Methsuximide is an oral succinimide-derivative anticonvulsant chemically related to ethosuximide. It is used to control absence (petit mal) seizures that are refractory to other agents. Similar to other succinimide anticonvulsants, methsuximide is ineffective in treating tonic-clonic seizures. Unlike ethosuximide, methsuximide does not usually precipitate tonic-clonic seizures and concurrent administration with other anticonvulsants in the treatment of mixed seizure types (i.e. absence and tonic-clonic) is generally acceptable. Although not an approved indication, the use of methsuximide as adjunct treatment for refractory complex partial seizures has been studied in a limited number of patients ; further study is needed before the drug can be routinely recommended for this purpose. Methsuximide was approved by the FDA in 1957, and remains on the US market today (personal communication. Pfizer, February 2004).
NOTE: In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). In the analysis, patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.22%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Drug data were analyzed by the FDA for carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide; however, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
A MedGuide is available that discusses the risks associated with the use of anticonvulsant medications, such as methsuximide, including suicidal thoughts and behaviors.
Route-Specific Administration
Oral Administration
-May be administered orally without regard to meals.
-Avoid abrupt discontinuation.
Psychiatric adverse reactions that have been reported during methsuximide administration include confusion, instability (emotional lability), irritability, depression, hypochondriacal behavior, and aggressiveness. Rarely, psychosis, suicidal behavior, and auditory hallucinations have also been reported. Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Depression and suicidal behavior have been rarely reported during methsuximide use. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Methsuximide should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. The manufacturer recommends slow withdrawal of the drug on the appearance of unusual depression, aggressiveness, or other behavioral changes. Clinicians should monitor patients with a diagnosis of depression or schizophrenia closely for possible exacerbation of symptoms while receiving methsuximide.
Many of the common adverse effects associated with methsuximide therapy are centrally-mediated. Ataxia, dizziness, and drowsiness are the most common central nervous system (CNS) effects to occur during methsuximide administration. Other CNS effects include headache, mental slowness (impaired cognition), nervousness, and insomnia. Alcohol consumption may intensify the CNS depressant effects of the drug and should be avoided. Patients receiving methsuximide should be advised to avoid driving or operating machinery until the effects on their cognition are known. Methsuximide may increase the frequency of grand mal seizures when used as monotherapy to treat mixed types of epilepsy. Abrupt withdrawal of anticonvulsants may precipitate petit mal seizures.
Adverse gastrointestinal effects occur frequently during methsuximide administration. These effects include epigastric and abdominal pain, anorexia, constipation, diarrhea, nausea/vomiting, and weight loss. Administration with food may help minimize some gastrointestinal effects such as dyspepsia, nausea, and vomiting. Animal studies have reportedly shown that administration of succinimides can result in functional and morphological hepatic changes, although the specific nature of these changes has not been described. For this reason, the manufacturer advises caution during use of methsuximide in patients with known liver disease. Periodic assessment of liver function tests is recommended during methsuximide therapy. Ethosuximide, a chemically related succinimide compound, has been rarely associated with elevated hepatic enzymes and the onset of liver dysfunction (e.g., hepatitis or jaundice). Serious hepatic dysfunction may be an indication of drug hypersensitivity or other drug-induced reaction, which may require drug discontinuation.
Blood dyscrasias with fatal outcomes have been reported with the use of succinimides. Various blood abnormalities have occurred during methsuximide therapy including eosinophilia, leukopenia, monocytosis, and pancytopenia with and without bone marrow suppression. Although the likelihood of developing hematological complications is rare, periodic CBC monitoring is recommended. Patients should be instructed to report signs or symptoms of infection, such as fever or sore throat, as soon as possible.
Dermatologic reactions that have been reported during therapy with methsuximide include pruritus, skin rash (unspecified), Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling of the skin), and urticaria. Drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred during treatment with related compounds (i.e., ethosuximide). Due to the possibility of Stevens-Johnson syndrome or other serious reactions, patients should be instructed to promptly notify their provider if symptoms such as a skin rash or erythema develop. Reactions may indicate hypersensitivity to the drug. Cases of lupus-like symptoms and systemic lupus erythematosus have developed during use of succinimides.
A variety of ocular effects have been reported during methsuximide administration, although the frequencies are unknown. These effects include blurred vision, periorbital edema (e.g., blepharedema) and photophobia.
Methsuximide administration has been associated with the development of proteinuria and microscopic hematuria. Periodic evaluation of renal functioning through urinalysis is recommended by the manufacturer in those receiving methsuximide therapy.
Adverse reactions not listed elsewhere that have occurred during methsuximide therapy include hiccups and hyperemia. One case of osteomalacia has been reported during long-term use of methsuximide. The symptoms improved after discontinuation of the drug.
Methsuximide is contraindicated in patients with a known hypersensitivity to methsuximide or a history of succinimide hypersensitivity.
In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), corresponding to an estimated 2.1 per 1000 (95% CI: 0.7-4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. Depression and suicidal behavior have been reported with methsuximide administration. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
Abrupt discontinuation of methsuximide should be avoided, since absence (petit mal) seizure activity may be precipitated. Similar to other anticonvulsants, the dosage of methsuximide should be slowly tapered during discontinuation whenever possible to minimize the occurrence of rebound seizures. Succinimide anticonvulsants should not be used alone to treat mixed seizure types since the frequency of grand mal seizures may increase.
Methsuximide should be avoided if possible in patients with hematological disease including bone marrow suppression because various blood abnormalities have occurred during methsuximide therapy including eosinophilia, leukopenia, monocytosis, and pancytopenia with and without bone marrow suppression. Although the likelihood of developing hematological complications is rare, periodic CBC monitoring is recommended. Patients should be instructed to report signs or symptoms of infection, such as fever or sore throat, as soon as possible.
Ataxia, dizziness, and drowsiness are the most common central nervous system (CNS) effects to occur during methsuximide administration. Therefore, patients receiving methsuximide should be advised to avoid driving or operating machinery until the effects on their cognition are known. Alcohol consumption may intensify the sedative effects of the drug and should be avoided.
Psychosis and auditory hallucinations have been reported with methsuximide administration. Clinicians should carefully monitor patients with a diagnosis of schizophrenia for possible exacerbation of symptoms while receiving methsuximide.
Methsuximide should be used with caution in patients with intermittent porphyria because the drug could exacerbate this condition.
Animal studies have reportedly shown that administration of succinimides can result in functional and morphological hepatic changes, although the specific nature of these changes has not been described. Ethosuximide, a chemically related succinimide compound, has been rarely associated with an increase in liver enzymes and the onset of liver dysfunction (e.g., hepatitis or jaundice). Theoretically, these effects are possible with methsuximide; therefore, the drug should be used cautiously in those with hepatic disease. Liver function tests should be performed periodically during methsuximide therapy.
Methsuximide should be used cautiously in those with renal impairment or renal disease. Administration of a related compound, ethosuximide, has been associated with the development of nephrotic syndromes. Methsuximide has been associated with proteinuria, and microscopic hematuria. Periodic evaluation of renal functioning through urinalysis is recommended by the manufacturer in those receiving methsuximide therapy.
The use of succinimide anticonvulsants has been associated with the development of systemic lupus erythematosus (SLE). Methsuximide should be cautiously in those with a diagnosis of SLE.
There are no controlled trials of methsuximide use in pregnant women. Reports from 1 pregnancy in which methsuximide was used during the first trimester revealed no evidence of teratogenicity or harmful effects to the fetus. Succinimide derivatives (i.e. ethosuximide) are the preferred anticonvulsants when treating absence (petit mal) seizures. Anticonvulsant drugs should not be discontinued in patients in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In cases where 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 even minor seizures may pose some hazard to the developing embryo or fetus. Weigh these considerations in treating or counseling epileptic females of childbearing potential. The effects of methsuximide during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to methsuximide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.
There is no information regarding the presence of methsuximide in human milk, the effects on the breast-fed infant, or the effects on milk production. The related succinimide derivative ethosuximide is excreted into human breast milk in concentrations similar to those in the maternal plasma. Ethosuximide was considered an acceptable treatment by previous American Academy of Pediatrics recommendations for use during breast-feeding, despite the potential for significant infant exposure via the milk. The available data are limited to case reports and small studies. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and efficacy of methsuximide in infants have not been established.
According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If methsuximide must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
For the treatment of generalized absence seizures:
Oral dosage:
Adults: Initially, 300 mg PO daily for 1 week; increase, if necessary, at weekly intervals for 3 weeks by 300 mg increments, up to a maximum of 1.2 g/day PO given in 3-4 divided doses.
Adolescents and Children: Initially, 10-15 mg/kg PO given in 3-4 divided doses. Increase weekly up to a maximum of 30 mg/kg/day PO. Mean dosages are 20 mg/kg/day PO for children < 30 kg, and 14 mg/kg/day PO for children > 30 kg.
Therapeutic Drug Monitoring:
-Although a therapeutic range is not definitively established, serum N-desmethylsuximide concentrations may be used to guide dosing. Therapeutic N-desmethylsuximide serum concentrations usually range from 10-40 mcg/ml.
Maximum Dosage Limits:
-Adults
1.2 g/day PO.
-Elderly
1.2 g/day PO.
-Adolescents
30 mg/kg/day PO, not to exceed 1.2 g/day PO.
-Children
30 mg/kg/day PO.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, dosage adjustments may be needed. Discontinuation of methsuximide may need to be considered if significant hepatic impairment occurs during therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Amobarbital: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
Amphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
Amphetamine; Dextroamphetamine Salts: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
Amphetamine; Dextroamphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Barbiturates: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Butalbital; Acetaminophen: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Carbamazepine: (Moderate) Methsuximide is an inducer of the hepatic CYP3A4 isoenzyme and can increase the rate of carbamazepine metabolism, leading to subtherapeutic carbamazepine plasma concentrations. Also, methsuximide can be potentially affected by carbamazepine enzyme induction. Decreased methsuximide concentrations may occur.
Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Chlorpromazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Codeine; Phenylephrine; Promethazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Codeine; Promethazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of succinimides if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam.
Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Dextroamphetamine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethotoin: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Felbamate: (Moderate) Monitor concentrations of N-desmethylmethsuximide in patients treated with methsuximide and felbamate. Dosage adjustment of methsuximide may be required. Concomitant use of felbamate and methsuximide may result in increased plasma concentrations of N-desmethylmethsuximide. The cause of the increase in N-desmethylmethsuximide concentrations is not known.
Fluphenazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Fosphenytoin: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Hydantoins: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as methsuximide. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Isocarboxazid: (Moderate) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Lamotrigine: (Major) Methsuximide may reduce serum concentrations of lamotrigine by up to 70%. Conversely, if methsuximide is discontinued, lamotrigine doses may need to be adjusted downward. The mechanism by which this interaction occurs has not been established.
Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use lisdexamfetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide. The extent of absorption of ethosuximide is not known to be affected.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
Methohexital: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Monoamine oxidase inhibitors: (Moderate) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Pentobarbital: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Perphenazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Perphenazine; Amitriptyline: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Phenelzine: (Moderate) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Phenobarbital: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Phenothiazines: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Phenytoin: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Primidone: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Prochlorperazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Promethazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Promethazine; Dextromethorphan: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Promethazine; Phenylephrine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Secobarbital: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the hepatic metabolism of succinimides. This may lead to a decrease in succinimide plasma concentration and a reduction in half-life.
Thioridazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Tranylcypromine: (Moderate) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Trifluoperazine: (Major) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Valproic Acid, Divalproex Sodium: (Moderate) Concurrent administration of valproic acid, divalproex sodium and methsuximide may result in lowered valproic acid serum concentrations. Pre-morning-dose valproic acid serum concentrations were measured in 17 patients who had either started or stopped taking methsuximide, but whose dose of valproate and other medication remained unchanged. For all patients, the mean valproic acid concentration while not taking methsuximide was 81.9 +/- 5.3 mg/L and while taking methsuximide was 55.7 +/- 4.3 mg/L, a significant difference. In 8 patients who stopped taking methsuximide the mean serum concentration increased from 49.8 +/- 7.5 mg/L to 71.7 +/- 8.5 mg/L. It may be necessary to increase the valproate dose when methsuximide is added to avoid loss of therapeutic effect. Conversely, reduction of the valproate dose may be needed when methsuximide therapy stops, to avoid valproate toxicity.
Methsuximide elevates the seizure threshold and reduces the frequency of attacks through depression of nerve transmission in the cortex. The drug also suppresses the paroxysmal three-cycle-per-second spike and wave activity associated with lapses in consciousness which occur with absence seizures. N-desmethylmethsuximide, a metabolite of methsuximide, is thought to possess anticonvulsant properties.
Methsuximide is administered orally. Methsuximide undergoes N-demethylation in the liver to N-desmethylmethsuximide (NDM). One study indicates that during chronic administration of the drug, the plasma concentrations of the NDM metabolite are 700 times that of the parent compound. While therapeutic concentrations are not definitively established, some experts note effective concentrations of 10-40 mcg/ml for n-desmethylsuximide. Concentrations above or below this range appear to either be ineffective or toxic. The half-lives of the parent compound and NDM metabolite are 1.4 hours and 38 hours, respectively. Less than 1% of a dose is excreted in the urine as unchanged methsuximide. Other unspecified metabolites are renally eliminated.
-Route-Specific Pharmacokinetics
Oral Route
The rate and extent of methsuximide absorption has not been described; however, succinimide anticonvulsants are generally well absorbed orally. Peak plasma concentrations are attained 1-3 hours following a dose.