Ethosuximide

Class: Succinimides
VA Class: CN400
Chemical Name: 3-Ethyl-3-methyl-2,5-pyrrolidinedione
Molecular Formula: C₇H₁₁NO₂
CAS Number: 77-67-8
Brands: Zarontin

REMS:

FDA approved a REMS for ethosuximide oral to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

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

Uses for Ethosuximide

Absence (Petit Mal) Seizures

Alone or with other anticonvulsants (e.g., valproic acid) as first-line therapy in the prophylactic management of absence (petit mal) seizures.^{1 2 3 4 5 12 13 17}

Usually ineffective in management of partial seizures with complex symptomatology (psychomotor seizures)† or tonic-clonic (grand mal) seizures†.^a However, has been used with some success in management of partial seizures with complex symptomatology and myoclonic seizures†.^{a b}

When used alone in mixed seizures, may increase frequency of tonic-clonic seizures.^{1 2 3 4}

May use concomitantly with other anticonvulsants (e.g., phenytoin, phenobarbital, valproate) in patients with combined absence seizures and tonic-clonic seizures.^{1 2 3 4 5} (See Specific Drugs under Interactions.)

Ethosuximide Dosage and Administration

General

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  Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{8 c d} (See Suicidality Risk under Cautions.)

  
  


• 
  

  Proceed slowly with ethosuximide dosage increases or decreases, when adding or withdrawing another anticonvulsant, or when replacing one anticonvulsant with another.^{1 2 3 4 5} Do not discontinue abruptly to avoid precipitating seizures or absence status.^{1 2 3 4 5} (See Discontinuance of Therapy under Cautions and see Specific Drugs under Interactions.)

  
  

Administration

Administer orally as a capsule or oral solution without regard to meals.^{1 2 3 4 5 a b} However, administration with food and/or fluids may help minimize adverse GI effects.^b

Dosage

Carefully and slowly adjust dosage according to individual requirements and response.^{1 2 3 4 5}

Pediatric Patients

Absence (Petit Mal) Seizures

Oral

Children 3–6 years of age: Initially, 250 mg daily in a single dose.^{1 2 3 4 5}

Children ≥6 years of age: Initially, 500 mg daily in a single dose or divided doses.^{1 2 3 4 5}

Increase dosage in small increments.^{1 2 3 4 5} One method of establishing maintenance dosage is to slowly 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} Dosage usually should not be >1.5 g daily, given in divided doses.^{1 2 3 4 5} If dosage is >1.5 g daily, clinician must closely supervise patient.^{1 2 3 4 5}

Usual maintenance dosage: 20 mg/kg or 1.2 g/m² daily.^{1 2 3 4 5}

Some studies indicate that when patient is well stabilized, may give total daily dosage as one dose; however, clinical efficacy of once-daily regimen not established.^a

Adults

Absence (Petit Mal) Seizures

Oral

Initially, 500 mg daily in a single dose or divided doses.^{1 2 3 4 5}

Increase dosage in small increments.^{1 2 3 4 5} One method of establishing maintenance dosage is to slowly 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} Dosage usually should not be >1.5 g daily, given in divided doses.^{1 2 3 4 5} If dosage is >1.5 g daily, clinician must closely supervise patient.^{1 2 3 4 5}

Usual maintenance dosage: 20 mg/kg or 1.2 g/m² daily.^{1 2 3 4 5}

Some studies indicate that when patient is well stabilized, may give total daily dosage as one dose; however, clinical efficacy of once-daily regimen not established.^a

Prescribing Limits

Pediatric Patients

Absence (Petit Mal) Seizures

Oral

Maximum 1.5 g daily.^{1 2 3 4 5} Closely supervise patient if dosage is >1.5 g daily.^{1 2 3 4 5}

Adults

Absence (Petit Mal) Seizures

Oral

Maximum 1.5 g daily.^{1 2 3 4 5} Closely supervise patient if dosage is >1.5 g daily.^{1 2 3 4 5}

Special Populations

Renal Impairment

Patients undergoing hemodialysis may require a supplemental dose following each dialysis session or dosage adjustment.¹¹ (See Renal Impairment under Cautions.)

Cautions for Ethosuximide

Contraindications

• 
  

  Known hypersensitivity to ethosuximide or other succinimides (e.g., methsuximide, phensuximide [no longer commercially available in the US]).^{1 2 3 4 5}

  
  

Warnings/Precautions

Warnings

Shares the toxic potentials of the succinimide-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed.^{a b}

Hematologic Effects

Blood dyscrasias (e.g., leukopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, aplastic anemia, eosinophilia), sometimes fatal, reported.^{1 2 3 4 5 a} Obtain CBC at baseline and periodically during therapy.^{1 2 3 4 5 a b} Also obtain CBC if signs and/or symptoms of infection (e.g., sore throat, fever) develop.^{1 2 3 4 5}

Hepatic Effects

Morphological and functional liver changes reported in animals.^{1 2 3 4 5} Abnormal liver function test results reported in humans.^{1 2 3 4 5} Obtain baseline and periodic evaluations of hepatic function.^{1 2 3 4 5 a b} Consider discontinuance if evidence of hepatic damage occurs during therapy.^b

Renal Effects

Abnormal renal function test results reported.^{1 2 3 4 5} Obtain urinalyses periodically.^{1 2 3 4 5 a b} Consider discontinuance if evidence of renal damage occurs during therapy.^b

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) reported; clinicians should be alert to this possibility.^{1 2 3 4 5 a}

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{8 c d g} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{8 c g} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{8 c g}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{8 c d g} Anxiety, agitation, aggression, hostility, mania, and insomnia may be precursors to emerging suicidality.⁸

Balance risk of suicidality with the risk of untreated illness.^{8 c g} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{8 c g} If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{c d g} (See Advice to Patients.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; cases of birth defects reported with ethosuximide.^{b c g} Reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women; however, causal relationship to many anticonvulsants not established.^{b c g}

Do not discontinue anticonvulsants in pregnant women in whom the drugs are administered to prevent major seizures due to strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.^{b c g}

Carefully weigh these considerations when treating or counseling epileptic women of childbearing potential.^{b c g}

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

Possible dermatologic and hypersensitivity reactions (e.g., Stevens-Johnson syndrome, systemic lupus erythematosus, urticaria, pruritic erythematous rashes) reported.^{c g}

General Precautions

Seizures

May increase the frequency of tonic-clonic seizures when used alone in mixed seizures.^{a c g}

Discontinuance of Therapy

Abrupt withdrawal of anticonvulsants may precipitate seizures or absence (petit mal) status.^{a c g}

Cognitive/Physical Impairment

Performance of activities requiring mental alertness and physical coordination may be impaired.^{a b c g} (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.¹⁶ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also available on the website .^{c g}

Lactation

Distributes into breast milk.^{16 c g} Caution if used in nursing women.^{c g}

Pediatric Use

Safety and efficacy not established in children <3 years of age.^{c g}

Hepatic Impairment

Use with extreme caution in patients with hepatic impairment or abnormal liver function test values.^{a b c g} (See Hepatic Effects under Cautions.)

Renal Impairment

Use with extreme caution in patients with renal impairment.^{a c g} (See Renal Impairment under Dosage and Administration and see Renal Effects under Cautions.)

Common Adverse Effects

Adverse GI effects (anorexia and weight loss, gastric upset, cramps, epigastric and abdominal pain, diarrhea, nausea, vomiting),^{13 a b c g} hiccups,^{a b c g} drowsiness or tiredness.^{13 c g}

Interactions for Ethosuximide

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions with inhibitors or inducers of CYP3A4 are possible.^{7 10 14}

Protein-bound Drugs

Does not substantially bind to plasma proteins; pharmacokinetic interaction with drugs that are highly protein bound unlikely.^a

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potential additive CNS depressant effectsb
Anticonvulsants (e.g., phenobarbital, phenytoin; see also valproic acid entry in this table)	Pharmacokinetic interaction likely; possible increased and/or decreased antiepileptic concentrationsb c g 10 12	If used concomitantly, closely monitor serum concentrations and adjust dosage of both anticonvulsants as required b c g
Antidepressants, tricyclic	May precipitate seizuresb	Monitor closely for decreased seizure control; adjust ethosuximide dosage if necessaryb
CNS depressants	Potential additive CNS depressant effectsb
Isoniazid	Possible increased or decreased plasma ethosuximide concentrations and effects9 10
Oral contraceptives	Pharmacokinetic interaction unlikely6
Valproic acid	Pharmacokinetic interaction likely; possible increased and/or decreased antiepileptic concentrationsb c g 10 12 Valproic acid inhibits metabolism of ethosuximide; concurrent administration in healthy individuals resulted in a 25% increase in ethosuximide elimination half-life and a 15% decrease in total ethosuximide clearanceh	If used concomitantly, closely monitor serum concentrations and adjust dosage of both anticonvulsants as required, particularly if receiving other anticonvulsantsc h

Ethosuximide Pharmacokinetics

Absorption

Bioavailability

Readily absorbed from the GI tract.^a

Peak plasma concentrations generally attained within 4 hours after single-dose, oral administration.^a

Plasma Concentrations

Anticonvulsant therapeutic range generally considered to be 40–100 mcg/mL; plasma concentrations <40 mcg/mL are rarely effective and plasma concentrations ≤150 mcg/mL have been reported without toxicity.^{a g}

Distribution

Extent

Anticonvulsants generally are widely distributed in the body and succinimides are freely distributed throughout body water.^b

Crosses the placenta.^{c g} Distributed into milk.^{16 c g}

Plasma Protein Binding

Does not appear to be substantially protein bound.^a

Elimination

Metabolism

Metabolized in the liver via hydroxylation and glucuronide formation to several metabolites.^{14 a}

Elimination Route

Eliminated principally in urine, approximately 20% as unchanged drug and ≤50% as hydroxylated metabolite and/or its glucuronide.^{14 a} Small amount of unchanged drug excreted in bile and feces.^a

Half-life

Adults: 60 hours; children: about 30 hours.^a

Special Populations

Removed by hemodialysis; dosage adjustment may be necessary.^{11 b g}

Stability

Storage

Oral

Capsules

Tight containers at 25°C (may be exposed to 15–30°C).^{c g}

Solution

Tight, light-resistant containers at 20–25°C; avoid freezing.^{2 3 a f}

Actions

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  Ethosuximide shares the actions of succinimide-derivative anticonvulsants.^{a b}

  
  


• 
  

  Exact mechanism of anticonvulsant action not known.^b

  
  


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  Increases seizure threshold in the cortex and basal ganglia and reduces synaptic response to low-frequency repetitive stimulation.^{b c g}

  
  


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  Ethosuximide suppresses paroxysmal spike and wave activity of the EEG associated with lapses of consciousness common in absence seizures.^{b c g}

  
  

Advice to Patients

• 
  

  Importance of strictly adhering to prescribed directions for use and not altering the anticonvulsant regimen without first consulting with the clinician.^{c g} Importance of providing copy of written patient information (medication guide) each time ethosuximide is dispensed, and importance of reading this information prior to taking ethosuximide.^{c g}

  
  


• 
  

  Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{8 c d g i} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (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).^{c d g i}

  
  


• 
  

  Importance of not abruptly discontinuing therapy.^{a b c g}

  
  


• 
  

  Importance of informing patients that ethosuximide may cause serious, even life-threatening blood cell abnormalities such as reduced red or white blood cells and that periodic blood counts should therefore be performed.^c Advise patients to promptly contact their clinician if signs and/or symptoms of such blood cell abnormalities or infection (e.g., unusual bruising, sore throat, fever) develop.^{b c g}

  
  


• 
  

  Advise patients that drug may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).^{a c g}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses.^{c g}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; advise pregnant women of possible risk to fetus.^{c g} Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Cautions).^{c g}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{c g} (See Cautions.)

  
  

Preparations

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

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

Ethosuximide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	250 mg*	Ethosuximide Capsules
			Zarontin	Parke-Davis
	Solution	250 mg/5 mL*	Ethosuximide Solution
			Zarontin Solution	Parke-Davis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ethosuximide 250MG Capsules (TEVA PHARMACEUTICALS USA): 30/$38.99 or 90/$104.97

Ethosuximide 250MG/5ML Solution (PHARMACEUTICAL ASSOCIATES): 474/$58.99 or 1422/$167.97

Zarontin 250MG Capsules (PFIZER U.S.): 60/$106.81 or 180/$311.71

Zarontin 250MG/5ML Solution (PFIZER U.S.): 480/$186.38 or 1440/$540.57

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Parke-Davis. Zarontin (ethosuximide) capsules prescribing information. New York, NY; 2006 Oct.

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. [PubMed 8799524]

8. Food and Drug Administration. Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA web site.

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.

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.

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.

a. AHFS drug information 2008. McEvoy GK, ed. Ethosuximide. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2270-1.

b. AHFS drug information 2008. McEvoy GK, ed. Anticonvulsants general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2254-8.

c. Parke-Davis. Zarontin (ethosuximide) capsules prescribing information. New York, NY; 2009 Sep.

d. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2009 Oct 21.

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

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

g. Banner Pharmacaps, Inc. Ethosuximide capsules prescribing information. High Point, NC; 2009 May.

h. Abbott Laboratories. Depakene (valproic acid) solution and liquid-filled capsules prescribing information. North Chicago, IL; 2009 Nov.

i. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

More Ethosuximide resources

• Ethosuximide Side Effects (in more detail)
• Ethosuximide Use in Pregnancy & Breastfeeding
• Drug Images
• Ethosuximide Drug Interactions
• Ethosuximide Support Group
• 5 Reviews for Ethosuximide - Add your own review/rating

• Ethosuximide MedFacts Consumer Leaflet (Wolters Kluwer)


• Ethosuximide Prescribing Information (FDA)


• Ethosuximide Professional Patient Advice (Wolters Kluwer)


• ethosuximide Concise Consumer Information (Cerner Multum)


• ethosuximide Advanced Consumer (Micromedex) - Includes Dosage Information


• Zarontin Prescribing Information (FDA)

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