Celontin

Anticonvulsants, Succinimides

 
A MedGuide is available that discusses the risks associated with the use of anticonvulsant medications, such as methsuximide, including suicidal thoughts and behaviors.

May be administered orally without regard to meals.
Avoid abrupt discontinuation.

suicidal ideation / Delayed / Incidence not known
seizures / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known

ataxia / Delayed / 1.0-10.0
psychosis / Early / Incidence not known
depression / Delayed / Incidence not known
hallucinations / Early / Incidence not known
confusion / Early / Incidence not known
impaired cognition / Early / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
constipation / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
blurred vision / Early / Incidence not known
photophobia / Early / Incidence not known
hematuria / Delayed / Incidence not known
hyperemia / Delayed / Incidence not known
osteomalacia / Delayed / Incidence not known

emotional lability / Early / 1.0-10.0
irritability / Delayed / 1.0-10.0
dizziness / Early / 1.0-10.0
vomiting / Early / 1.0-10.0
nausea / Early / 1.0-10.0
drowsiness / Early / 10.0
dyspepsia / Early / 10.0
insomnia / Early / Incidence not known
headache / Early / Incidence not known
diarrhea / Early / Incidence not known
anorexia / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
weight loss / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known
blepharedema / Early / Incidence not known
hiccups / Early / Incidence not known

Celontin

Rx

Oral succinimide-derivative anticonvulsant; indicated for refractory absence seizures (petit mal); generally ineffective for tonic-clonic seizures; may have some activity in partial complex seizures; use with other anticonvulsants for mixed seizure types is generally acceptable; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

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.

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.

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.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
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.
Butabarbital: (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.
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.
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.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Celontin/Methsuximide Oral Cap: 300mg

1.2 g/day PO.

1.2 g/day PO.

30 mg/kg/day PO, not to exceed 1.2 g/day PO.

30 mg/kg/day PO.

Mechanism of Action: 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.

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.

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.[63114] 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.[47058]

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.