VA Class:CN400

AHFS Class:

• Succinimides 28:12.20

Generic Name(s):

• Methsuximide

Methsuximide is a succinimide-derivative anticonvulsant.

Methsuximide is used in the management of absence (petit mal) seizures. In contrast to ethosuximide and phensuximide (no longer commercially available in the US), methsuximide does not usually precipitate tonic-clonic (grand mal) seizures and therefore may be especially useful in conjunction with other anticonvulsants such as phenytoin or phenobarbital in the management of combined absence and tonic-clonic seizures. Methsuximide may also be useful alone or in conjunction with other anticonvulsants such as phenytoin or phenobarbital in the management of some cases of partial seizures with complex symptomatology (psychomotor seizures). Methsuximide is generally regarded as a drug to be used when other medications have failed to effectively control absence seizures or partial seizures with complex symptomatology.

Administration

Methsuximide is administered orally.

Patients who are currently receiving or beginning therapy with methsuximide and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.100,101,102 (See Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.)

Dosage

Dosage must be carefully and slowly adjusted according to individual requirements and response. Methsuximide should be withdrawn or dosage reduced slowly to avoid precipitating seizures or absence status.

The usual initial dosage of methsuximide for adults or children is 300 mg daily for the first week. If necessary, daily dosage may be increased by 300-mg increments at weekly intervals thereafter up to a maximum daily dosage of 1.2 g, administered in divided doses. Some clinicians report that the usual maintenance dosage is 10 mg/kg or 600 mg/m² daily.

Adverse Effects

Adverse GI effects occur frequently during methsuximide therapy and include nausea or vomiting, weight loss, anorexia, epigastric or abdominal pain, diarrhea, and constipation.

Adverse nervous system effects of methsuximide include drowsiness, ataxia, dizziness, irritability and nervousness, headache, photophobia, blurred vision, hiccups, and insomnia. The most common adverse nervous system effects are drowsiness, ataxia, and dizziness. Adverse psychologic effects have included instability, hypochondriacal behavior, aggressiveness, and mental confusion, depression, and slowness. Rarely, psychosis, suicidal behavior, and auditory hallucinations have been reported. (See Dosage and Administration: Administration and see Cautions: Precautions and Contraindications.)

Adverse hematologic effects associated with methsuximide include eosinophilia, leukopenia, monocytosis, and pancytopenia. Adverse dermatologic effects may include urticaria, pruritic erythematous rash, and Stevens-Johnson syndrome. Adverse genitourinary effects associated with methsuximide include proteinuria and microscopic hematuria. Periorbital edema and hyperemia have also occurred. Systemic lupus erythematosus has been associated with succinimide use.

Precautions and Contraindications

Methsuximide shares the toxic potentials of the succinimide-derivative anticonvulsants, and the usual precautions of anticonvulsant administration should be observed. (See Cautions in the Anticonvulsants General Statement 28:12.)

Clinicians should inform patients, their families, and caregivers about the potential for an increased risk of suicidal thinking and behavior (suicidality) associated with anticonvulsant therapy.100 For a complete discussion, see Cautions: CNS Effects and see Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.

Patients should be warned that methsuximide may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Methsuximide should be used with extreme caution in patients with known hepatic or renal disease. Complete blood counts, hepatic function tests, and urinalysis should be performed periodically in patients receiving the drug. Methsuximide is contraindicated in patients with a history of hypersensitivity to succinimides.

Pregnancy and Lactation

Pregnancy

Safe use of methsuximide during pregnancy has not been established. (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.)

Lactation

Safe use of methsuximide during lactation has not been established. (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.)

Pharmacology

Methsuximide shares the actions of the succinimide-derivative anticonvulsants.

Pharmacokinetics

Absorption

Methsuximide is absorbed from the GI tract and peak plasma concentrations are achieved in 1-3 hours. In one study, mean peak serum concentrations were 3 mcg/mL following a single 600-mg dose and 6-7 mcg/mL following a single 1.2-g dose of methsuximide.

Elimination

The plasma half-life of methsuximide is slightly less than 3 hours.

Limited studies in patients who have taken extremely high doses of methsuximide and one study involving a small number of patients receiving methsuximide for the management of epilepsy indicate that the drug is metabolized via N -demethylation to N -demethylmethsuximide (NDM). Profound CNS depression following methsuximide overdosage has been attributed to this metabolite, and it is probable that the anticonvulsant effects of the drug result from NDM. Overdosage of methsuximide may follow a biphasic course; patients have awakened and relapsed into coma within 24 hours. In one study in patients receiving methsuximide chronically, the plasma concentration of NDM was 700 times greater than the simultaneous plasma concentration of methsuximide. On the basis of this one study, a tentative therapeutic plasma NDM concentration of 10-40 mcg/mL has been proposed; plasma NDM concentrations exceeding 40 mcg/mL have been associated with toxicity and coma has been reported at plasma NDM concentrations of 150 mcg/mL.

Less than 1% of a dose of methsuximide is excreted unchanged in urine, although a number of as yet unidentified metabolites are excreted in urine.

Chemistry and Stability

Chemistry

Methsuximide is a succinimide-derivative anticonvulsant. The drug occurs as a white to grayish-white, crystalline powder and is slightly soluble in hot water and freely soluble in alcohol.

Stability

Methsuximide capsules should be stored in tight, light-resistant containers at a temperature less than 30°C, preferably between 15-30°C; exposure to temperatures exceeding 40°C should be avoided. Because methsuximide has a relatively low melting point (i.e., 51°C), storage conditions that may be associated with high temperatures (e.g., closed cars, delivery vans, storage near steam pipes) should be avoided. Capsules that are not full or in which the contents have melted should not be used since therapeutic potency may be reduced. Commercially available capsules have an expiration date of 5 years following the date of manufacture.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of methsuximide, see the Anticonvulsants General Statement 28:12.

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. Information for healthcare professionals: suicidality and antiepileptic drugs. FDA Alert; 2008 Jan 31. From the FDA website. [Web]

101. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]

102. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website. [Web]