Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Celontin: 300 mg [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]
Pharmacology
Mechanism of Action
Increases the seizure threshold and suppresses paroxysmal spike-and-wave pattern in absence seizures; depresses nerve transmission in the motor cortex
Pharmacokinetics/Pharmacodynamics
Metabolism
Metabolism: Hepatic; rapidly demethylated to N-desmethylmethsuximide (active metabolite)
Excretion
Urine (<1% as unchanged drug)
Time to Peak
Serum: 1 to 3 hours
Half-Life Elimination
2 to 4 hours
N-desmethylmethsuximide: Children: 26 hours; Adults: 28 to 80 hours
Use: Labeled Indications
Absence (petit mal) seizures, refractory: Control of absence (petit mal) seizures that are refractory to other drugs
Contraindications
History of hypersensitivity to succinimides
Dosage and Administration
Dosing: Adult
Absence (petit mal) seizures, refractory: Oral: 300 mg daily for the first week; may increase by 300 mg/day at weekly intervals up to 1.2 g/day in 2 to 4 divided doses; slower titrations may be considered to avoid toxic accumulation of active metabolite (N-desmethylmethsuximide) (Brown 1983).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Seizures, refractory; adjunct therapy: Limited data available in various seizure types except absence; has been found useful especially in Lennox-Gastaut syndrome and symptomatic focal epilepsies (Sigler 2001): Children and Adolescents: Oral: Initial: 5 mg/kg/day once daily; titrate at weekly intervals in 3.2 to 5.5 mg/kg/week increments as tolerated in divided doses every 6 to 8 hours to clinical response and target serum concentrations; maximum daily dose: 30 mg/kg/day not to exceed 1,200 mg/day in divided doses. For the active metabolite, N-desmethylmethsuximide (NDMSM), a therapeutic range of 25 to 45 mcg/mL in pediatric patients has been suggested; in a retrospective analysis of 15 patients, the reported mean dose was 20.4 mg/kg/day and mean serum concentration 34.3 mg/L (Nelson 1996; Sigler 2001; Tennison 1991)
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); protect from excessive heat 40°C (104°F). Protect from light and moisture. Note: Methsuximide has a relatively low melting temperature (124°F); do not store in conditions that promote high temperatures (eg, in a closed vehicle).
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification
Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Monitor therapy
CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification
Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Adverse Reactions
Frequency not defined.
Cardiovascular: Hyperemia
Central nervous system: Aggressiveness, ataxia, confusion, depression, dizziness, drowsiness, hallucinations (auditory), headache, hypochondriacal behavior, insomnia, irritability, mental instability, mental slowness, nervousness, psychosis, suicidal behavior
Dermatologic: Pruritus, rash, Stevens-Johnson syndrome, urticaria
Gastrointestinal: Abdominal pain, anorexia, constipation, diarrhea, epigastric pain, nausea, vomiting, weight loss
Genitourinary: Hematuria (microscopic), proteinuria
Hematologic: Eosinophilia, leukopenia, monocytosis, pancytopenia
Ocular: Blurred vision, periorbital edema, photophobia
Miscellaneous: Hiccups, systemic lupus erythematosus
Warnings/Precautions
Concerns related to adverse effects:
- Blood dyscrasias: Succinimides have been associated with severe blood dyscrasias (sometimes fatal). Monitor blood counts periodically, especially if signs/symptoms of infection develop.
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
- SLE: Succinimides have been associated with cases of systemic lupus erythematosus (SLE).
- Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with hepatic impairment.
- Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
- Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Other warnings/precautions:
- Appropriate use: Must be used in combination with other anticonvulsants in patients with both absence and tonic-clonic seizures. May increase tonic-clonic seizures when used alone in patients with mixed seizure disorders.
- Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Monitoring Parameters
CBC, hepatic function tests, urinalysis; suicidality (eg, suicidal thoughts, depression, behavioral changes); serum concentrations of concomitant antiepileptic drugs (Besag 2000; Besag 2001; Browne 1983).
Pregnancy
Pregnancy Considerations
Epilepsy itself, the number of medications, genetic factors, or a combination of these may influence the teratogenicity of anticonvulsant therapy. In general, polytherapy may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended (Harden 2009). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued up to once a month during pregnancy in women with stable seizure control (Patsalos 2008; Patsalos 2018).
Patients exposed to methsuximide during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience fatigue, dizziness, headache, nausea, vomiting, diarrhea, abdominal pain, constipation, lack of appetite, weight loss, trouble sleeping, or hiccups. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), signs of depression (thoughts of suicide, anxiety, emotional instability, or confusion), agitation, irritability, panic attacks, mood changes, confusion, change in balance, vision changes, sensitivity to light, severe loss of strength and energy, bruising, bleeding, swollen glands, seizures, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
