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Anticonvulsants, Succinimide (Systemic)

This monograph includes information on the following:

1) Ethosuximide
2) Methsuximide

INN:
Methsuximide —Mesuximide

VA CLASSIFICATION
Primary: CN400

Commonly used brand name(s): Celontin²; Zarontin¹.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category:

Anticonvulsant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Epilepsy, absence seizure pattern (treatment)^{09}^{11}^{12}^{14}^{27}^{33}^{34}—Ethosuximide, the drug of choice, ^{04} ^{23} ^{27} ^{28} is indicated for the control of seizures in absence (petit mal) epilepsy. Methsuximide is indicated for the management of absence seizures refractory to other medication. ^{10} ^{13}

[Epilepsy, complex partial seizure pattern (treatment)]¹—Methsuximide may be used in the treatment of complex partial seizures. ^{27} ^{29} ^{31} ^{32}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Ethosuximide: 141.17
    Methsuximide: 203.24

Mechanism of action/Effect:

Poorly defined ^{27}; 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. ^{12} ^{13} ^{14} ^{33} ^{34} The frequency of attacks is reduced by depression of nerve transmission in the motor cortex. ^{12} ^{13} ^{14} ^{33} These effects may be due to direct modification of membrane function in excitable cells and/or alteration of chemically mediated neurotransmission. ^{27} 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. ^{28}

Absorption:

Generally rapid and complete. ^{24} ^{27}

Distribution:

Freely distributed to all body tissues, except fat. ^{07} ^{27} Concentrations of ethosuximide in saliva and tears are equivalent to plasma concentrations. ^{27} Concentrations of ethosuximide in breast milk may approach 94% of plasma concentrations. ^{27}

Protein binding:

Not significant. ^{24} ^{27}

Biotransformation:

Hepatic. ^{24} ^{27} Methsuximide metabolized to the active metabolite N-desmethylmethsuximide. ^{10} ^{17}

Half-life:

Ethosuximide:

Adults: 56 to 60 hours. ^{08} ^{27}

Children: 30 to 36 hours. ^{07} ^{27}

Methsuximide:

1 to 3 hours. ^{10} ^{27}

N-desmethylmethsuximide:

34 to 80 hours. ^{27}

Time to peak concentration:

Ethosuximide:

Adults: 2 to 4 hours. ^{27}

Children: 3 to 7 hours. ^{27}

Methsuximide:

1 to 4 hours. ^{27}

Therapeutic serum concentration

Ethosuximide—40 to 100 mcg/mL ^{27} (283.4 to 708.4 micromoles per L).

N-desmethylmethsuximide—10 to 40 mcg/mL ^{10} ^{17} ^{27} (49.2 to 196.8 micromoles per L).

Elimination:
    Renal ^{10} ^{27} (ethosuximide, up to 20% unchanged). ^{24} ^{27}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one succinimide anticonvulsant may be sensitive to the other also.

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented; however, teratogenic effects have been associated with other anticonvulsant medications. ^{09} ^{10} ^{11} ^{12} ^{13} ^{14}

Breast-feeding

Ethosuximide is distributed into breast milk. ^{16} It is not known whether methsuximide is distributed into breast milk. Problems in humans have not been documented.

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of succinimide anticonvulsants in children.

Geriatrics

Appropriate studies on the relationship of age to the effects of succinimide anticonvulsants have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Dental

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.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol or
» Central nervous system (CNS) depression–producing medications, other (see Appendix II )    (CNS depression may be enhanced ^{01} ^{24})

Antidepressants, tricyclic,^{18}^{25} or
Loxapine or
Maprotiline or
Molindone^{04}^{25} or
Monoamine oxidase (MAO) inhibitors^{25} or
Phenothiazines^{25} or
Pimozide or
Thioxanthenes^{25}    (concurrent use may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication)

Carbamazepine or
Phenobarbital or
Phenytoin or
Primidone^{03}^{19}^{21}^{24}^{27}    (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 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)

Folic acid    (requirements for folic acid may be increased in patients receiving anticonvulsant therapy ^{19})

» Haloperidol    (concurrent use 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 ^{25})

Phenacemide    (concurrent use may result in additive toxicity ^{15})

Valproic acid^{21}^{23}^{24}^{27}    (concurrent use of valproic acid has been reported to both increase and decrease ethosuximide concentrations due to changes in metabolism; monitoring of serum concentrations as a guide to dosage is recommended)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Risk-benefit should be considered when the following medical problems exist
Blood dyscrasias    (condition may be exacerbated)

Hepatic function impairment^{09}^{10}^{11}^{12}^{13}^{14} or
Renal function impairment, severe^{09}^{10}^{11}^{12}^{13}^{14}    (morphological and functional changes may occur in liver or kidneys ^{05})

Intermittent porphyria^{29}^{30}^{31}^{32}    (condition may be exacerbated)

Sensitivity to succinimide anticonvulsants

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood cell counts, including platelets,^{09}^{10}^{11}^{12}^{13}^{14}^{27} and
Hepatic function determinations^{09}^{10}^{11}^{12}^{13}^{14}^{27} and
Renal function determinations and
Urinalysis^{09}^{10}^{11}^{12}^{13}^{14}    (recommended at periodic intervals for patients on prolonged therapy)

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Stevens-Johnson syndrome^{09}^{10}^{12}^{13} or systemic lupus erythematosus^{09}^{10}^{11}^{12}^{13}^{14} (skin rash and itching; swollen glands; sore throat and fever; muscle pain)

Incidence less frequent

Aggressiveness^{09}^{10}^{12}^{13}

difficulty in concentrating^{09}^{12}

mental depression^{09}^{10}^{12}^{13}

nightmares^{09}^{12}

Incidence rare

Blood dyscrasias, including agranulocytosis^{09}^{11}^{12}^{14} (chills; fever; sore throat; unusual tiredness or weakness)

aplastic anemia^{09}^{12} (shortness of breath, troubled breathing, wheezing, or tightness in chest; sores, ulcers, or white spots on lips or in mouth; swollen or painful glands; unusual bleeding or bruising)

eosinophilia^{09}^{10}^{12}^{13} (fever)

leukopenia^{09}^{10}^{11}^{12}^{13}^{14} (fever; chills; sore throat)

pancytopenia^{09}^{10}^{11}^{12}^{13}^{14} (nosebleeds or other unusual bleeding or bruising)

precipitation of tonic-clonic convulsions^{05}^{09}^{10}^{11}^{12}^{13}^{14}

paranoid psychosis^{09}^{10}^{12}^{13} (mood or mental changes)

pruritic^{09}^{10}^{12}^{13} erythematous rash^{09}^{10}^{11}^{12}^{13}^{14} (skin rash and itching)

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Anorexia^{09}^{10}^{11}^{12}^{13}^{14} (loss of appetite)

ataxia^{09}^{10}^{11}^{12}^{13}^{14} (clumsiness or unsteadiness)

dizziness^{09}^{10}^{11}^{12}^{13}^{14}

drowsiness^{09}^{10}^{11}^{12}^{13}^{14}

headache^{09}^{10}^{11}^{12}^{13}^{14}

hiccups^{09}^{10}^{13}

nausea or vomiting^{09}^{10}^{11}^{12}^{13}^{14}^{33}

stomach cramps^{09}^{10}^{12}^{13}

Incidence less frequent

Irritability^{09}^{10}^{12}^{13}

unusual tiredness or weakness^{09}^{12}^{14}

Overdose
For specific information on the agents used in the management of succinimide anticonvulsants, see: Charcoal, Activated (Oral-Local) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Central nervous system (CNS) depression (severe drowsiness)

severe nausea and vomiting

respiratory depression (shortness of breath; slow or irregular breathing; troubled breathing)
Note: Methsuximide poisoning may have a biphasic profile due to the N-desmethyl metabolite; therefore it is important to monitor serum concentrations of N-desmethylmethsuximide. ^{22}

Treatment of overdose
Because no specific antidote is available, treatment is essentially symptomatic and supportive. ^{21} ^{22}

To decrease absorption:
Induction of emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing) or gastric lavage. ^{21} ^{22}

Instillation of activated charcoal. ^{21} ^{22}

Use of cathartics. ^{21} ^{22}

To enhance elimination:
Hemodialysis may be useful in treating ethosuximide overdoses. ^{21}

Charcoal hemoperfusion may be useful to remove the N-desmethyl metabolite of methsuximide. ^{22}

Forced diuresis and exchange transfusions are ineffective in the treatment of succinimide anticonvulsant overdoses. ^{21} ^{22}

Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anticonvulsants, Succinimide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to succinimide anticonvulsants

Pregnancy—Possible birth defects
Other medications, especially CNS depressants or haloperidol
Other medical problems, especially blood dyscrasias, hepatic function impairment, severe renal function impairment, or intermittent porphyria

Proper use of this medication
» Compliance with therapy; taking daily in regularly spaced doses as ordered

Taking with food or milk to reduce gastric irritation

» Proper dosing
Missed dose: Taking as soon as possible; if remembered within 4 hours of next dose, skipping missed dose and continuing on regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing this medication; gradual dosage reduction may be necessary

» Not starting or stopping other medication without physician's advice

» Avoiding the use of alcoholic beverages and other CNS depressants while taking this medication ^{06}

» Possibility of drowsiness; caution if driving or doing jobs requiring alertness ^{09} ^{10} ^{11} ^{12} ^{13} ^{14}

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

Carrying medical identification card or bracelet

For methsuximide
Not taking capsules that are melted or not full; effectiveness may be reduced

Side/adverse effects
Signs of potential side effects, especially Stevens-Johnson syndrome, systemic lupus erythematosus, aggressiveness, difficulty in concentration, mental depression, nightmares, blood dyscrasias, tonic-clonic convulsions, paranoid psychosis, or pruritic erythematous rash

General Dosing Information
When succinimide anticonvulsants are to be discontinued, dosage should be reduced gradually to prevent possible occurrence of petit mal status. ^{09} ^{10} ^{11} ^{12} ^{13} ^{14}

When used to replace other anticonvulsant therapy, the dosage of the succinimide anticonvulsant should be increased gradually while that of the other medication is gradually decreased, to maintain seizure control. ^{10} ^{11} ^{12} ^{13} ^{14}

If succinimide anticonvulsants are used to supplement an existing anticonvulsant regimen, their dosage should be gradually increased to the required level. ^{10} ^{11} ^{12} ^{13} ^{14}

When succinimide anticonvulsants are used alone in mixed types of epilepsy, the frequency of primary generalized tonic-clonic seizures may be increased in some patients. ^{05} ^{09} ^{10} ^{11} ^{12} ^{13} ^{14}

ETHOSUXIMIDE

Summary of Differences

Pharmacology/pharmacokinetics:
Half-life—56 to 60 hours in adults; 30 to 36 hours in children.

Peak effect—3 to 7 hours.

Serum concentrations, therapeutic—40 to 100 mcg/mL.

Additional Dosing Information
See also General Dosing Information.

Strict supervision by the physician is required if total daily dosage of ethosuximide exceeds 1.5 grams ^{12} for adults or 1 gram for children up to 6 years of age.

Ethosuximide dosage may be initiated at maintenance level. When this medication is used concurrently with intravenous diazepam in management of absence status epilepticus (petit mal status), higher-than-usual starting doses may be required to rapidly achieve a therapeutic serum level.

Oral Dosage Forms

ETHOSUXIMIDE CAPSULES USP

Usual adult and adolescent dose
Anticonvulsant
Oral, 15 to 30 mg per kg of body weight a day ^{20}; or initially 250 mg two times a day, the dosage being increased by an additional 250 mg a day at four- to seven-day intervals until seizure control is obtained or until the total daily dose reaches 1.5 grams. ^{09} ^{12}

Usual pediatric dose
Anticonvulsant
Children up to 6 years of age: Oral, 15 to 40 mg per kg of body weight a day; ^{20} or initially 250 mg once a day, the dosage being increased by an additional 250 mg a day at four- to seven-day intervals until seizure control is obtained ^{09} ^{12} or until the total daily dose reaches 1 gram.

Children 6 years of age and over: See Usual adult and adolescent dose.

Note: The optimal dosage for most children is 20 mg per kg of body weight a day. ^{12}

Strength(s) usually available
U.S.—

250 mg (Rx) [Zarontin]

Canada—

250 mg (Rx) [Zarontin]

Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Keep container tightly closed.

ETHOSUXIMIDE SYRUP

Usual adult and adolescent dose
See Ethosuximide Capsules USP .

Usual pediatric dose
See Ethosuximide Capsules USP .

Strength(s) usually available
U.S.—

250 mg per 5 mL (Rx) [Zarontin (sucrose)][Generic]

Canada—

250 mg per 5 mL (Rx) [Zarontin]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • May cause drowsiness.

METHSUXIMIDE

Summary of Differences

Category:
Indicated in absence seizures refractory to other medication.

Pharmacology/pharmacokinetics:
Half-life—1 to 3 hours (36 to 45 hours for active metabolites).

Serum concentration, therapeutic—10 to 40 mcg/mL.

Oral Dosage Forms

METHSUXIMIDE CAPSULES USP

Usual adult and adolescent dose
Anticonvulsant
Oral, initially 300 mg once a day ^{10} ^{13} ^{27}, the dosage being increased by 300 mg a day at one-week intervals until seizure control is obtained ^{10} ^{13} or until the total daily dose reaches 1.2 grams. ^{10} ^{13} ^{35}^{27} Alternatively, some clinicians advocate making dosage increases of 150 to 300 mg at intervals of no less than 14 days to allow plasma concentrations to reach steady-state levels. ^{27}

Usual pediatric dose
See Usual adult and adolescent dose. (Small children may require dosage adjustments utilizing the 150-mg capsules.) ^{13}

Strength(s) usually available
U.S.—

150 mg (Rx) [Celontin]

300 mg (Rx) [Celontin]

Canada—

300 mg (Rx) [Celontin]

Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Avoid exposure to excessive heat.

Stability:
Methsuximide has a relatively low melting range (50 to 56 °C [122 to 133 °F]). Improper storage may result in melting and subsequent impaired absorption of the capsule contents.

Auxiliary labeling:
• May cause drowsiness.

Note: Do not dispense or use capsules that are not full or in which contents have melted. ^{10} ^{13} Protect from excessive heat (40 °C [104 °F]). ^{10} ^{13}

Revised: 02/05/2001

References

Note: The following references have been used only for recent revisions to this monograph. References used for monograph development and/or earlier revisions have not yet been incorporated into the computer database, but they will be provided upon request.

USP DI, 1987. Addendum IV.

The United States pharmacopeia. The national formulary. USP 21st revision (January 1, 1985). NF 16th ed (January 1, 1985). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1985 and Supplements.

Panelist comment, 8/87.

Panelist comment, 8/87.

Methsuximide (Celontin, PD). Phensuximide (Milontin, PD). Ethosuximide (Zarontin, PD). In: PDR Physicians" desk reference 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988.

Panelist comment, 8/87.

Buchanan RA, Fernandez L, Kinkel AW. Absorption and elimination of ethosuximide in children. J Clin Pharmacol 1969 Nov 9: 393-8.

Dill WA, et al. Physiologic disposition of alpha-methyl-alpha-ethylsuccinimide (ethosuximide; Zarontin) in animals and man. American Chemical Abstracts, 149th National Meeting, Detroit, Michigan (April 5-9, 1965): 30N.

Ethosuximide (Zarontin, PD). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 1162-3.

Methsuximide (Celontin, PD) In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 187-8.

Phensuximide (Milontin, PD). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 611.

Ethosuximide (Zarontin, Parke-Davis). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1599-600.

Methosuximide (Celontin, Parke-Davis). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1528-9.

Phensuximide (Milontin, Parke-Davis). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1571.

Phenacemide (Phenurone, Abbott). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, l989: 562-3.

Kuhnz W, et al. Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status, Br J Clin Pharmacol 1984; 18: 671-7.

Miles MV, Tennison IMB, Greenwood RS. Pharmacokinetics of N-desmethylmethsuximide in pediatric patients, J Pediatrics 1989 Apr; 114(4)(Part l): 647-50.

Hansten PD, Horn JR. Drug interactions. 5th ed. Philadelphia: Lea & Febiger, 1985: 115.

Shinn AF, Shewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby, 1985: 233, 272.

Panelist comment, 5/89.

Ethosuximide package insert (Zarontin, Parke-Davis—US), Rev 6/89, 11/89.

Methsuximide package insert (Celontin, Parke-Davis—US), Rev 7/89, Rec 11/89.

Drugs for epilepsy. Med Lett 1986 Sep 26; 28(273): 91-4.

Pisani F, Perucca E, DePerri R. Clinically relevant antiepileptic drug interactions. J Int Med Res 1990; 18: 1-15.

Itil TM, Soldatos C. Epileptogenic side effects of psychotropic drugs. Practical recommendations. JAMA 1980 Sep 26; 244(13): 1460-2.

Beck DJ, Orme ML"E. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18(6): 472-84.

Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE, editors. Antiepileptic drugs. 3rd ed. New York: Raven Press Ltd., 1989: 419, 653-714.

Rogawski MA, Porter RJ. Antiepileptic drugs: Pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacological Reviews 1990; 42(3): 223-86.

Panel comment, 1/20/91.

Panel comment, 1/15/91.

Panel comment, 1/15/91.

Panel comment, 1/8/91.

Methsuximide package insert (Celontin, Parke-Davis—US), Rev 6/92, Rec 7/29/93.

Ethosuximide syrup package insert (Copley—US), Rev 11/91, Rec 10/5/93.

Product Information: Celontin, methsuximide capsules. Parke-Davis, Scarborough, Ontario, Canada. (PI Issued 09/2000) PI reviewed 01/2001.

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