Methsuximide

203.24

203.24

201-026-7

760075

DTXSID5023293

Crystals from dilute alcohol|White to grayish white, crystalline powder

N - Nervous system

2925190100

37.4

1.45 (est)

Solid

1.59g/cm3

52-53 °C

121-122 °C @ Press: 0.1 Torr

191.7ºC

1.692

2.8g/L(25 ºC)

Refrigerator

4.77X10-6 mm Hg at 25 deg C (est)

LD50 orally in mice: 0.9 g/kg (Marshall, Vallance)

Odorless to slight odor

Henry's Law constant = 5.69X10-9 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 2.21X10-11 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

Methsuximide has a relatively low melting range (50 to 56 deg C or 122 to 133 deg F). Improper storage may result in melting and subsequent impaired absorption of the capsule contents. /Methsuximide Capsules USP/

P301 + P312 + P330

H302-H412

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl methsuximide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Schardein JL; Chemically Induced Birth Defects 2: 157-207 (1993). Anticonvulsant induced birth defects.|Gilstrap LC, Little BB; Drugs and Pregnancy 125-32 (1992). Anticonvulsant drugs during pregnancy.|Battino D, et al; Clin Pharmacokinet 29: 257-86 (1995). An overview of the clinical pharmacokinetics of ... methsuximide ... in pediatric patients is considered.|Briggs GG, et al; Drugs Preg Lactation 203-63 (1984). Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P273, P301+P312, P330, and P501|Aggregated GHS information provided by 40 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Acute overdoses may produce nausea, vomiting, and CNS depression including coma with respiratory depression. Levels greater than 40 µg/mL have caused toxicity and coma has been seen at levels of 150 µg/mL.

Prospective studies suggest that chronic methsuximide therapy is not accompanied by significant elevations in serum aminotransferase levels, although it has been shown to have hepatotoxicity in animals. Clinically apparent hepatotoxicity from methsuximide has not been reported, although hypersensitivity reactions with fever and rash are not uncommon (1% to 5%). The product label for methsuximide warns of hepatic dysfunction and recommends periodic liver function studies. Nevertheless, clinically apparent liver injury from methsuximide must be very rare, if it occurs at all.

Concurrent use /with alcohol; central nervous system depression-producing medications; tricyclic antidepressants; loxapine; maprotiline; molindone; monoamine oxidase inhibitors; phenothiazines; pimozide; thioxanthenes/ may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication. /Succinimide anticonvulsants/|Requirements for folic acid may be increased in patients receiving anticonvulsant therapy. /Succinimide anticonvulsants/|Induction of hepatic microsomal enzyme activity resulting in increased metabolism and decreased serum concentrations and elimination half-lives of succinimide anticonvulsants and/or these medications /carbamazepine, phenobarbital, phenytoin, primidone/ may occur during concurrent therapy; monitoring of serum concentrations as a guide to dosage is recommended, especially when any anticonvulsant is added to or withdrawn from an existing regimen. /Succinimide anticonvulsants/|Concurrent use /with haloperidol/ may cause a change in the pattern and/or the frequency of epileptiform seizures; dosage adjustments of the anticonvulsant may be necessary; serum concentrations of haloperidol may be significantly reduced. /Succinimide anticonvulsants/|For more Interactions (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

LD50 Mouse oral 900 mg/kg

While data specific to methsuximide were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

For the control of absence (petit mal) seizures that are refractory to other drugs.

Methsuximide is a succinimide-based anticonvulsant similar to ethosuximide that is used for absence (petit mal) seizures in both adults and children. Methsuximide was associated with hepatic injury in experimental animals, but has not been linked to serum enzyme elevations during treatment or to cases of clinically apparent liver injury with jaundice.

Anticonvulsants

Anticonvulsants|Methsuximide is indicated for the management of absence seizures refractory to other medication. /Included in US product label/|Methsuximide may be used in the treatment of complex partial seizures (epilepsy). /Not included in US product label/|The use of methsuximide to control seizures in 25 children (mean age, 10.2 yr) with intractable epilepsy who were given methsuximide at a mean dose of 20.4 mg/kg/day in addition to their regular antiepileptic drug /therapy was examined/. Results showed that in 15 patients the drug was well tolerated and resulted in a 50% or greater reduction in seizure frequency. No serious or irreversible adverse effects were seen. Methsuximide is frequently overlooked and may be an effective adjunctive antiepileptic for children with intractable seizures.|Methsuximide was administered for 8 weeks to 26 patients with complex partial seizures (CPS) refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction in CPS frequency was obtained in eight patients. MSM therapy was continued chronically in these eight patients, and five continued to have a 50% or greater reduction in CPS frequency after 3 to 34 months of follow-up. ...

The blood dyscrasia-causing effects of succinimide anticonvulsants may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks. /Succinimide anticonvulsants/|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.|Adverse hematologic effects associated with methsuximide include eosinophilia, leukopenia, monocytosis, and pancytopenia. Adverse dermatologic effects may include urticaria, pruritic erythematous rash, and Steven-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.|For more Drug Warnings (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

Used in the treatment of epilepsy. Methsuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)

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 ug/mL following a single 600-mg dose and 6-7 ug/mL following a single 1.2-g dose of methsuximide.|Methsuximide is rapidly absorbed & metabolized. It is not bound significantly to plasma proteins.|Methsuximide is rapidly distributed throughout body after.../oral/ doses to rats, &.../it/ freely crosses blood-brain barrier.|Succinimide anticonvulsants are freely distributed to all body tissues, except fat.|For more Absorption, Distribution and Excretion (Complete) data for METHSUXIMIDE (7 total), please visit the HSDB record page.

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 methsuccimide 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 ug/mL has been proposed; plasma NDM concentrations exceeding 40 ug/mL have been associated with toxicity and coma has been reported at plasma NDM concentrations of 150 ug/mL.|The pharmacokinetics of methsuximide and its major metabolite 2-methyl-2-phenylsuccinimide were studied in dogs after single intravenous doses. Plasma methsuximide levels were described by a two-compartment open model, and those of the metabolite were described by a one-compartment open model. An expression was derived that describes both methsuximide and metabolite plasma levels after methsuximide administration. Excellent fits were obtained between observed data and those predicted from the model. The metabolite, 2-methyl-2-phenylsuccinimide accounted for 40% of the overall elimination of methsuximide, and the half-life of the metabolite (15 hr) was much greater than that of the parent drug (1-3.5 hr). The results suggest that pharmacological effects after methsuximide administration may be due primarily to the metabolite, which may accumulate in the body during repeated doses.|Metabolism by hepatic microsomal enzymes in dog yields n-demethyl & parahydroxyphenyl derivatives & their glucuronides. ...|Following oral admin of 1-2 g methsuximide to dogs, alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide & n-methyl-alpha-(p-hydroxyphenyl)-alpha-methylsuccinimide isolated from 48 hr urine as major metab & alpha-methyl-alpha-phenylsuccinimide as minor. No parent drug found.|Metab, n-desmethylmethsuximide level higher in phensuximide than methsuximide treated patients. Plasma elimination was 32 & 1-2 hr.

1.4-2.6 hours for mesuximide and 28-38 hours for the active metabolite.|The plasma half-life of methsuximide is slightly less than 3 hours.|The clinical efficacy of ... methsuximide was studied in relation to plasma concentrations of this compound and its desmethyl metabolite. Single- and chronic-dose studies of /methsuximide/ were carried out in five patients with intractable seizures. Patients were evaluated before and during treatment by 6-hour simultaneous video and telemetered electroencephalographic recordings to characterize the seizure type and by daily determinations of plasma antiepileptic drug concentrations. ... Methsuximide had a short half-life, averaging 1.4 hours, but its desmethyl metabolite had a mean half-life of 38 hours and therefore accumulated to levels in excess of 40 micrograms per milliliter. ...|Methsuximide ... was administered for 8 wk to 26 patients with complex partial seizures refractory to phenytoin and carbamazepine and phenobarbital or primidone. A 50% or greater reduction of complex partial seizure frequency was obtained in 8 patients. ... N-desmethylmethsuximide was the principle /metabolite/ detected in plasma and had the following pharmacokinetic values: accumulation half life, 49.7 hr; time to steady state, 10.4 days; elimination half life, 72.2 hr. ...

Binds to T-type voltage sensitive calcium channels. Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channels is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.|Succinimide anticonvulsants are thought to increase the seizure threshold and suppress the paroxysmal three-cycle-per-second spike-and-wave pattern seen with absence (petit mal) seizures. The frequency of attacks is reduced by depression of nerve transmission in the motor cortex. These effects may be due to direct modification of membrane function in excitable cells and/or alteration of chemically mediated neurotransmission. The specific effect of ethosuximide against absence seizures appears to be due to its ability to block T-type calcium channels at concentrations that do not affect other ion channels. /Succinimide anticonvulsants/|Inhibition of T-type Ca(2+) channels has been proposed to play a role in the therapeutic action of succinimide antiepileptic drugs. Despite the widespread acceptance of this hypothesis, recent studies using rat and cat neurons have failed to confirm inhibition of T-type currents at therapeutically relevant concentrations. The present study re-examines this issue using the three cloned human channels that constitute the T-type family: alpha 1G, alpha 1H, and alpha 1I. The cloned cDNAs were stably transfected and expressed into mammalian cells, leading to the appearance of typical T-type currents. The results demonstrate that both ethosuximide and the active metabolite of methsuximide, alpha-methyl-alpha-phenylsuccinimide (MPS), block human T-type channels in a state-dependent manner, with higher affinity for inactivated channels. In contrast, succinimide analogs that are not anticonvulsive were relatively poor blockers. The apparent affinity of MPS for inactivated states of the three channels was estimated using two independent measures: K(I) for alpha 1G and alpha 1I was 0.3 to 0.5 mM and for alpha 1H was 0.6 to 1.2 mM. T-type channels display current at the end of long pulses (persistent current), and this current was especially sensitive to block (ethosuximide IC(50) = 0.6 mM). These drugs also reduced both the size of the T-type window current region and the currents elicited by a mock low threshold spike. /The authors/ conclude that succinimide antiepileptic drugs are capable of blocking human T-type channels at therapeutically relevant concentrations.

Because no specific antidote is available, treatment is essentially symptomatic and supportive and may consist of the following: ... Instillation of activated charcoal. Use of cathartics. To enhance elimination - charcoal hemoperfusion may be useful to remove the N-desmethyl metabolite of methsuximide. Supportive care - patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Note: forced diuresis and exchange transfusions are ineffective in the treatment of succinimide anticonvulsant overdoses. /Succinimide anticonvulsants/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Adverse hematologic effects associated with methsuximide include eosinophilia, leukopenia, monocytosis, and pancytopenia. Adverse dermatologic effects may include urticaria, pruritic erythematous rash, and Steven-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.|/SIGNS AND SYMPTOMS/ GI disturbances such as ... diarrhea, wt loss, epigastric & abdominal pain, & constipation occur frequently. Hemopoietic complications including eosinophilia ... Monocytosis, & pancytopenia have been reported. Neurologic & sensory reactions observed including ... irritability, nervousness ... blurred vision, photophobia...and insomnia.|/SIGNS AND SYMPTOMS/ Dermatologic disturbances including urticaria, Stevens-Johnson syndrome, & pruritic erythematous rashes.|/SIGNS AND SYMPTOMS/ Drowsiness, gastrointestinal disturbance, hiccups, irritability, and headache /are/ the common side effects of methsuximide.|For more Human Toxicity Excerpts (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

Celontin

CELONTIN|MESUXIMIDE|MESUXIMIDUM|METHSUXIMID|For more Formulations/Preparations (Complete) data for METHSUXIMIDE (6 total), please visit the HSDB record page.

Analyte: methsuximide; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: methsuximide; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: methsuximide; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards|Analyte: methsuximide; matrix: pharmaceutical preparation (capsule); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for METHSUXIMIDE (9 total), please visit the HSDB record page.

METHSUXIMIDE WORKING RANGE IS ABOUT 10-100 MG/L FOR MACRO- & 2-100 MG/L FOR MICRO-METHOD IN SERUM. METHSUXIMIDE METAB, N-DESMETHYLMETHSUXIMIDE, IS INCL IN BOTH METHODS.|LIQUID COLUMN CHROMATOGRAPHY. 50 MUL VOL OF SERUM WERE SUFFICIENT FOR DETECTION. LINEAR CURVES OBTAINED FOR WORKING RANGE OF 1-100 MG/L OF DRUG IN SERUM. SENSITIVITY IS 5 NG. AMOBARBITAL & PHENOBARBITAL INTERFERE.|HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR SIMULTANEOUS ANALYSIS OF SOME COMMON ANTICONVULSANTS & THEIR METAB INCL METHSUXIMIDE IN AS LITTLE AS 25 MUL OF SERUM IS DESCRIBED. LOWER LIMIT OF DETECTION IS LESS THAN 10 NG/SAMPLE. 1.0 MG/L SENSITIVITY OBTAINED ROUTINELY.|An HPLC method was developed and used for the analysis of the active metabolite N-desmethylmethsuximide in the plasma of patients treated with methsuximide.|For more Clinical Laboratory Methods (Complete) data for METHSUXIMIDE (7 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients