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Ethosuximide

Pronunciation

(eth oh SUKS i mide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Zarontin: 250 mg [contains fd&c yellow #10 (quinoline yellow)]

Generic: 250 mg

Solution, Oral:

Zarontin: 250 mg/5 mL (474 mL) [raspberry flavor]

Generic: 250 mg/5 mL (473 mL, 474 mL)

Brand Names: U.S.

  • Zarontin

Pharmacologic Category

  • Anticonvulsant, Succinimide

Pharmacology

Increases the seizure threshold and suppresses paroxysmal spike-and-wave pattern in absence seizures; depresses nerve transmission in the motor cortex

Absorption

Complete and rapid

Distribution

Vd: 0.7 L/kg (Battino 1995)

Metabolism

Hepatic (to 3 inactive metabolites)

Excretion

Urine, slowly (12% to 20% as unchanged drug)

Time to Peak

Serum: 1 to 7 hours

Half-Life Elimination

Serum: Children: 30 hours; Adults: 50 to 60 hours

Use: Labeled Indications

Absence (petit mal) seizures: Management of absence (petit mal) seizures

Contraindications

Hypersensitivity to ethosuximide or any component of the formulation.

Dosing: Adult

Absence (petit mal) seizures:

Manufacturer’s dosing: Oral: Initial: 500 mg/day. Individualize dose based on patient response by increasing in small increments (eg, ≤250 mg) every 4 to 7 days as needed; doses >1,500 mg/day, in divided doses, should only be used under the strict supervision of a physician; higher doses may be necessary in some patients.

Alternate dosing: Single daily doses have been shown to be effective and well tolerated in clinical trials (in children) and pharmacokinetic analysis (Buchanan 1976; Colburn 1978; Vajda 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Absence (petit mal) seizures:

Manufacturer’s dosing:

Children 3 to 6 years: Oral: Initial: 250 mg/day. Individualize dose based on patient response by increasing in small increments (eg, ≤250 mg) every 4 to 7 days as needed; usual optimal dose: 20 mg/kg/day; doses >1,500 mg/day, in divided doses, should only be used under the strict supervision of a physician; higher doses may be necessary in some patients.

Children ≥6 years and Adolescents: Oral: Initial: 500 mg/day. Individualize dose based on patient response by increasing in small increments (eg, ≤250 mg) every 4 to 7 days as needed; usual optimal daily dose: 20 mg/kg/day; doses >1,500 mg/day, in divided doses, should only be used under the strict supervision of a physician; higher doses may be necessary in some patients.

Alternate dosing: Children ≥2 years and Adolescents: Oral: Initial: 10 mg/kg/day, titrated to response in 5 to 10 mg/kg/day increments every 7 days as required; usual range: 20 to 30 mg/kg/day in 2 to 3 divided doses (Glauser 2010; Kleigman 2016). Single daily doses have also been shown to be effective and well tolerated (Buchanan 1976; Dooley 1990). Doses reported in literature range from 6.5 to 50 mg/kg/day (Browne 1975; Sato 1982). Maximum daily dose: 60 mg/kg/day or 2,000 mg/day, whichever is less (Glauser 2010).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with extreme caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with extreme caution.

Storage

Capsules:

US labeling: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Canadian labeling: Store at 15ºC to 25ºC (59°F to 77°F). Protect from heat.

Solution:

US labeling: Store at 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light.

Canadian labeling: Store at 15ºC to 25ºC (59°F to 77°F); do not freeze. Protect from light.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Amphetamines: May diminish the therapeutic effect of Ethosuximide. Amphetamines may decrease the serum concentration of Ethosuximide. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of Ethosuximide. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: Ethosuximide may enhance the CNS depressant effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Fosphenytoin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: Ethosuximide may enhance the CNS depressant effect of Phenytoin. Phenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Phenytoin. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Valproate Products: Ethosuximide may decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Frequency not defined.

Central nervous system: Aggressive behavior, ataxia, delusional paranoid disorder, depression (with cases of overt suicidal intentions), disturbed sleep dizziness, drowsiness, euphoria, fatigue, headache, hyperactivity, irritability, lack of concentration, lethargy, night terrors

Dermatologic: Pruritus, skin rash, Stevens-Johnson syndrome, urticaria

Endocrine & metabolic: Hirsutism, increased libido, weight loss

Gastrointestinal: Abdominal pain, anorexia, abdominal cramps, diarrhea, epigastric pain, gastric distress, gingival hyperplasia, hiccups, nausea, swollen tongue, vomiting

Genitourinary: Occult blood in urine, vaginal hemorrhage

Hematologic & oncologic: Agranulocytosis, eosinophilia, leukopenia, pancytopenia

Hypersensitivity: Hypersensitivity reaction

Immunologic: DRESS syndrome (drug rash with eosinophilia and systemic symptoms)

Neuromuscular & skeletal: Systemic lupus erythematosus

Ophthalmic: Myopia

Warnings/Precautions

Concerns related to adverse effects:

• Blood dyscrasias: Severe blood dyscrasias (some fatal) have been reported. Monitor blood counts periodically, especially if signs/symptoms of infection develop.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Severe reactions, including Stevens-Johnson syndrome (SJS), have been reported with an onset usually within 28 days, but may be observed later. Drug should be discontinued if there are any signs of rash, unless the rash is clearly not drug-related. If SJS is suspected do not resume ethosuximide and consider alternative therapy.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, have been reported. Monitor for signs and symptoms (eg, fever, rash, exfoliative dermatitis, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, pneumonitis, myocarditis, pericarditis). If DRESS is suspected, discontinue therapy.

• Systemic lupus erythematous: Cases of systemic lupus erythematosus (SLE) have been reported.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment.

• Renal impairment: Use with extreme caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: May be used in combination with other anticonvulsants in patients with both absence and tonic-clonic seizures. May increase tonic-clonic seizures when used alone in patients with mixed seizure disorders.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Monitoring Parameters

Seizure frequency; trough serum concentrations, CBC, platelets, liver enzymes (periodic), urinalysis (periodic); signs of rash; suicidality (eg, suicidal thoughts, depression, behavioral changes)

Pregnancy Considerations

Ethosuximide crosses the placenta. Birth defects have been reported in infants. Epilepsy itself, the number of medications, genetic factors, or a combination of these may influence the teratogenicity of anticonvulsant therapy. In general, polytherapy may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended (Harden 2009). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued up to once a month during pregnancy in women with stable seizure control (Patsalos 2008).

Patients exposed to ethosuximide during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, dizziness, hiccups, nausea, vomiting, diarrhea, lack of appetite, abdominal pain, abdominal cramps, or weight loss. Have patient report immediately to prescriber signs of infection, signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs), enlarged lymph nodes, angina, confusion, hallucinations, inability to focus, nightmares, insomnia, change in balance, abnormal gait, urinary retention, change in amount of urine passed, severe loss of strength and energy, bruising, bleeding, petechiae, seizures, agitation, irritability, panic attacks, mood changes, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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