Ethosuximide

Earn CME/CE in your profession:


Continuing Education Activity

Ethosuximide is a central nervous system agent used to treat absence epilepsy, and this educational session equips healthcare professionals with the necessary information for delivering targeted and personalized care. This activity outlines the indications, actions, and contraindications for ethosuximide, providing essential information for its effective application in clinical settings. The mechanism of action, adverse event profile, dosing guidelines, monitoring requirements, and relevant interactions of ethosuximide are thoroughly reviewed. A review of this pharmacological information assists healthcare professionals in crafting tailored treatment plans that meet individual patient needs, optimizing therapeutic outcomes while minimizing potential adverse reactions. The discussion focuses on enhancing informed decision-making among healthcare providers during ethosuximide administration. Additionally, this activity highlights the interprofessional healthcare team's crucial role in effectively managing ethosuximide therapy.

Objectives:

  • Evaluate the mechanism of action of ethosuximide.

  • Identify the indications for ethosuximide therapy.

  • Assess the most common adverse drug reactions associated with ethosuximide therapy.

  • Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from ethosuximide therapy.

Indications

Ethosuximide is FDA-approved for the management of absence seizures in patients 3 or older.[1] Additionally, several studies have suggested ethosuximide may also have some analgesic effects, making it a potential therapy for neuropathic pain.[2][3]

FDA-Approved Indications

Ethosuximide has demonstrated level A evidence for managing childhood absence seizures and has been effectively used to treat this condition since the 1960s.[4][5] A 2010 trial demonstrated that ethosuximide and valproic acid were more effective than lamotrigine for treating absence seizures.[6] The seizure freedom rates with initial ethosuximide and valproic acid treatment were 53% and 58%, respectively. These patients were then followed for 12 months to evaluate their long-term outcomes. This study data was published in 2013 and demonstrated ethosuximide has better tolerability than valproic acid.[7] Ethosuximide has similar efficacy compared to valproic acid in adolescent patients.[8] 

Due to its effectiveness and relatively limited adverse event profile, ethosuximide is considered the first-line therapy for absence epilepsy. If absence seizures are refractory to ethosuximide monotherapy, valproic acid can be added to increase the probability of seizure control.[9] While ethosuximide is effective for absence seizures, it is typically reserved solely for this condition. Ethosuximide has demonstrated no benefit in symptomatic epilepsies or other generalized epilepsies. Valproic acid is recommended over ethosuximide as initial monotherapy for patients with concurrent generalized tonic-clonic (GTC) seizures, as ethosuximide does not help control GTC seizures and can potentially exacerbate them.

Off-Label Uses

The International League Against Epilepsy (ILAE) recommends ethosuximide for treating neurodevelopmental delay with generalized epilepsy (NDD with generalized epilepsy). This type of epilepsy is characterized by generalized seizure activity along with neurodevelopmental delays and responds well to medications like valproate, ethosuximide, or lamotrigine. The ILAE consensus highlights the importance of selecting appropriate treatments based on the specific phenotypes and genetic characteristics of sodium channel neuron 8A (SCN8A)-related disorders. The ILAE recommends valproic acid as the initial treatment for epilepsy with eyelid myoclonia (EEM), a condition previously known as Jeavons syndrome. There is moderate consensus regarding the efficacy of ethosuximide and clobazam in treating this condition. Levetiracetam or lamotrigine are preferred alternatives for women of childbearing age. However, additional randomized controlled trials are required.[10][11]

Mechanism of Action

Ethosuximide (3-ethyl-3-methyl pyrrolidine-2,5-dione) is a succinimide agent with anticonvulsant properties. Phensuximide and methsuximide, the other 2 succinimides, have less favorable adverse effect profiles and lower efficacy than ethosuximide.[12] This drug class was first studied in the 1950s using mouse models.

Thalamocortical neurons are thought to use low-threshold T-type calcium channels to generate the classic 3 Hz "spike-and-wave" discharges associated with absence seizures. Ethosuximide can reduce the threshold of T-type calcium currents and disrupt the oscillatory activity of thalamocortical circuitry by blocking T-type calcium channels.[13]

Pharmacokinetics

Absorption: Ethosuximide's bioavailability exceeds 90%.

Distribution: Ethosuximide demonstrates negligible protein binding, readily crosses the blood-brain barrier, and has a distribution volume of approximately 0.7 L/kg.[14]

Metabolism: Ethosuximide is metabolized hepatically (80%) into inactive metabolites, primarily by CYP3A4 enzymes.[15]

Elimination: Approximately 10% to 20% of ethosuximide is excreted unchanged in the urine. If the patient's creatinine clearance falls below 10 mL/min, the dose should be decreased by 25%. Caution is advised when administering ethosuximide to patients with hepatic impairment, though no dose adjustments have been defined for these patients. Ethosuximide has a relatively long half-life: 30 hours in children and 50 to 60 hours in adults. Because of its long half-life, ethosuximide can take 7 to 10 days to reach steady state.

Administration

Available Dosage Forms and Strengths

Ethosuximide is administered using 250 mg capsules or a 250 mg/5 mL oral suspension. The oral suspension demonstrates faster absorption than the capsules.

Adult Dosing

The typical adult ethosuximide dose is 500 mg orally once daily. This daily dose may be increased by 250 mg every 4 to 7 days to a maximum daily dose of 1500 mg.

Specific Patient Populations

Hepatic impairment: The product labeling does include dosage adjustments for patients with hepatic impairment. Ethosuximide should be used cautiously for these patients.

Renal impairment: No dosage adjustment is necessary for patients with a creatinine clearance (CrCl) greater than 30 mL/min. For patients with CrCl less than 30 mL/min, ethosuximide should be administered cautiously using low initial doses.[16] Patients on hemodialysis may require additional doses before or after their sessions to maintain therapeutic levels.[16]

Pregnancy considerations: Ethosuximide is a category C drug (possibly unsafe in pregnancy) known to cross the placenta. Serum concentrations of ethosuximide in neonates are comparable to that of mothers receiving ethosuximide.[17] Ethosuximide should be used as monotherapy at the lowest effective dose possible during pregnancy. Ethosuximide levels should be obtained before the patient becomes pregnant and monitored during pregnancy. The American Academy of Neurology (AAN), American Epilepsy Society (AES), and Society for Maternal-Fetal Medicine (SMFM) 2024 guidelines advise that women who are pregnant (or may become pregnant) with epilepsy on antiseizure medications (including ethosuximide) should be informed of the limited data on pregnancy-related outcomes associated with these drugs.[18]

Breastfeeding considerations: Ethosuximide can be excreted in breast milk, making breastfeeding while taking ethosuximide potentially hazardous. Transfer rates can reach 25%-30% of maternal levels. Close monitoring is recommended for infants exposed to ethosuximide through breast milk. No specific adverse effects have been linked solely to exposure to this medication, but observed adverse effects include drowsiness, impaired feeding, and developmental delays, particularly in younger or exclusively breastfed infants. The potential for additive effects with other maternal anticonvulsants should be considered. Obtaining the infant's serum ethosuximide level can assuage or confirm concerns regarding infant exposure or potential toxicity.[19] 

Pediatric patients: According to the American Academy of Neurology (AAN), ethosuximide or valproic acid are the first-line treatment options for reducing seizure frequency in patients with childhood absence epilepsy.[20] Dosing should start at 125 mg twice daily for children aged 3 to 6. Children 6 or older and adults can be administered 250 mg twice daily. The total daily dose may be increased by 250 mg every 4 to 7 days to 20 mg/kg, divided into twice daily dosing. The dosing and serum concentrations of ethosuximide demonstrate a linear relationship. When discontinuing, ethosuximide should be tapered slowly as abrupt withdrawal may cause absence status epilepticus.

Older patients: Ethosuximide is effective for absence seizures in children, but there is limited data on its long-term efficacy and safety in older adults. Agranulocytosis and drug-induced neutropenia have been reported.[21]

Adverse Effects

The overall incidence of adverse effects associated with ethosuximide therapy is lower compared to most other anti-seizure medications (ASMs).[22] Gastrointestinal adverse effects (eg, nausea, vomiting, diarrhea, anorexia) are common initially and often diminish within 2 weeks. Other common adverse effects include drowsiness, lethargy, insomnia, and hiccups. Headache may occur in 14% of children taking ethosuximide. 

Documented rare idiosyncratic reactions include Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, and systemic lupus erythematosus. If idiosyncratic reactions occur, ethosuximide should be discontinued. Full recovery may take some time following discontinuation.[23][24] Drug-induced lupus erythematosus is characterized by anti-histone and antinuclear antibodies.[25] Priapism has been reported infrequently.[26]

Drug-Drug Interactions

  • Enzyme-inducing ASMs such as phenytoin, carbamazepine, and phenobarbital can reduce serum concentrations of ethosuximide by accelerating its elimination.[27] Valproic acid has various effects on ethosuximide concentrations.[28][29][30][31] 
  • Ethosuximide may increase phenytoin levels, but it has no enzyme-inducing properties. 
  • Isoniazid may reduce ethosuximide metabolism, while rifampicin can increase ethosuximide clearance.[32][33]
  • One study indicated that ethosuximide significantly reduced lamotrigine serum concentrations based on patient age. Specifically, children and adolescents treated with ethosuximide showed a 37% reduction in lamotrigine levels compared to 14% in adults.[34]

Contraindications

Patients with hypersensitivity to succinimide medications should avoid taking ethosuximide.

Warnings and precautions

  • Ethosuximide should be administered cautiously to patients with hepatic disease, as dosing adjustments for patients with these conditions are undefined.
  • Antiseizure medications such as ethosuximide increase the risk of suicidal thoughts or behaviors. Patients receiving ethosuximide should be monitored for depression, suicidal ideation, or unusual changes in mood or behavior.[35][36]
  • Ethosuximide can cause drug-induced immune thrombocytopenia (DITP). [37] DITP typically occurs 1 to 3 weeks after initiation, with recurrence within 24 hours upon re-challenge. Platelet counts may drop by 3,000/mm³. Management involves discontinuation, monitoring platelet counts, and considering antiplatelet antibody assessment. Ethosuximide should be avoided in patients with a history of ethosuximide-induced DITP.

Monitoring

There are no guidelines for therapeutic drug monitoring of ethosuximide. Any ethosuximide dosage adjustment should be based on the patient's clinical response and electroencephalography (EEG) results. Ethosuximide levels are monitored by measuring the patient's trough levels. The therapeutic concentration for ethosuximide ranges from 40 to 100 μg/mL. Patients with absence status epilepticus may require concentrations above 120 μg/mL to achieve seizure control.[14] A dimple HPLC-UV method has been developed for therapeutic drug monitoring (TDM) of ethosuximide and other ASM levels. This method allows for the simultaneous determination of ethosuximide alongside several other ASMs and metabolites and requires only 100 µL of human plasma that may be prepared using a simple process. The dimple HPLC-UV is practical for pediatric, pregnant, older, and critically ill patients.[38]

A complete blood count (CBC) and liver function tests (LFTs) can also be obtained intermittently to monitor for severe but rare hematologic dyscrasias (eg, pancytopenia, agranulocytosis, leukopenia). However, no evidence suggests this is sufficient to alert physicians of a severe idiosyncratic reaction. The pattern of serum enzyme elevations is typically mixed cholestatic-hepatocellular. Any ethosuximide-induced liver injury resolves quickly after discontinuing and typically recurs promptly after re-exposure.[15]

Toxicity

Signs and Symptoms of Overdose

Studies using mouse models suggest the earliest symptom of ethosuximide toxicity is ataxia. Toxic patients can progress to dyspnea, respiratory failure, and death.[39] In cases of acute ethosuximide overdose in humans, clinical features may include nausea, vomiting, central nervous system depression, and coma with respiratory depression.

Management of Overdose

There is no antidote for ethosuximide toxicity. Recommendations involve observation in an emergency room or inpatient setting.[40] Treatment typically involves the administration of activated charcoal and supportive care. Hemodialysis can safely and effectively clear ethosuximide from the body.[41][42]

Enhancing Healthcare Team Outcomes

Primary care clinicians are commonly the first medical care providers to be informed about staring episodes or poor school performance. These symptoms suggest absence seizures, prompting a referral to neurology. After diagnosing absence epilepsy and initiating ethosuximide, both primary care physicians and neurologists should monitor for clinical benefit from ethosuximide therapy. If a patient remains seizure-free for longer than 2 years while on ethosuximide, and if the patient's EEG has normalized, the medication may be slowly tapered over weeks to see if the patient has developed terminal remission. A pediatric neurologist should be consulted for seizures refractory to ethosuximide. 

Ethosuximide is the most effective treatment for new-onset childhood absence epilepsy. However, initial monotherapy fails in 47% of cases. One pharmacokinetic study involving 211 participants revealed that area under the curve (AUC) levels of 1,027 and 1,489 μg·h/mL correspond to a 50% and 75% probability of seizure freedom, respectively. Monte Carlo simulations recommend daily doses of 40 and 55 mg/kg. Dosage adjustments based on body weight can enhance the success of the treatment.[43]

Ethosuximide therapy requires an interprofessional healthcare team, including clinicians, nursing staff, pharmacists, and mental health professionals. Nursing can counsel on medications and the disease state and serve as a liaison between other disciplines. Pharmacists should verify dosing, check for potential drug-drug interactions, and guide administration. Specialists may also offer their opinions and work with the prescribing clinicians to ensure the patient receives the appropriate therapeutic interventions. An interprofessional team approach and communication among clinicians (MDs, DOs, NPs, PAs), neurologists, pharmacists, and nurses are crucial to decreasing potential adverse effects, improving disease course and quality of life, and improving patient outcomes associated with ethosuximide.


Details

Updated:

7/2/2024 12:12:31 AM

References


[1]

Flatters SJ, Bennett GJ. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain. 2004 May:109(1-2):150-61     [PubMed PMID: 15082137]


[2]

Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F. Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain. 2003 Sep:105(1-2):159-68     [PubMed PMID: 14499432]


[3]

Hamidi GA, Ramezani MH, Arani MN, Talaei SA, Mesdaghinia A, Banafshe HR. Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain. European journal of pharmacology. 2012 Jan 15:674(2-3):260-4. doi: 10.1016/j.ejphar.2011.11.026. Epub 2011 Nov 23     [PubMed PMID: 22134003]


[4]

Weinstein AW, Allen RJ. Ethosuximide treatment of petit mal seizures. A study of 87 pediatric patients. American journal of diseases of children (1960). 1966 Jan:111(1):63-7     [PubMed PMID: 4954419]


[5]

Browne TR, Dreifuss FE, Dyken PR, Goode DJ, Penry JK, Porter RJ, White BG, White PT. Ethosuximide in the treatment of absence (peptit mal) seizures. Neurology. 1975 Jun:25(6):515-24     [PubMed PMID: 805382]


[6]

Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC, Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. The New England journal of medicine. 2010 Mar 4:362(9):790-9. doi: 10.1056/NEJMoa0902014. Epub     [PubMed PMID: 20200383]


[7]

Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Adamson PC, Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. 2013 Jan:54(1):141-55. doi: 10.1111/epi.12028. Epub 2012 Nov 21     [PubMed PMID: 23167925]


[8]

Brigo F, Igwe SC. Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. The Cochrane database of systematic reviews. 2017 Feb 14:2(2):CD003032. doi: 10.1002/14651858.CD003032.pub3. Epub 2017 Feb 14     [PubMed PMID: 28195639]

Level 1 (high-level) evidence

[9]

Le Roux M, Benallegue N, Gueden S, Rupin-Mas M, Van Bogaert P. Care of pharmaco-resistant absence seizures in childhood. Revue neurologique. 2024 Apr:180(4):251-255. doi: 10.1016/j.neurol.2024.01.002. Epub 2024 Feb 21     [PubMed PMID: 38388226]


[10]

Conecker G, Xia MY, Hecker J, Achkar C, Cukiert C, Devries S, Donner E, Fitzgerald MP, Gardella E, Hammer M, Hegde A, Hu C, Kato M, Luo T, Schreiber JM, Wang Y, Kooistra T, Oudin M, Waldrop K, Youngquist JT, Zhang D, Wirrell E, Perry MS. Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders. Epilepsia. 2024 May 27:():. doi: 10.1111/epi.17992. Epub 2024 May 27     [PubMed PMID: 38802994]

Level 3 (low-level) evidence

[11]

Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Jones H, Knupp KG, Mugar J, Nordli DR Jr, Riva A, Stern JM, Striano P, Thiele EA, Zawar I. Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel. Epilepsia. 2023 Sep:64(9):2342-2350. doi: 10.1111/epi.17682. Epub 2023 Jun 23     [PubMed PMID: 37326215]

Level 3 (low-level) evidence

[12]

GOLDENSOHN ES, HARDIE J, BOREA ED. Ethosuximide in the treatment of epilepsy. JAMA. 1962 Jun 9:180():840-2     [PubMed PMID: 13899742]


[13]

Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacology. 2020 May 15:168():107966. doi: 10.1016/j.neuropharm.2020.107966. Epub 2020 Jan 14     [PubMed PMID: 32120063]


[14]

Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008 Jul:49(7):1239-76. doi: 10.1111/j.1528-1167.2008.01561.x. Epub     [PubMed PMID: 18397299]

Level 1 (high-level) evidence

[15]

. Ethosuximide. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:():     [PubMed PMID: 31643206]


[16]

Mahmoud SH, Zhou XY, Ahmed SN. Managing the patient with epilepsy and renal impairment. Seizure. 2020 Feb 10:76():143-152. doi: 10.1016/j.seizure.2020.02.006. Epub 2020 Feb 10     [PubMed PMID: 32087549]


[17]

Kuhnz W, Koch S, Jakob S, Hartmann A, Helge H, Nau H. Ethosuximide in epileptic women during pregnancy and lactation period. Placental transfer, serum concentrations in nursed infants and clinical status. British journal of clinical pharmacology. 1984 Nov:18(5):671-7     [PubMed PMID: 6508976]


[18]

Pack AM, Oskoui M, Williams Roberson S, Donley DK, French J, Gerard EE, Gloss D, Miller WR, Munger Clary HM, Osmundson SS, McFadden B, Parratt K, Pennell PB, Saade G, Smith DB, Sullivan K, Thomas SV, Tomson T, Dolan O'Brien M, Botchway-Doe K, Silsbee HM, Keezer MR. Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM. Neurology. 2024 Jun:102(11):e209279. doi: 10.1212/WNL.0000000000209279. Epub 2024 May 15     [PubMed PMID: 38748979]

Level 1 (high-level) evidence

[19]

. Ethosuximide. Drugs and Lactation Database (LactMed®). 2006:():     [PubMed PMID: 30000278]


[20]

Kanner AM, Ashman E, Gloss D, Harden C, Bourgeois B, Bautista JF, Abou-Khalil B, Burakgazi-Dalkilic E, Llanas Park E, Stern J, Hirtz D, Nespeca M, Gidal B, Faught E, French J. Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018 Jul 10:91(2):74-81. doi: 10.1212/WNL.0000000000005755. Epub 2018 Jun 13     [PubMed PMID: 29898971]

Level 1 (high-level) evidence

[21]

Lorenzo-Villalba N, Alonso-Ortiz MB, Maouche Y, Zulfiqar AA, Andrès E. Idiosyncratic Drug-Induced Neutropenia and Agranulocytosis in Elderly Patients. Journal of clinical medicine. 2020 Jun 10:9(6):. doi: 10.3390/jcm9061808. Epub 2020 Jun 10     [PubMed PMID: 32531979]


[22]

Monti Guarnieri N, Pompilio A, Marini C, Ortenzi GB, Andresciani E, Garzone AMF, Ieracitano MC, Polidori C. A pharmacovigilance study on antiepileptic medications in a paediatric hospital in Italy. European journal of hospital pharmacy : science and practice. 2023 Dec 27:31(1):46-49. doi: 10.1136/ejhpharm-2021-003053. Epub 2023 Dec 27     [PubMed PMID: 35410875]


[23]

Glauser TA. Idiosyncratic reactions: new methods of identifying high-risk patients. Epilepsia. 2000:41 Suppl 8():S16-29     [PubMed PMID: 11092609]


[24]

Teoh PC, Chan HL. Lupus-scleroderma syndrome induced by ethosuximide. Archives of disease in childhood. 1975 Aug:50(8):658-61     [PubMed PMID: 812426]


[25]

Kaya Akca U, Sener S, Batu ED, Balik Z, Basaran O, Bilginer Y, Ozen S. Drug-induced lupus erythematosus in childhood: Case-based review. Lupus. 2024 Jun:33(7):737-748. doi: 10.1177/09612033241245078. Epub 2024 Apr 5     [PubMed PMID: 38580326]

Level 3 (low-level) evidence

[26]

Petrović NZ, Pejčić AV, Milovanović IR. Priapism associated with anti-seizure medications: a pharmacovigilance study and a review of published cases. Expert opinion on drug safety. 2024 Jan:23(1):67-78. doi: 10.1080/14740338.2023.2293208. Epub 2023 Dec 11     [PubMed PMID: 38062555]

Level 3 (low-level) evidence

[27]

Giaccone M, Bartoli A, Gatti G, Marchiselli R, Pisani F, Latella MA, Perucca E. Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. British journal of clinical pharmacology. 1996 Jun:41(6):575-9     [PubMed PMID: 8799524]


[28]

Bauer LA, Harris C, Wilensky AJ, Raisys VA, Levy RH. Ethosuximide kinetics: possible interaction with valproic acid. Clinical pharmacology and therapeutics. 1982 Jun:31(6):741-5     [PubMed PMID: 6804151]


[29]

Pisani F, Narbone MC, Trunfio C, Fazio A, La Rosa G, Oteri G, Di Perri R. Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia. 1984 Apr:25(2):229-33     [PubMed PMID: 6423377]


[30]

Mattson RH, Cramer JA. Valproic acid and ethosuximide interaction. Annals of neurology. 1980 Jun:7(6):583-4     [PubMed PMID: 6776874]


[31]

Battino D, Cusi C, Franceschetti S, Moise A, Spina S, Avanzini G. Ethosuximide plasma concentrations: influence of age and associated concomitant therapy. Clinical pharmacokinetics. 1982 Mar-Apr:7(2):176-80     [PubMed PMID: 6802548]


[32]

Bachmann KA, Jauregui L. Use of single sample clearance estimates of cytochrome P450 substrates to characterize human hepatic CYP status in vivo. Xenobiotica; the fate of foreign compounds in biological systems. 1993 Mar:23(3):307-15     [PubMed PMID: 8498093]


[33]

van Wieringen A, Vrijlandt CM. Ethosuximide intoxication caused by interaction with isoniazid. Neurology. 1983 Sep:33(9):1227-8     [PubMed PMID: 6684262]


[34]

Hagemann A, Herting A, Klimpel D, Bien CG, Polster T. Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction. Epilepsia. 2024 Jun:65(6):e73-e78. doi: 10.1111/epi.17952. Epub 2024 Apr 12     [PubMed PMID: 38606683]


[35]

Chien J. Ethosuximide-induced mania in a 10-year-old boy. Epilepsy & behavior : E&B. 2011 Aug:21(4):483-5. doi: 10.1016/j.yebeh.2011.05.004. Epub     [PubMed PMID: 21689989]


[36]

Datta AN. The impact of anti-seizure medications on psychiatric disorders among children with epilepsy: Both a challenge and an opportunity? Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent. 2023 Aug:32(3):177-184     [PubMed PMID: 37534124]


[37]

Shatara M, Regling K, Sabo C, Figueroa M, Taub JW, Rajpurkar M. Ethosuximide-induced Thrombocytopenia: A Case Report. Journal of pediatric hematology/oncology. 2019 Jul:41(5):420-421. doi: 10.1097/MPH.0000000000001310. Epub     [PubMed PMID: 30212418]

Level 3 (low-level) evidence

[38]

Milosheska D, Roškar R. Simple HPLC-UV Method for Therapeutic Drug Monitoring of 12 Antiepileptic Drugs and Their Main Metabolites in Human Plasma. Molecules (Basel, Switzerland). 2023 Nov 28:28(23):. doi: 10.3390/molecules28237830. Epub 2023 Nov 28     [PubMed PMID: 38067559]


[39]

CHEN G, WESTON JK, BRATTON AC Jr. Anticonvulsant activity and toxicity of phensuximide, methsuximide and ethosuximide. Epilepsia. 1963 Mar:4():66-76     [PubMed PMID: 14020499]


[40]

McCrea S. Antiepileptic drug overdose. Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association. 2002 Feb:9(9):13-8     [PubMed PMID: 11845727]


[41]

Marbury TC, Lee CS, Perchalski RJ, Wilder BJ. Hemodialysis clearance of ethosuximide in patients with chronic renal disease. American journal of hospital pharmacy. 1981 Nov:38(11):1757-60     [PubMed PMID: 7304633]


[42]

Wells L, Stanton M, Gummin DD, Brooks M, Feldman R. Hemodialysis enhances elimination of ethosuximide in massive overdose. Clinical toxicology (Philadelphia, Pa.). 2022 Sep:60(9):1078-1079. doi: 10.1080/15563650.2022.2102505. Epub 2022 Jul 27     [PubMed PMID: 35894638]


[43]

Mizuno K, Capparelli EV, Fukuda T, Dong M, Adamson PC, Blumer JL, Cnaan A, Clark PO, Reed MD, Shinnar S, Vinks AA, Glauser TA, Childhood Absence Epilepsy Study Group. Model-Informed Precision Dosing Guidance of Ethosuximide Developed from a Randomized Controlled Clinical Trial of Childhood Absence Epilepsy. Clinical pharmacology and therapeutics. 2023 Aug:114(2):459-469. doi: 10.1002/cpt.2965. Epub 2023 Jun 25     [PubMed PMID: 37316457]

Level 1 (high-level) evidence