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  • CLASSES

    Anticonvulsants, Succinimides

    DEA CLASS

    Rx

    DESCRIPTION

    Oral succinimide-derivative anticonvulsant; one of the drugs of choice for managing absence seizures (petit mal); generally ineffective for complex partial and tonic-clonic seizures; less teratogenic potential than some of the other drugs used in absence seizures; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

    COMMON BRAND NAMES

    Zarontin

    HOW SUPPLIED

    Ethosuximide/Zarontin Oral Cap: 250mg
    Ethosuximide/Zarontin Oral Sol: 5mL, 250mg

    DOSAGE & INDICATIONS

    For the treatment of generalized absence seizures.
    Oral dosage
    Adults, Adolescents, and Children > 6 years

    Initially, 250 mg PO twice daily. May increase dosage by 250 mg/day PO at 4—7 day intervals, until seizure control is achieved, or to a maximum daily dose of 1.5 g. The usual maintenance dose is 20—40 mg/kg/day PO, given in 2 divided doses. The usual therapeutic range for ethosuximide serum levels is 40—100 mcg/mL. In a small number of patients, concentrations up to 150 mcg/mL may be needed to achieve complete seizure control.

    Children 3—6 years

    Initially, 15 mg/kg/day PO, given in 2 divided doses (Max initial dose: 250 mg). Increase every 4—7 days; usual maintenance dose is 15—40 mg/kg/day PO, given in 2 divided doses. The optimal dose for most pediatric patients is 20 mg/kg/day PO. The usual therapeutic range for ethosuximide serum levels is 40—100 mcg/mL.

    MAXIMUM DOSAGE

    Adults

    1.5 g/day PO.

    Elderly

    1.5 g/day PO.

    Adolescents

    1.5 g/day PO.

    Children

    > 6 years: 1.5 g/day PO
    3—6 years: Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of ethosuximide serum levels and other clinical parameters.
    < 3 years: Safe and effective use has not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; dosage adjustments may be needed. Ethosuximide may cause hepatic dysfunction and discontinuation may need to be considered if significant hepatic impairment occurs during therapy.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    A MedGuide is available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications. The MedGuide should be dispensed with each new prescription and prescription refill.

    Oral Administration

    May be administered orally without regard to meals.

    STORAGE

    Zarontin:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Succinimide hypersensitivity

    Ethosuximide is contraindicated in patients with a history of succinimide hypersensitivity because of possible cross-sensitivity and serious adverse reactions. Drug hypersensitivity can include adverse hematologic or hepatic reactions to the drug.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), corresponding to an estimated 2.1 per 1000 (95% CI: 0.7—4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Abrupt discontinuation

    Ethosuximide, when used alone in mixed types of epilepsy, may increase the frequency of grand mal seizures in some patients. As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medications. Abrupt discontinuation of anticonvulsant medication may precipitate absence (petit mal) status.

    Hepatic disease, hepatitis, jaundice

    Ethosuximide should be used with caution in patients with preexisting hepatic disease. Like many anticonvulsants, the drug has rarely been associated with increased LFTs and the onset of liver dysfunction (e.g., hepatitis or jaundice). LFT monitoring should be performed periodically. If serious hepatic adverse effects occur, drug discontinuation may need to be considered.

    Porphyria

    Ethosuximide should be used with caution in patients with intermittent porphyria because the drug could exacerbate this condition.

    Renal disease

    Ethosuximide should be used with extreme caution in patients with renal disease because potentially fatal nephrotic syndromes can occur. Patients may recover renal function upon discontinuation of the drug but may require additional therapy. Urinalysis should be performed regularly, especially in patients at risk.

    Agranulocytosis, bone marrow suppression, fever, hematological disease, infection

    Ethosuximide should be used with caution in patients with bone marrow suppression or any hematological disease. Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, periodic blood counts should be performed. Patients should promptly contact their prescriber if they develop signs and/or symptoms suggesting an infection (e.g., sore throat, fever). Consider discontinuation of the drug if severe bone marrow suppression occurs, including reactions like agranulocytosis or aplastic anemia.

    Avoid ethanol ingestion, driving or operating machinery

    Ethosuximide commonly causes dizziness, drowsiness, and fatigue. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether ethosuximide adversely affects their mental and/or motor performance. Avoid ethanol ingestion since ethanol (alcohol) can enhance CNS depressant effects and also lower seizure thresholds.

    Children, infants, neonates

    Safety and efficacy in neonates, infants and children < 3 years of age  have not been established.

    Pregnancy

    Use ethosuximide with caution during pregnancy. Ethosuximide crosses the placenta. There are case reports of birth defects with ethosuximide; however, available data cannot be regarded as adequate to prove a definite cause and effect relationship. In many cases, the mother was receiving combination therapy with other anticonvulsants. In a study of 10 epileptic mothers, 2 major malformations (bilateral clefting and hare-lip) were observed in infants of 2 mothers taking either primidone or phenobarbitone with ethosuximide. In 1 mother who received ethosuximide monotherapy, minor anomalies noted among 2 siblings including mammalian line, over-extensible joints, broad thumbs, epicanthal folds, broad nasal bridge, dimples, and misshaped ear. Overall, the mean number of minor anomalies in infants exposed to ethosuximide was higher than in the matched control group (6.2 vs. 2.1) but similar to the group of infants whose mothers received antiepileptic drugs (AEDs) other than ethosuximide (5.1). In an analysis of 5 prospective European studies including 1,221 children with AED exposure during pregnancy, 1 major congential abnormality was reported among 13 pregnancies exposed to ethosuximide monotherapy. Major congential abnormalities occurred in 2 of 5 pregnancies exposed to combination therapy with phenobarbital and ethosuximide and in 3 of 39 pregnancies exposed to combination therapy with valproic acid and ethosuximide. Anticonvulsant drugs should not be discontinued in patients in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In cases where the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although even minor seizures may pose some hazard to the developing embryo or fetus. Weigh these considerations in treating or counseling epileptic females of childbearing potential. Encourage pregnant patients receiving ethosuximide to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must call 1-888-233-2334 to enroll in the registry. Information on the registry can also be found at the website at www.aedpregnancyregistry.org. The effects of ethosuximide during labor and delivery are unknown.

    Breast-feeding

    Ethosuximide should be used during breast-feeding only if the benefits clearly outweigh the potential risks because the effects of the drug on the breast-fed infant are unknown. Limited evidence indicates that ethosuximide is excreted into human breast milk in concentrations similar to those in the maternal plasma. In 1 patient who received ethosuximide and primidone, the milk to serum ethosuximide concentration ratio was 0.94 +/- 0.06 at 4 to 6 days after delivery. Assuming a constant maternal ethosuximide concentration of 64 mcg/mL and a breast milk consumption of 200 to 600 mL/day by a breast-feeding infant weighing 3.5 kg, the authors calculated a theoretical infant dose of 3.6 to 11 mg/kg/day. The maternal weight-adjusted dose was 15.6 mg/kg. In a separate case, a mother receiving ethosuximide monotherapy and her breast-feeding infant were followed for 4.5 months postpartum. On the third day after delivery, the milk concentration of ethosuximide was similar to that in maternal plasma (milk:maternal plasma concentration ratio of 1.03). Subsequently, the mean milk/maternal plasma concentration ratio decreased to 0.80 (based on 3 samples taken approximately 10 days, 5 weeks, and 2 months after delivery). The infant developed normally, and no adverse effects occurred during the observation period. In another study that included 5 women who received ethosuximide during pregnancy and who breast-fed their infants after delivery, the mean milk:maternal serum ethosuximide concentration ratio was 0.86 +/- 0.08 for samples taken between postpartum days 3 and 28. Two of the breast-fed infants experienced hyperexcitability, 1 infant experienced sedation for 5 weeks and no weight gain for 4 weeks, and the remaining 2 infants exhibited normal neonatal behavior. The mother of 1 of the infants who experienced hyperexcitability received ethosuximide monotherapy while the remaining 4 mothers received combination therapy with other anticonvulsants. Although previous American Academy of Pediatrics recommendations considered ethosuximide as compatible with breast-feeding, the available data are limited to case reports and small studies.

    Geriatric

    According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If ethosuximide must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known

    Moderate

    depression / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    gingival hyperplasia / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    myopia / Delayed / Incidence not known
    vaginal bleeding / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known

    Mild

    vomiting / Early / 1.0-10.0
    nausea / Early / 1.0-10.0
    dyspepsia / Early / 10.0
    anorexia / Delayed / Incidence not known
    hiccups / Early / Incidence not known
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    irritability / Delayed / Incidence not known
    nightmares / Early / Incidence not known
    lethargy / Early / Incidence not known
    dizziness / Early / Incidence not known
    emotional lability / Early / Incidence not known
    agitation / Early / Incidence not known
    insomnia / Early / Incidence not known
    headache / Early / Incidence not known
    libido increase / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    fatigue / Early / Incidence not known
    drowsiness / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    rash (unspecified) / Early / Incidence not known
    hirsutism / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
    Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Amphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Amphetamine; Dextroamphetamine Salts: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Amphetamine; Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Amprenavir: (Moderate) Protease Inhibitors may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if ethosuximide and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ethosuximide-related adverse effects for several days after administration of a multi-day aprepitant regimen. This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects. Ethosuximide is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ethosuximide. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Atazanavir: (Moderate) Atazanavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Atazanavir; Cobicistat: (Moderate) Atazanavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide. (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Barbiturates: (Moderate) Barbiturates induce hepatic microsomal enzymes and increase the hepatic metabolism of ethosuximide, leading to a decrease in ethosuximide plasma concentrations and half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if barbiturate therapy is added to or withdrawn from ethosuximide therapy.
    Benzphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use benzphetamine with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as ethosuximide. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering ethosuximide with boceprevir due to an increased potential for ethosuximide-related adverse events. If ethosuximide dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ethosuximide. Ethosuximide is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated ethosuximide plasma concentrations.
    Bosentan: (Moderate) Bosentan is an inducer of CYP3A4 enzymes, and may decrease concentrations of drugs metabolized by these enzymes including ethosuximide.
    Brodalumab: (Moderate) Coadministration of brodalumab may result in altered exposure to ethosuximide. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as ethosuximide. Monitor for changes in ethosuximide concentrations if brodalumab is initiated or discontinued in a patient taking ethosuximide; ethosuximide dose adjustments may be needed.
    Carbamazepine: (Moderate) Carbamazepine induces hepatic microsomal enzymes. Increased hepatic metabolism of ethosuximide leads to a decrease in its plasma concentration and a reduction in its half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if additional anticonvulsant therapy is added to or withdrawn from ethosuximide therapy.
    Ceritinib: (Major) Avoid coadministration of ceritinib with ethosuximide due to increased ethosuximide exposure. If coadministration is unavoidable, monitor for ethosuximide-related adverse reactions. Ceritinib is a CYP3A4 inhibitor and ethosuximide is primarily metabolized by CYP3A4.
    Chlorpromazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Ciprofloxacin: (Moderate) Close clinical monitoring is advised when administering ethosuximide with ciprofloxacin due to an increased potential for ethosuximide-related adverse events. If ethosuximide dose adjustments are made, re-adjust the dose upon completion of ciprofloxacin treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ethosuximide. Ethosuximide is metabolized by the hepatic isoenzyme CYP3A4; ciprofloxacin inhibits this isoenzyme. Coadministration may result in elevated ethosuximide plasma concentrations.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Cobicistat: (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of succinimides if coadministered. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as ethosuximide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with ethosuximide. Treatment with ethosuximide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with crizotinib is necessary. Ethosuximide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
    Danazol: (Minor) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of ethosuximide, a CYP3A4 substrate. Patients receiving these agents should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of either drug may be necessary if danazol therapy is discontinued.
    Darunavir: (Moderate) Darunavir may inhibit the CYP3A4 metabolism of ethosuximide, and may necessitate up to a 50% dose reduction of ethosuximide. Closely monitor patients during concurrent therapy.
    Darunavir; Cobicistat: (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide. (Moderate) Darunavir may inhibit the CYP3A4 metabolism of ethosuximide, and may necessitate up to a 50% dose reduction of ethosuximide. Closely monitor patients during concurrent therapy.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed.
    Dasatinib: (Moderate) Dasatinib inhibits CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme, such as ethosuximide, are administered concurrently with dasatinib as increased adverse reactions may occur.
    Delavirdine: (Moderate) Delavirdine may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Diltiazem: (Moderate) Diltiazem is an inhibitor of the CYP3A4 isoenzyme. Co-administration with diltiazem may lead to an increase in serum levels of drugs that are CYP3A4 substrates including ethosuximide.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with ethosuximide is necessary, and monitor for an increase in ethosuximide-related adverse effects. Dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Ethosuximide is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to ethosuximide. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as ethosuximide. Monitor ethosuximide concentrations if dupilumab is initiated or discontinued in a patient taking ethosuximide; ethosuximide dose adjustments may be needed.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ethosuximide.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ethosuximide.
    Elbasvir; Grazoprevir: (Moderate) Administering ethosuximide with elbasvir; grazoprevir may result in elevated ethosuximide plasma concentrations. Ethosuximide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Ethanol: (Major) Ethanol and other CNS depressants may increase the risk for CNS depression during ethosuximide treatments. In addition, ethanol intoxication may lower seizure thresholds, making an anticonvulsant drug less effective.
    Ferric Citrate: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of ethosuximide from ferric citrate. According to the manufacturer of ferric citrate, clinicians should consider separating the timing of administration of ferric citrate and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. Because ethosuximide has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of ferric citrate.
    Fluconazole: (Moderate) Fluconazole may inhibit the CYP3A4 metabolism of ethosuximide. This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects.
    Fluphenazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Fosamprenavir: (Moderate) Fosamprenavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and ethosuximide may result in decreased exposure of ethosuximide. Ethosuximide is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of ethosuximide during coadministration.
    Haloperidol: (Moderate) Concomitant use of ethosuximide with haloperidol can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as ethosuximide. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ethosuximide, a CYP3A substrate, as ethosuximide toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imatinib: (Moderate) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 isoenzymes including 2D6, 2C9, and 3A4. Decreased metabolism of ethosuximide and an increased risk of toxicity may occur when these drugs are given together. Closely monitor patients during concurrent therapy.
    Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Indinavir: (Moderate) Indinavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with ethosuximide may result in increased serum concentrations of ethosuximide. Ethosuximide is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Itraconazole: (Moderate) Itraconazole may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and ethosuximide concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ethosuximide, can increase ethosuximide exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ketoconazole: (Moderate) Ketoconazole may inhibit the CYP3A4 metabolism of ethosuximide. This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects.
    Lanreotide: (Major) Avoid coadministration of lanreotide with ethosuximide due to increased ethosuximide exposure. If coadministration is unavoidable, monitor for ethosuximide-related adverse reactions. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index. Limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of CYP3A4 substrates, which may be due to the suppression of growth hormone; it cannot be excluded that lanreotide has this effect.
    Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use lisdexamfetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide. The extent of absorption of ethosuximide is not known to be affected.
    Lopinavir; Ritonavir: (Moderate) Lopinavir; ritonavir may inhibit the CYP3A4 metabolism of ethosuximide, and may necessitate up to a 50% dose reduction of ethosuximide. Closely monitor patients during concurrent therapy (Moderate) Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed.
    Loxapine: (Moderate) Concomitant use of ethosuximide with loxapine can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of ethosuximide and lumacaftor; ivacaftor is not recommended. Lumacaftor; ivacaftor may decrease the systemic exposure of ethosuximide, a narrow therapeutic index drug. Ethosuxamide is a substrate of CYP3A, and lumacaftor; ivacaftor is a potent CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and ethosuximide concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as ethosuximide, can increase ethosuximide exposure leading to increased or prolonged therapeutic effects and adverse events.
    Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Mesoridazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving ethosuximide, drug concentration monitoring should be performed and the ethosuximide dosage adjusted as needed. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as ethosuximide.
    Mitotane: (Major) Use caution if mitotane and ethosuximide are used concomitantly, and monitor for decreased efficacy of ethosuximide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and ethosuximide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ethosuximide.
    Molindone: (Moderate) Concomitant use of ethosuximide with molindone can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Monoamine oxidase inhibitors: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Nelfinavir: (Moderate) Nelfinavir may inhibit the metabolism of other substrates of cytochrome P450 3A4, such as ethosuximide. Closely monitor patients during concurrent therapy. A 50% dose reduction of ethosuximide may be needed.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ethosuximide. The plasma concentrations of ethosuximide can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nevirapine: (Moderate) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, such as ethosuximide, may require dosage adjustments.
    Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as ethosuximide.
    Nilotinib: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ethosuximide, a CYP3A4 substrate, may result in increased ethosuximide levels. A ethosuximide dose reduction may be necessary if these drugs are used together.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed.
    Oritavancin: (Moderate) Avoid use of oritavancin with drugs that have a narrow therapeutic window, such as ethosuximide. Ethosuximide is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of ethosuximide may be reduced if these drugs are administered concurrently. Monitor for lack of ethosuximide efficacy.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and ethosuximide, a CYP3A4 substrate, may cause an increase in systemic concentrations of ethosuximide. Use caution when administering these drugs concomitantly.
    Perphenazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Perphenazine; Amitriptyline: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Phenelzine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Phenothiazines: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Phenytoin: (Moderate) Phenytoin induces hepatic microsomal enzymes. Increased hepatic metabolism of ethosuximide leads to a decrease in its plasma concentration and a reduction in its half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if additional anticonvulsant therapy is added to or withdrawn from ethosuximide therapy.
    Pimozide: (Moderate) Concomitant use of ethosuximide with pimozide can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Posaconazole: (Moderate) Posaconazole and ethosuximide should be coadministered with caution due to an increased potential for ethosuximide-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide. These drugs used in combination may result in elevated ethosuximide plasma concentrations, causing an increased risk for ethosuximide-related adverse events.
    Prochlorperazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Ranolazine: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase the plasma concentrations of ethosuximide.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with ethosuximide is necessary, as the systemic exposure of ethosuximide may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and ethosuximide is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with ethosuximide is necessary, as the systemic exposure of ethosuximide may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and ethosuximide is a CYP3A4 substrate.
    Ritonavir: (Moderate) Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as ethosuximide, may occur during concurrent use with rufinamide.
    Saquinavir: (Moderate) Saquinavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Selegiline: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of ethosuximide from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because ethosuximide has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of ethosuximide, which is a CYP3A4 substrate. Monitor patients for adverse effects of ethosuximide, such as CNS or GI effects.
    Tamoxifen: (Moderate) Ethosuximide is a CYP3A4 substrate and tamoxifen inhibits CYP3A4. Coadministration may result in increased ethosuximide exposure. If concomitant use is necessary, monitor for increased ethosuximide side effects.
    Teduglutide: (Moderate) Teduglutide may increase absorption of ethosuximide because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of ethosuximide is recommended.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering ethosuximide with telaprevir due to an increased potential for ethosuximide-related adverse events. If ethosuximide dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of ethosuximide. Ethosuximide is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated ethosuximide plasma concentrations.
    Telithromycin: (Moderate) Concentrations of ethosuximide may be increased with concomitant use of telithromycin. Ethosuximide is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ethosuximide is necessary, as the systemic exposure of ethosuximide may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ethosuximide; consider increasing the dose of ethosuximide if necessary. Ethosuximide is primarily metabolized by CYP3A4. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Thiethylperazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Thioridazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Thiothixene: (Moderate) Concomitant use of ethosuximide with thiothixene can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Tipranavir: (Moderate) Tipranavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    Trandolapril; Verapamil: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates including ethosuximide.
    Tranylcypromine: (Moderate) MAOIs can cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required. Also, additive CNS depression is possible if MAOIs and anticonvulsants are coadministered.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Trifluoperazine: (Moderate) Concomitant use of ethosuximide with phenothiazines can lower the seizure threshold and reduce the effectiveness of ethosuximide as an anticonvulsant. Additive CNS effects, such as drowsiness, may also occur.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase drowsiness and CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Valproic Acid, Divalproex Sodium: (Moderate) Valproate inhibits the metabolism of ethosuximide and may lead to elevated serum concentrations of ethosuximide. Additionally, concurrent administration of valproic acid, divalproex sodium and ethosuximide may result in lowered valproic acid serum concentrations. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs due to complicated pharmacokinetic drug interactions.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as ethosuximide, could be expected with concurrent use. Use caution, and monitor therapeutic effects of ethosuximide when coadministered with vemurafenib.
    Verapamil: (Moderate) Verapamil is an inhibitor of CYP3A4 isoenzymes. Co-administration with verapamil may lead to an increase in serum levels of drugs that are CYP3A4 substrates including ethosuximide.
    Voriconazole: (Moderate) Voriconazole is an inhibitor of CYP3A4 isoenzyme. Ethosuximide is a substrate for CYP3A4, and when combined with voriconazole, may theoretically have reduced metabolism, and therefore higher serum concentrations resulting in toxicity.

    PREGNANCY AND LACTATION

    Pregnancy

    Use ethosuximide with caution during pregnancy. Ethosuximide crosses the placenta. There are case reports of birth defects with ethosuximide; however, available data cannot be regarded as adequate to prove a definite cause and effect relationship. In many cases, the mother was receiving combination therapy with other anticonvulsants. In a study of 10 epileptic mothers, 2 major malformations (bilateral clefting and hare-lip) were observed in infants of 2 mothers taking either primidone or phenobarbitone with ethosuximide. In 1 mother who received ethosuximide monotherapy, minor anomalies noted among 2 siblings including mammalian line, over-extensible joints, broad thumbs, epicanthal folds, broad nasal bridge, dimples, and misshaped ear. Overall, the mean number of minor anomalies in infants exposed to ethosuximide was higher than in the matched control group (6.2 vs. 2.1) but similar to the group of infants whose mothers received antiepileptic drugs (AEDs) other than ethosuximide (5.1). In an analysis of 5 prospective European studies including 1,221 children with AED exposure during pregnancy, 1 major congential abnormality was reported among 13 pregnancies exposed to ethosuximide monotherapy. Major congential abnormalities occurred in 2 of 5 pregnancies exposed to combination therapy with phenobarbital and ethosuximide and in 3 of 39 pregnancies exposed to combination therapy with valproic acid and ethosuximide. Anticonvulsant drugs should not be discontinued in patients in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In cases where the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although even minor seizures may pose some hazard to the developing embryo or fetus. Weigh these considerations in treating or counseling epileptic females of childbearing potential. Encourage pregnant patients receiving ethosuximide to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must call 1-888-233-2334 to enroll in the registry. Information on the registry can also be found at the website at www.aedpregnancyregistry.org. The effects of ethosuximide during labor and delivery are unknown.

    Ethosuximide should be used during breast-feeding only if the benefits clearly outweigh the potential risks because the effects of the drug on the breast-fed infant are unknown. Limited evidence indicates that ethosuximide is excreted into human breast milk in concentrations similar to those in the maternal plasma. In 1 patient who received ethosuximide and primidone, the milk to serum ethosuximide concentration ratio was 0.94 +/- 0.06 at 4 to 6 days after delivery. Assuming a constant maternal ethosuximide concentration of 64 mcg/mL and a breast milk consumption of 200 to 600 mL/day by a breast-feeding infant weighing 3.5 kg, the authors calculated a theoretical infant dose of 3.6 to 11 mg/kg/day. The maternal weight-adjusted dose was 15.6 mg/kg. In a separate case, a mother receiving ethosuximide monotherapy and her breast-feeding infant were followed for 4.5 months postpartum. On the third day after delivery, the milk concentration of ethosuximide was similar to that in maternal plasma (milk:maternal plasma concentration ratio of 1.03). Subsequently, the mean milk/maternal plasma concentration ratio decreased to 0.80 (based on 3 samples taken approximately 10 days, 5 weeks, and 2 months after delivery). The infant developed normally, and no adverse effects occurred during the observation period. In another study that included 5 women who received ethosuximide during pregnancy and who breast-fed their infants after delivery, the mean milk:maternal serum ethosuximide concentration ratio was 0.86 +/- 0.08 for samples taken between postpartum days 3 and 28. Two of the breast-fed infants experienced hyperexcitability, 1 infant experienced sedation for 5 weeks and no weight gain for 4 weeks, and the remaining 2 infants exhibited normal neonatal behavior. The mother of 1 of the infants who experienced hyperexcitability received ethosuximide monotherapy while the remaining 4 mothers received combination therapy with other anticonvulsants. Although previous American Academy of Pediatrics recommendations considered ethosuximide as compatible with breast-feeding, the available data are limited to case reports and small studies.

    MECHANISM OF ACTION

    Ethosuximide elevates the seizure threshold and reduces the frequency of attacks through depression of nerve transmission in the cortex. Ethosuximide appears to have a specific action in reducing the current in the T-type calcium channel found on primary afferent neurons. Activation of the T channel causes low-threshold calcium spikes in relay neurons, which are believed to play a role in the spike-and-wave pattern observed during petit mal seizures. Anticonvulsants that are ineffective in treating absence seizures have insignificant effects on T-type calcium channels. Ethosuximide has little action in limiting the post-tetanic potentiation of synaptic transmission.

    PHARMACOKINETICS

    Ethosuximide is administered orally. Therapeutic serum concentrations range from 40—100 mcg/mL. Within this range, roughly 80% of patients achieve at least partial control of seizures. Pharmacokinetics are linear, and a given percentage increase in dosage will produce a corresponding change in the serum drug concentration. In a small number of patients, concentrations up to 150 mcg/mL may be needed to achieve complete seizure control; therefore, dosage is often based upon clinical status/seizure control rather than on serum concentrations alone. Ethosuximide is widely distributed, except into fat. The drug crosses the placenta. One study (n = 7) reported a mean fetal to maternal serum concentration ratio of 0.97 +/- 0.02. Limited evidence indicates it is excreted into human breast milk in concentrations similar to concentrations in the maternal plasma; the ratio of milk to maternal serum ethosuximide concentration has most often been reported in the range of 0.78—1. Ethosuximide concentrations in the tears, saliva, and CSF also approximate plasma concentrations. The drug is not significantly bound to plasma proteins.
     
    All ethosuximide metabolites result from hydroxylation via hepatic microsomal enzymes. The hepatic microsomal isoenzyme CYP3A4 appears to be involved. Hydroxylation of the ethyl side chain at the C-1 position yields the major metabolite, the hydroxy-ethyl derivative (30—50% of the dose); the metabolite is inactive. Other inactive metabolites include other hydroxylated products. Ethosuximide does not inhibit or induce the hepatic CYP450 microsomal enzymes or UGT (UDP-glucuronosyltransferase). The plasma half-life in adults is roughly 60 hours. Elimination occurs primarily through renal excretion, with about 12—20% of the drug unchanged and the majority (40—60%) as glucuronide-conjugates of the metabolites. The remainder of a dose is excreted in the bile and feces.
     
    Affected cytochrome P450 isoenzymes: CYP3A4
    The hepatic microsomal isoenzyme CYP3A4 appears to be involved in ethosuximide metabolism; it does not inhibit or induce the hepatic CYP450 microsomal enzymes.

    Oral Route

    Following oral administration, ethosuximide is rapidly and completely absorbed from the GI tract. Peak plasma concentrations are attained in about 4 hours in adults. There is a delay of 4—7 days before steady-state plasma concentrations are reached.