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Introduction

VA Class:CN400

AHFS Class:

Generic Name(s):

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Molecular Formula:

Ethosuximide is a succinimide-derivative anticonvulsant; the drug is structurally related to other succinimide anticonvulsants (e.g., methsuximide, phensuximide [no longer commercially available in the US]).1,2,3,4,5

Uses

Ethosuximide is used as monotherapy or adjunctive therapy (i.e., in conjunction with other anticonvulsants) in the prophylactic management of absence (petit mal) seizures and is generally considered the first-line anticonvulsant drug of choice for such seizures.1,2,3,4,5,12,13,17,18,19,20 Ethosuximide is usually ineffective in the management of other seizure types such as partial seizures or tonic-clonic (grand mal) seizures, although some clinicians have reported good results with ethosuximide in controlling partial seizures with complex symptomatology and myoclonic seizures. (For additional information on the treatment of absence seizures, see Uses: Seizure Disorders, in the Anticonvulsants General Statement 28:12.) In a randomized controlled study comparing ethosuximide, valproic acid, and lamotrigine for initial monotherapy in children with absence epilepsy, ethosuximide and valproic acid were more effective than lamotrigine in controlling seizures; among these anticonvulsants, adverse effects generally were more frequent with valproic acid.19,20 Based on these findings, experts recommend the use of ethosuximide for optimal efficacy and tolerability in children and adolescents with absence seizures.19 Ethosuximide may be used in combination with other anticonvulsants (e.g., valproic acid) for the treatment of coexisting seizure types (e.g., generalized tonic-clonic seizures).1,2,3,4,5

Dosage and Administration

Ethosuximide is administered orally as a capsule or oral solution.1,2,3,4,5

Patients who are currently receiving or beginning therapy with ethosuximide and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,196 (See Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.)

Dosage must be carefully and slowly adjusted according to individual requirements and response.1,2,3,4,5 Ethosuximide should be withdrawn or dosage reduced slowly to avoid precipitating seizures or absence status.1,2,3,4,5

The usual initial dosage of ethosuximide for patients 3-6 years of age is 250 mg daily in a single dose; for patients 6 years of age or older, 500 mg may be given daily in a single dose or in divided doses.1,2,3,4,5 One method of establishing the maintenance dosage is to increase the daily dosage by 250 mg every 4-7 days until seizure control is achieved with minimal adverse effects.1,2,3,4,5 The usual maintenance dosage is 20 mg/kg or 1.2 g/m2 daily.1,2,3,4,5 Dosage should not usually exceed 1.5 g daily, given in divided doses.1,2,3,4,5 When the dosage exceeds 1.5 g daily, the patient must be closely supervised by the clinician.1,2,3,4,5 Some studies indicate that when the patient is well stabilized, the total daily dosage may be given as one dose; however, clinical efficacy of this once-daily regimen has not been established.

Patients undergoing hemodialysis may require a supplemental dose of ethosuximide following each dialysis session or may require dosage adjustment.11 (See Cautions: Precautions and Contraindications and also see Pharmacokinetics: Elimination.)

Cautions

[Section Outline]

GI Effects !!navigator!!

The most common adverse effects of ethosuximide are GI symptoms including anorexia and weight loss, vague gastric upset, cramps, abdominal pain, diarrhea, nausea, vomiting, and epigastric distress.

Nervous System Effects !!navigator!!

Adverse nervous system effects including drowsiness, headache, fatigue, dizziness, ataxia, irritability, euphoria, hyperactivity, lethargy, and hiccups may occur. Adverse psychiatric or psychologic effects have also occurred, particularly in patients who had previously manifested psychologic abnormalities, and have included sleep disturbances, night terrors, aggressiveness, and inability to concentrate. Rarely, paranoid psychosis, increased libido, and increased state of mental depression with overt suicidal intentions have been reported. (See Dosage and Administration and also see Cautions: Precautions and Contraindications.)

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants, including ethosuximide.1 An analysis of suicidality reports from placebo-controlled studies using various anticonvulsants found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,196,198,212 The analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain).1,196,198,212 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,196,198 Although patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality compared with placebo, the relative risk was found to be higher in patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,196,198 (See Cautions: Precautions and Contraindications.)

Hematologic Effects !!navigator!!

The use of ethosuximide has also been associated with blood dyscrasias including leukopenia, eosinophilia, agranulocytosis, pancytopenia (with or without bone marrow depression), and aplastic anemia which have sometimes resulted in fatalities. Ethosuximide has also been implicated in the production of positive direct Coombs' test results.

Dermatologic and Sensitivity Reactions !!navigator!!

Urticaria and pruritic erythematous rashes have occurred in patients receiving ethosuximide. Serious, potentially fatal, dermatologic reactions including Stevens-Johnson syndrome have been reported in patients receiving ethosuximide.1 Such reactions can develop at any time, but generally have been reported within the first 28 days of therapy.1

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with ethosuximide.1 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems also may occur.1

Other Adverse Effects !!navigator!!

Systemic lupus erythematosus has been reported in patients receiving ethosuximide.

Renal and hepatic abnormalities also have been observed in preclinical and clinical studies.1 Other adverse reactions reported following ethosuximide therapy include myopia, vaginal bleeding, microscopic hematuria, gum hypertrophy, hirsutism, and swelling of the tongue.

Precautions and Contraindications !!navigator!!

Ethosuximide shares the toxic potentials of the succinimide-derivative anticonvulsants, and the usual precautions of anticonvulsant administration should be observed. (See Cautions in the Anticonvulsants General Statement 28:12.)

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.1,196,198,212 (See Suicidality Risk under Cautions: Nervous System Effects.) Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.1,196,198 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality and to pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences.1,196 In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).196 If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately.1,196 Clinicians who prescribe ethosuximide or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1,196 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.1 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.1

Ethosuximide should be discontinued at the first sign of a rash (unless the rash is clearly not drug related); if manifestations are suggestive of Stevens-Johnson syndrome, the drug should not be resumed and alternative therapies should be considered.1 If signs and symptoms of multi-organ hypersensitivity (DRESS) occur during ethosuximide therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued.1 (See Cautions: Dermatologic and Sensitivity Reactions.)

Patients should be warned that ethosuximide may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1,2,3,4,5

Ethosuximide should be used with extreme caution in patients with hepatic impairment, abnormal liver function test values, and/or renal impairment.1,2,3,4,5 (See Dosage and Administration.) Complete blood cell counts, liver function tests, and urinalyses should be performed periodically in patients receiving the drug.1,2,3,4,5

Ethosuximide is contraindicated in patients with known hypersensitivity to ethosuximide or other succinimides (e.g., methsuximide, phensuximide [no longer commercially available in the US]).1,2,3,4,5

Pediatric Precautions !!navigator!!

Safety and efficacy of ethosuximide in pediatric patients younger than 3 years of age have not been established.1

Pregnancy and Lactation !!navigator!!

Cases of birth defects have been reported with ethosuximide.1 Several reports suggest an association between the use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women; however, a definite causal relationship has not been established.1 (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.)

Anticonvulsant drugs should not be discontinued in pregnant women in whom the drugs are administered to prevent major seizures due to the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.1 In individual cases, when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drugs may be considered prior to and during pregnancy; however, there is a possibility that even minor seizures can adversely affect the developing fetus.1 The clinician should carefully weigh these considerations in treating or counseling epileptic women of childbearing potential.1

Women who become pregnant while receiving ethosuximide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry; patients can enroll by calling 888-233-2334.1 Information on the registry also can be found on the website [Web].1

Lactation

Ethosuximide is distributed into human milk.1,4,5,16 The drug should be used with caution in nursing women and only when the benefits clearly outweigh the risks; women should be advised to notify their clinician if they plan to breast-feed.1,2,3,4,5 (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.)

Other Information

[Section Outline]

Pharmacology

Ethosuximide shares the actions of the succinimide-derivative anticonvulsants.

Pharmacokinetics

Absorption !!navigator!!

Ethosuximide is readily absorbed from the GI tract. Following oral administration of a single dose, peak blood concentrations are reached within 4 hours; however, about 4-7 days of therapy at the usual dosage are required to achieve steady-state plasma concentrations. The plasma concentration required for therapeutic effect is generally considered to range from 40-100 mcg/mL; plasma concentrations less than 40 mcg/mL are rarely effective.2,3,4,5 The relationship between plasma ethosuximide concentrations and toxic effects of the drug has not been clearly established; however, plasma concentrations as high as 150 mcg/mL have not been associated with signs of toxicity.2,3,4,5

Distribution !!navigator!!

In vitro data suggest that there is no substantial degree of protein binding for ethosuximide. In one study in children, peak CSF concentrations of 25-50 mcg/mL were achieved within 1-2 hours following a single 250-mg dose of ethosuximide. These concentrations were maintained for 12-24 hours, and the drug was still detectable in the CSF 65 hours after the drug was given.

Ethosuximide crosses the placenta.1,4,5 The drug also is distributed into milk.1,4,5,16

Elimination !!navigator!!

The plasma half-life of ethosuximide is about 60 hours in adults and about 30 hours in children.

Ethosuximide is excreted slowly in urine. Approximately 20% of a dose is excreted unchanged and up to 50% may be excreted in urine as the hydroxylated metabolite and/or its glucuronide. Small amounts of unchanged drug are also excreted in bile and feces.

Ethosuximide is removed by hemodialysis.2,3,5,11 (See Dosage and Administration and see Cautions: Precautions and Contraindications.)

Chemistry and Stability

Chemistry !!navigator!!

Ethosuximide is a succinimide-derivative anticonvulsant.1,2,3,4,5 The drug occurs as a white to off-white, crystalline powder or waxy solid with a characteristic odor and is freely soluble in water and very soluble in alcohol. Ethosuximide has a pKa of 9.0.

Stability !!navigator!!

Ethosuximide capsules should be stored in tight containers at 15-30°C.1,5 Ethosuximide oral solution should be stored in tight, light-resistant containers at 20-25°C; freezing should be avoided.1,2,3,4

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of ethosuximide, see the Anticonvulsants General Statement 28:12.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ethosuximide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg*

Ethosuximide Capsules

Zarontin®

Pfizer

Solution

250 mg/5 mL*

Ethosuximide Syrup

Zarontin® Syrup

Pfizer

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions July 2, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

References

1. Pfizer. Zarontin® (ethosuximide) capsules prescribing information. New York, NY; 2016 May.

2. Mikart, Inc. Ethosuximide syrup 250 mg/5 mL prescribing information. Atlanta, GA; 2003 Mar.

3. Teva Pharmaceuticals USA. Ethosuximide solution 250 mg/5 mL prescribing information. Sellersville, PA; 2003 Oct.

4. Parke-Davis. Zarontin® (ethosuximide) solution prescribing information. New York, NY; 2006 Oct.

5. Banner Pharmacaps, Inc. Ethosuximide capsules prescribing information. High Point, NC; 2008 Feb.

6. Crawford P. Interaction between antiepileptic drugs and hormonal contraception. CNS Drugs . 2002; 16:263-72. [PubMed 11945109]

7. Giaccone M, Bartoli A, Gatti G et al. Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. Br J Clin Pharmacol . 1996; 41:575-9. [PubMedCentral][PubMed 8799524]

9. van Wieringen A, Vrijlandt CM. Ethosuximide intoxication caused by interaction with isoniazid. Neurology . 1983; 33:1127-8.

10. Bachmann K, Chu CA, Greear V. In vivo evidence that ethosuximide is a substrate for cytochrome P450IIIA. Pharmacology . 1992; 45:121-8. [PubMed 1438522]

11. Marbury TC, Lee CS, Perchalski RJ et al. Hemodialysis clearance of ethosuximide in patients with chronic renal disease. Am J Hosp Pharm . 1981; 38:1757-60. [PubMed 7304633]

12. Sälke-Kellermann RA, May T, Boenigk HE. Influence of ethosuximide on valproic acid concentrations. Epilepsy Res . 1997; 26:345-9.

13. Posner EB, Mohamed K, Marson AG. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Systematic Reviews . 2005; 4. Art. No.: CD003032. DOI: 10.1002/14651858.CD003032.pub2.

14. Millership JS, Mifsud J, Galea D et al. Chiral aspects of the human metabolism of ethosuximide. Biopharm Drug Dispos . 2005; 26:225-32. [PubMed 15931663]

15. Food and Drug Administration. Drugs or vaccines used in registries for specific diseases. From the FDA web site. Rockville, MD; Undated. Accessed 2008 Mar 20. [Web]

16. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:614-5.

17. AHFS drug information 2008. McEvoy GK, ed. Valproate sodium, valproic acid, divalproex sodium. Bethesda, MD: American Society of Health-System Pharmacists; 2008: 2307-14.

18. Glauser T, Ben-Menachem E, Bourgeois B et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia . 2013; 54:551-63. [PubMed 23350722]

19. Brigo F, Igwe SC. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Syst Rev . 2017; 2:CD003032. [PubMed 28195639]

20. Glauser TA, Cnaan A, Shinnar S et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med . 2010; 362:790-9. [PubMed 20200383]

196. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

198. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

212. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.