that the anticonvulsant effects of the drug are due to NDM. In one study, which measured methsuximide and NDM levels simultaneously in plasma of patients who were receiving methsuximide chronically, the concentration of NDM was 700 times greater than the concentration of methsuximide. On the basis of this study, a tentative therapeutic plasma level of 10 to 40 µg/mL of NDM has been proposed.
Less than 1% of a dose of methsuximide is excreted unchanged in the urine, although a number of as yet unidentified metabolites are excreted in urine.
Indications And Clinical Uses: The control of absence (petit mal) seizures refractory to other drugs.
Contra-Indications: Methsuximide should not be used in patients with a history of hypersensitivity to succinimides.
Precautions: Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of succinimides; therefore, periodic blood counts should be performed.
It has been reported that succinimides have produced morphological and functional changes in animal liver. For this reason, administer methsuximide with extreme caution to patients with known liver or renal disease. Periodic urinalysis and liver function studies are advised for all patients receiving the drug.
Cases of systemic lupus erythematosus have been reported with the use of succinimides. The physician should be alert to this possibility.
Pregnancy: Recent reports indicate an association between the use of anticonvulsant drugs and an elevated incidence of birth defects in children born to epileptic women taking such medications during pregnancy. The incidence of congenital malformations in the general population is regarded to be approximately 2%; in children of treated epileptic women this incidence may be increased 2- to 3-fold. The increase is largely due to specific defects, e.g., congenital malformations of the heart, and cleft lip and/or palate. Nevertheless, the great majority of mothers receiving anticonvulsant medications deliver normal infants.
Data are more extensive with respect to phenytoin and phenobarbital, but these drugs are also the most commonly prescribed anticonvulsants. Some reports indicate a possible similar association with the use of other anticonvulsants, including trimethadione and paramethadione. However, the possibility also exists that other factors, e.g., genetic predisposition or the epileptic condition itself may contribute to or may be mainly responsible for the higher incidence of birth defects.
Anticonvulsant drugs should not be discontinued 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 risk to both the mother and the unborn child. With regard to drugs given for minor seizures, the risk of discontinuing medications prior to or during pregnancy should be weighed against the risk of congenital defects in the particular case and with the particular family history.
Epileptic women of childbearing age should be encouraged to seek professional counsel and should report the onset of pregnancy promptly to their physician. Where the necessity for continued use of the antiepileptic medication is in doubt, appropriate consultation might be indicated.
The preceding considerations should be borne in mind and methsuximide should be used in women of childbearing potential only when the expected benefits to the patients warrant the possible risk to a fetus.
Lactation: Mothers receiving methsuximide should not breast-feed their infants.
Occupational Hazards: Methsuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a motor vehicle or other such activities requiring alertness; therefore, caution the patient accordingly.
Withdraw the drug slowly on the appearance of unusual depression, aggression, or other behavioral alterations.
Proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt withdrawal of anticonvulsant medications may precipitate petit mal status.
Methsuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients.
Adverse Reactions: Gastrointestinal: Gastrointestinal symptoms occur frequently and have included nausea or vomiting, anorexia, diarrhea, weight loss, epigastric and abdominal pain, and constipation.
Hemopoietic: eosinophilia, leukopenia, monocytosis, pancytopenia.
Nervous System: Neurologic and sensory reactions reported during therapy with methsuximide have included drowsiness, ataxia or dizziness, irritability and nervousness, headache, blurred vision, photophobia, hiccups, and insomnia.
Drowsiness, ataxia, and dizziness have been the most frequent adverse effects noted.
Psychological abnormalities have included confusion, instability, mental slowness, depression, hypochondriacal behavior, and aggression. There have been rare reports of psychosis, suicidal behavior and auditory hallucinations.
Integumentary System: Dermatologic manifestations which have occurred in the administration of methsuximide have included urticaria, Stevens-Johnson syndrome, and pruritic erythematous rashes.
Miscellaneous: periorbital edema, hyperemia.
Dosage: Optimal dosage (that which is just sufficient to control seizures without causing disturbing side effects) must be determined by trial and should be individualized according to the needs of each patient. A suggested schedule is 300 mg daily for the first week. If required, the daily dosage may be increased at weekly intervals by 300 mg/day for the 3 weeks following to a daily dosage of 1 200 mg.
Availability And Storage: Each yellow capsule with orange cap contains: methsuximide USP 300 mg. Nonmedicinal ingredients: cornstarch; capsule shell: D&C Yellow No. 10, FD&C Red No. 3, FD&C Yellow No. 6 and gelatin. Energy: 1.57 kJ (0.38 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100.
CELONTIN® Parke-Davis Methsuximide Anticonvulsant