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  • CLASSES

    Anticonvulsants, Succinimides

    DEA CLASS

    Rx

    DESCRIPTION

    Oral succinimide anticonvulsant
    Used for the treatment of absence seizures
    May increase the frequency of grand mal seizures when used alone in mixed types of epilepsy

    COMMON BRAND NAMES

    Zarontin

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of absence seizures.
    Oral dosage
    Adults

    250 mg PO twice daily, initially. May increase dosage by 250 mg/day every 4 to 7 days, until seizure control is achieved with minimal side effects. Adjust dose based on effectiveness and plasma concentrations. Usual Max: 1.5 g/day, in divided doses.

    Children and Adolescents 6 to 17 years

    250 mg PO twice daily, initially. May increase dosage by 250 mg/day every 4 to 7 days, until seizure control is achieved with minimal side effects. Adjust dose based on effectiveness and plasma concentrations. Usual Dose: 20 mg/kg/day. Usual Max: 1.5 g/day, in divided doses.

    Children 3 to 6 years

    250 mg PO once daily, initially. May increase dosage by 250 mg/day every 4 to 7 days, until seizure control is achieved with minimal side effects. Adjust dose based on effectiveness and plasma concentrations. Usual Dose: 20 mg/kg/day. Usual Max: 1.5 g/day, in divided doses.

    MAXIMUM DOSAGE

    Adults

    1.5 g/day PO.

    Geriatric

    1.5 g/day PO.

    Adolescents

    1.5 g/day PO.

    Children

    3 to 11 years: 1.5 g/day PO.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    STORAGE

    Zarontin:
    - 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.

    Depression, suicidal ideation

    Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving ethosuximide closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). 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 and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). 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.

    Abrupt discontinuation

    As with other anticonvulsants, it is important to proceed slowly when increasing or decreasing dosage, as well as when adding or eliminating other medication. Abrupt discontinuation of anticonvulsant medication may precipitate absence (petit mal) status.

    Infection

    Blood dyscrasias, including some with fatal outcome, have been reported to be associated with the use of ethosuximide; therefore, monitor blood counts periodically. If signs and/or symptoms of infection (e.g., sore throat, fever) develop, consider obtaining blood counts.

    Hepatic disease

    Use ethosuximide with extreme caution in patients with known hepatic disease. Periodic liver function studies are advised for all patients receiving ethosuximide. Ethosuximide is capable of producing morphological and functional changes in the animal liver. In humans, abnormal liver function studies have been reported.

    Renal disease

    Use ethosuximide with extreme caution in patients with known renal disease. Periodic urinalysis is advised for all patients receiving ethosuximide. Abnormal renal function studies have been reported.

    Driving or operating machinery

    Ethosuximide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving or operating machinery or other such activity requiring alertness; therefore, caution the patient accordingly.

    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, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If ethosuximide must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of 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 as outlined in the OBRA guidelines.[60742]

    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. The effects of ethosuximide during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ethosuximide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

    Breast-feeding

    Use ethosuximide in a breast-feeding mother only if the benefits clearly outweigh the risks.  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.

    ADVERSE REACTIONS

    Severe

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

    Moderate

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

    Mild

    diarrhea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    nausea / Early / Incidence not known
    irritability / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    fatigue / Early / Incidence not known
    libido increase / Delayed / Incidence not known
    headache / Early / Incidence not known
    nightmares / Early / Incidence not known
    lethargy / Early / Incidence not known
    drowsiness / Early / Incidence not known
    hiccups / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    hirsutism / Delayed / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    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.
    Amlodipine: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Atorvastatin: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Benazepril: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Celecoxib: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Olmesartan: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Valsartan: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Amphetamine: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Minor) Use caution if ethosuximide and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ethosuximide-related adverse effects for several days after multi-day aprepitant regimens. 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. Single dose oral aprepitant or IV fosaprepitant regimens do not have the same effect.
    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 a strong 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) If brodalumab is initiated or discontinued in a patient taking ethosuximide, monitor ethosuximide concentrations; ethosuximide dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as ethosuximide.
    Canakinumab: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with canakinumab is necessary. Inhibition of IL-1 signaling by canakinumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ergotamine, may have fluctuations in drug levels and therapeutic effect when canakinumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping canakinumab. Ergotamine is a CYP3A4 substrate and a narrow therapeutic index drug.
    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: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ceritinib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ceritinib is a strong CYP3A4 inhibitor.
    Chlordiazepoxide; 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.
    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.
    Clofazimine: (Moderate) Monitor for increased toxicity of ethosuximide if used concomitantly with clofazimine. Concomitant use may increase the concentration of ethosuximide, increasing the risk of adverse effects. Ethosuximide is a CYP3A4 substrate that has a narrow therapeutic index; in vitro data suggest clofazimine inhibits CYP3A4.
    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 a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Codeine; Phenylephrine; Promethazine: (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.
    Codeine; Promethazine: (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.
    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.
    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 a strong 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.
    Darunavir; Cobicistat; 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 a strong 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.
    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: (Moderate) 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: (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.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    Elvitegravir; Cobicistat; 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 a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Elvitegravir; Cobicistat; 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 a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
    Emapalumab: (Moderate) Monitor for decreased efficacy of ethosuximide and adjust the dose as needed during coadministration with emapalumab. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    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.
    Fostamatinib: (Moderate) Monitor for ethosuximide toxicities that may require ethosuximide dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; ethosuximide is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    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.
    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) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    Istradefylline: (Moderate) Monitor for ethosuximide-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. ethosuximide is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
    Itraconazole: (Moderate) Itraconazole may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide.
    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.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of ethosuximide may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ethosuximide is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Levamlodipine: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    Levoketoconazole: (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.
    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.
    Lonafarnib: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with lonafarnib is necessary. Concurrent use may increase the plasma concentrations of ethosuximide. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and lonafarnib is a strong CYP3A4 inhibitor.
    Lopinavir; 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.
    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.
    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.
    Meperidine; Promethazine: (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.
    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) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    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, Fosnetupitant; 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.
    Nirmatrelvir; 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.
    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.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    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.
    Palbociclib: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with palbociclib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and palbociclib is a weak time-dependent CYP3A4 inhibitor.
    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.
    Perindopril; Amlodipine: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    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) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    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.
    Promethazine: (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.
    Promethazine; Dextromethorphan: (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.
    Promethazine; Phenylephrine: (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) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ribociclib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ribociclib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ribociclib is a strong CYP3A4 inhibitor.
    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.
    Sarilumab: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with sarilumab is necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ethosuximide, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ethosuximide is a CYP3A4 substrate and narrow therapeutic index drug.
    Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking ethosuximide, monitor ethosuximide concentrations; ethosuximide dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as ethosuximide. These interactions remain theoretical. Results from a drug-drug interaction study in subjects with moderate to severe psoriasis showed no clinically relevant interaction for drugs metabolized by CYP3A4.
    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.
    Siltuximab: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with siltuximab is necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ethosuximide, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ethosuximide is a CYP3A4 substrate and narrow therapeutic index drug.
    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.
    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.
    Telmisartan; Amlodipine: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
    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.
    Tocilizumab: (Moderate) Monitor for reduced efficacy of ethosuximide, monitor drug concentrations, and adjust the dose of ethosuximide as appropriate if coadministration with tocilizumab is necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as ethosuximide, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Ethosuximide is a CYP3A4 substrate and narrow therapeutic index drug.
    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) Additive CNS depression is possible if MAOIs and succinimides are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    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.
    Tucatinib: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with tucatinib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and tucatinib is a strong CYP3A4 inhibitor.
    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) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with voriconazole is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and voriconazole is a strong CYP3A4 inhibitor.

    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. The effects of ethosuximide during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to ethosuximide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.

    Use ethosuximide in a breast-feeding mother only if the benefits clearly outweigh the risks.  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 is a succinimide anticonvulsant. Ethosuximide suppresses the paroxysmal 3 cycle/second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli.

    PHARMACOKINETICS

    Ethosuximide is administered orally. Ethosuximide is not bound to plasma proteins and its concentrations in cerebrospinal fluid, saliva, or tears are similar to those in plasma. Ethosuximide is distributed through body water, and Vd has been reported as 0.7 L/kg in either children or adults. Approximately 80% of ethosuximide undergoes hepatic metabolism, which is mediated primarily by cytochrome P450 isoenzymes, with a major contribution from CYP3A and, to a lesser extent, from CYP2E and CYP2C/B. About 20% of an administered dose of ethosuximide is excreted unchanged in the urine. The hydroxyethyl derivative, which is the major metabolite of ethosuximide, is inactive and excreted as glucuronide in the urine. The elimination half-life of ethosuximide is 30 to 60 hours in adults and 30 to 40 hours in neonates or children.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A
    Ethosuximide is a CYP3A substrate.

    Oral Route

    After oral administration, ethosuximide is rapidly and completely absorbed; the syrup is absorbed at a faster rate. The bioavailability of ethosuximide is 95% to 100%. After a single ethosuximide 750 mg oral dose, peak plasma concentrations reached 15 mcg/mL at 3 to 5 hours and remained at this concentration for 24 hours. To reach ethosuximide steady-state plasma concentrations, 7 to 12 days are required.