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  • CLASSES

    Anticonvulsants, Miscellaneous

    DEA CLASS

    Rx

    DESCRIPTION

    Sulfonamide anticonvulsant
    Used for adjunctive treatment of partial seizures
    Monitor for suicidal thoughts/behavior or depression

    COMMON BRAND NAMES

    Zonegran

    HOW SUPPLIED

    Zonegran/Zonisamide Oral Cap: 25mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For use as adjunctive therapy in the treatment of partial seizures.
    Oral dosage
    Adults and Adolescents >= 16 years

    The initial dose should be 100 mg PO once daily. After two weeks, the dose may be increased to 200 mg PO once daily for at least two weeks. The dose can then be increased to 300 mg PO once daily and 400 mg PO once daily, with the dose stable for at least two weeks to achieve steady state at each dose. Doses of 100—600 mg/day were effective based on evidence from controlled trials, but there was no suggestion of increased response to doses > 400 mg/day. There is little experience with doses greater than 600 mg/day.

    Children and Adolescents < 16 years†

    Safe and effective use has not been established. However, experts suggest an initial dose of 1—2 mg/kg/day PO given once daily or in divided doses twice daily. Titration is usually slow, with increases of 1—2 mg/kg/day only every 1 or 2 weeks. The reported target range is 4—8 mg/kg/day PO. Maximum suggested dose is 12 mg/kg/day.

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Elderly

    600 mg/day PO.

    Adolescents

     >= 16 years: 600 mg/day PO.
     < 16 years: 12 mg/kg/day PO has been suggested.

    Children

    12 mg/kg/day PO has been suggested.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Because zonisamide is hepatically metabolized, patients with hepatic disease should be treated with caution. Slower titration and more frequent monitoring may be required. No quantitative recommendations are available.

    Renal Impairment

    Because zonisamide is excreted by the kidneys, patients with renal impairment or renal disease should be treated with caution. Slower titration and more frequent monitoring may be required. No quantitative recommendations are available.

    ADMINISTRATION

    A MedGuide that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications will be available.

    Oral Administration
    Oral Solid Formulations

    Zonisamide may be taken with or without food. Swallow capsules whole.

    STORAGE

    Zonegran:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    Sulfonamide hypersensitivity

    Zonisamide is contraindicated in patients who have demonstrated zonisamide hypersensitivity or sulfonamide hypersensitivity. Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately.[28843]

    Depression, suicidal ideation

    Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving zonisamide 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 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 vs. 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.

    Hepatic disease

    Use zonisamide with caution in patients with hepatic dysfunction. Because zonisamide is metabolized in the liver, slower titration and more frequent monitoring may be needed in patients with hepatic disease.[28843]

    Renal disease, renal failure, renal impairment

    Use zonisamide with caution in patients with renal impairment or renal failure. Because zonisamide is excreted by the kidneys, slower titration and more frequent monitoring may be needed in patients with renal disease. Zonisamide has been associated with a mean increase in the concentrations of serum creatinine and blood urea nitrogen (BUN). Consider monitoring renal function periodically.[28843]

    Diarrhea, metabolic acidosis, pulmonary disease, status epilepticus

    Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis. Conditions or therapies that predispose to acidosis, such as renal disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or specific drugs, may be additive to the bicarbonate lowering effects of zonisamide. Measurement of baseline and periodic serum bicarbonate during zonisamide treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing zonisamide.  If the decision is made to continue patients on zonisamide in the face of persistent acidosis, consider alkali treatment. Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg/day.[28843]

    Ambient temperature increase, anticholinergic medications, children, infants, neonates

    Neonates, infants, and children appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Monitor patients, especially pediatric patients, treated with zonisamide closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather (ambient temperature increase). Use caution when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and anticholinergic medications. Pediatric patients may also be more likely to develop metabolic acidosis. Conditions or therapies that predispose to acidosis, such as renal disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or specific drugs, may be additive to the bicarbonate lowering effects of zonisamide. Measurement of baseline and periodic serum bicarbonate during zonisamide treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing zonisamide.  If the decision is made to continue patients on zonisamide in the face of persistent acidosis, consider alkali treatment. Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg/day.[28843]

    Geriatric

    Clinical studies of zonisamide did not include sufficient numbers of subjects 65 years and older to determine whether they respond differently from younger adults. Other reported clinical experience has not identified differences in responses. In general, initial dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range. According to the Beers Criteria, anticonvulsants such as zonisamide 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 zonisamide 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]

    Abrupt discontinuation

    As with other antiepileptic drugs, abrupt discontinuation of zonisamide in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Gradually reduce the zonisamide dose to discontinue.[28843]

    Driving or operating machinery

    Zonisamide may produce drowsiness, especially at higher doses. Advise patients against driving or operating machinery until they have gained experience on zonisamide sufficient to determine whether it affects their performance.[28843]

    Mitochondrial disease

    Hyperammonemia and encephalopathy have been reported with zonisamide use. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity (mitochondrial disease) may be at an increased risk for hyperammonemia with or without encephalopathy, and this risk may be increased by zonisamide use. The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy (e.g., unexplained change in mental status, vomiting, or lethargy) occur. Hyperammonemia resulting from zonisamide resolves with zonisamide discontinuation. A reduction in zonisamide daily dose may resolve or decrease the severity of hyperammonemia.[28843]

    Pregnancy

    Use zonisamide during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies with zonisamide in pregnant women. Zonisamide was teratogenic in multiple animal species. Fetal abnormalities or embryofetal deaths occurred in animals at zonisamide dosage and maternal plasma concentrations similar to or lower than therapeutic concentrations in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent. The effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy due to other causes may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus's ability to tolerate labor. Monitor pregnant patients for metabolic acidosis and treat as in the non-pregnant state. Monitor newborns of mothers treated with zonisamide for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis after birth. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to zonisamide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28843]

    Breast-feeding

    Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue breast-feeding or discontinue zonisamide, taking into account the importance of the drug to the mother.[28843] In a case report of a mother who was breast-feeding her infant while receiving 300 mg/day of zonisamide, the mean milk to plasma concentration ratio was 0.93 +/- 0.09 (range: 0.81 to 1.03) based on 4 pairs of milk/plasma samples collected between days 3 and 30 after delivery. The sampling times were 1.5 to 2.5 hours after zonisamide ingestion. No behavioral problems were observed in the nursing infant during the study.[40275] In a separate case in which the breast-feeding mother had received zonisamide 400 mg/day, carbamazepine 1,000 mg/day, and clonazepam 1 mg/day throughout pregnancy and after birth, the concentrations of zonisamide in maternal serum and cord blood at the time of delivery were 15.7 mcg/mL and 14.4 mcg/mL, respectively, resulting in a placental transfer rate at the time of delivery of 92%. It appears that the maternal zonisamide dose was unchanged during the breast-feeding period, and the infant's plasma zonisamide concentration decreased from a concentration approximating the maternal plasma concentration at birth to 3.9 mcg/mL by day 24.[40274]

    ADVERSE REACTIONS

    Severe

    stroke / Early / 0.1-1.0
    peptic ulcer / Delayed / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    ocular hypertension / Delayed / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    rhabdomyolysis / Delayed / 0.1-1.0
    cholecystitis / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    heart failure / Delayed / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    atrial fibrillation / Early / 0-0.1
    lupus-like symptoms / Delayed / 0-0.1
    apnea / Delayed / 0-0.1
    seizures / Delayed / 1.0
    suicidal ideation / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    memory impairment / Delayed / 6.0-6.0
    ataxia / Delayed / 6.0-6.0
    depression / Delayed / 6.0-6.0
    confusion / Early / 6.0-6.0
    nystagmus / Delayed / 4.0-4.0
    nephrolithiasis / Delayed / 3.0-4.0
    constipation / Delayed / 2.0-2.0
    peripheral neuropathy / Delayed / 0.1-1.0
    hypertonia / Delayed / 0.1-1.0
    neuritis / Delayed / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    hyperreflexia / Delayed / 0.1-1.0
    euphoria / Early / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    melena / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0.1-1.0
    gingival hyperplasia / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    hypertension / Early / 0.1-1.0
    palpitations / Early / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    myasthenia / Delayed / 0.1-1.0
    flank pain / Delayed / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    chest pain (unspecified) / Early / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    peripheral edema / Delayed / 0.1-1.0
    edema / Delayed / 0.1-1.0
    encephalopathy / Delayed / 0.1-1.0
    dyskinesia / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    myoclonia / Delayed / 0-0.1
    jaundice / Delayed / 0-0.1
    fecal incontinence / Early / 0-0.1
    colitis / Delayed / 0-0.1
    cholangitis / Delayed / 0-0.1
    oral ulceration / Delayed / 0-0.1
    esophagitis / Delayed / 0-0.1
    iritis / Delayed / 0-0.1
    photophobia / Early / 0-0.1
    proteinuria / Delayed / 0-0.1
    hemoptysis / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    hyponatremia / Delayed / 0-0.1
    hyperesthesia / Delayed / 1.0
    amblyopia / Delayed / 1.0
    hallucinations / Early / Incidence not known
    psychosis / Early / Incidence not known
    myopia / Delayed / Incidence not known
    heat intolerance / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    anhidrosis / Delayed / Incidence not known
    osteomalacia / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    hyperammonemia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 17.0-17.0
    dizziness / Early / 13.0-13.0
    anorexia / Delayed / 13.0-13.0
    headache / Early / 10.0-10.0
    irritability / Delayed / 9.0-9.0
    agitation / Early / 9.0-9.0
    nausea / Early / 9.0-9.0
    fatigue / Early / 8.0-8.0
    insomnia / Early / 6.0-6.0
    abdominal pain / Early / 6.0-6.0
    diplopia / Early / 6.0-6.0
    diarrhea / Early / 5.0-5.0
    paresthesias / Delayed / 4.0-4.0
    influenza / Delayed / 4.0-4.0
    anxiety / Delayed / 3.0-3.0
    dyspepsia / Early / 3.0-3.0
    rash / Early / 3.0-3.0
    weight loss / Delayed / 3.0-3.0
    xerostomia / Early / 2.0-2.0
    dysgeusia / Early / 2.0-2.0
    rhinitis / Early / 2.0-2.0
    ecchymosis / Delayed / 2.0-2.0
    libido decrease / Delayed / 0.1-1.0
    vertigo / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    gingivitis / Delayed / 0.1-1.0
    flatulence / Early / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    myalgia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    nocturia / Early / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    malaise / Early / 0.1-1.0
    weight gain / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0-0.1
    gynecomastia / Delayed / 0-0.1
    petechiae / Delayed / 0-0.1
    tremor / Early / 1.0
    vomiting / Early / 1.0
    pruritus / Rapid / 1.0
    tinnitus / Delayed / 1.0
    asthenia / Delayed / 1.0
    pharyngitis / Delayed / 1.0
    cough / Delayed / 1.0
    oligohidrosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetazolamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with other carbonic anhydrase inhibitors. Concomitant use of zonisamide with another carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Afatinib: (Moderate) If the concomitant use of zonisamide and afatinib is necessary, monitor for afatinib-related adverse reactions, especially when starting or stopping zonisamide or changing the zonisamide dose. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of zonisamide. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Aliskiren: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Aliskiren; Amlodipine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Aliskiren; Valsartan: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and aliskiren is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Alogliptin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    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 CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Amlodipine; Atorvastatin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and atorvastatin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Amobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and clarithromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Amphetamines: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Anticholinergics: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Apalutamide: (Moderate) Monitor for decreased efficacy of zonisamide if coadministration with apalutamide is necessary; adjust the dose of zonisamide as clinically appropriate. Zonisamide is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the zonisamide half-life by 8 to 19 hours. These effects are unlikely to be of clinical significance when zonisamide is added to apalutamide therapy; however, changes in zonisamide concentrations may occur if apalutamide is added, dose adjusted, or withdrawn from zonisamide therapy.
    Apixaban: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and apixaban is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if zonisamide and a multi-day regimen of oral aprepitant are used concurrently and monitor for an increase in zonisamide-related adverse effects for several days after administration. Zonisamide 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 zonisamide. 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.
    Aripiprazole: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Asenapine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Asparaginase Erwinia chrysanthemi: (Moderate) Concomitant use of zonisamide with asparaginase may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Atorvastatin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and atorvastatin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Atorvastatin; Ezetimibe: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and atorvastatin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Atropine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Atropine; Difenoxin: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Atropine; Edrophonium: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    atypical antipsychotic: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Barbiturates: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug. (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Belladonna; Opium: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Benztropine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking zonisamide. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving zonisamide. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving zonisamide. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; zonisamide inhibits P-gp.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering zonisamide with boceprevir due to an increased potential for zonisamide-related adverse events. If zonisamide 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 zonisamide. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated zonisamide plasma concentrations.
    Bosentan: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Bosentan ia an inducer of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Brexpiprazole: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Budesonide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and budesonide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Budesonide; Formoterol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and budesonide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and budesonide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with some anticonvulsant drugs that induce hepatic microsomal isoenzyme function.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with some anticonvulsant drugs that induce hepatic microsomal isoenzyme function.
    Butabarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Butalbital; Acetaminophen: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Canagliflozin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Carbamazepine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Carbamazepine is an inducer of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Carbonic anhydrase inhibitors: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with other carbonic anhydrase inhibitors. Concomitant use of zonisamide with another carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Cariprazine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Carvedilol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and carvedilol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Chlordiazepoxide; Clidinium: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Clarithromycin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and clarithromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Clozapine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and zonisamide is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and zonisamide is a weak, in vitro, P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Codeine; Phenylephrine; Promethazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Codeine; Promethazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Colchicine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and colchicine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Colesevelam: (Major) The manufacturer for colesevelam suggests monitoring serum drug concentrations and/or clinical effects for those drugs for which alterations in serum blood concentrations have a clinically significant effect on safety or efficacy. To minimize potential for interactions, consider administering oral anticonvulsants such as zonisamide at least 1 hour before or at least 4 hours after colesevelam.
    Cyclosporine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and cyclosporine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with zonisamide, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like zonisamide in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with zonisamide, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dapagliflozin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Desipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Desogestrel; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Dexamethasone: (Minor) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as dexamethasone, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Dextromethorphan; Quinidine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and quinidine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Dichlorphenamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with dichlorphenamide. Concomitant use of zonisamide with another carbonic anhydrase inhibitor, like dichlorphenamide, may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose. If metabolic acidosis develops, consider reducing the dose or discontinuing dichlorphenamide.
    Dicyclomine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Digoxin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and digoxin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Diphenoxylate; Atropine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Docetaxel: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and docetaxel is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Doxorubicin Liposomal: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and doxorubicin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Doxorubicin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and doxorubicin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Zonisamide 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.
    Drospirenone; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as zonisamide.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as zonisamide. (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as zonisamide. (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering zonisamide with elbasvir; grazoprevir may result in elevated zonisamide plasma concentrations. Zonisamide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and eletriptan is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Empagliflozin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Enzalutamide: (Moderate) Closely monitor for decreased efficacy of zonisamide if enzalutamide is added to existing zonisamide therapy or if the dose of enzalutamide is increased or decreased; the dose of zonisamide may need to be adjusted. This interaction is unlikely to be of clinical significance when zonisamide is added to existing enzalutamide therapy. Zonisamide is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. The half-life of zonisamide decreased from 46 hours to 27 to 38 hours when administered with a weak CYP3A4 inducer.
    Ertugliflozin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Erythromycin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and erythromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Erythromycin; Sulfisoxazole: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and erythromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethinyl Estradiol; Norelgestromin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethinyl Estradiol; Norgestrel: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Ethotoin: (Moderate) Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including zonisamide.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Etonogestrel; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with zonisamide is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Felbamate: (Moderate) Concomitant use of zonisamide with felbamate may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Flavoxate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Fosamprenavir: (Moderate) Concomitant use of zonisamide and fosamprenavir may result in elevated fosamprenavir and altered zonisamide plasma concentrations. Zonisamide is a substrate of the hepatic isoenzyme CYP3A4 and an inhibitor of the drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is substrate of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
    Fosphenytoin: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as fosphenytoin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and zonisamide as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); zonisamide is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and zonisamide as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); zonisamide is an inhibitor of P-gp.
    Glipizide; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Glyburide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and glyburide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Glyburide; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and glyburide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Glycopyrrolate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Glycopyrrolate; Formoterol: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Haloperidol: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Homatropine; Hydrocodone: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as zonisamide. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hyoscyamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with zonisamide, a CYP3A substrate, as zonisamide toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Imipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Indacaterol; Glycopyrrolate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Indinavir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and indinavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with zonisamide may result in increased serum concentrations of zonisamide. Zonisamide 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 for adverse effects, such as metabolic acidosis or CNS effects, are advised if these drugs are used together.
    Isocarboxazid: (Moderate) Additive CNS depression is possible if MAOIs and zonisamide are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4 (CYP3A4). Inducers of CYP3A4, such as rifampin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug. Coadminister these drugs with caution.
    Isoniazid, INH; Rifampin: (Major) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4 (CYP3A4). Inducers of CYP3A4, such as rifampin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug. Coadminister these drugs with caution.
    Itraconazole: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and itraconazole is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., zonisamide), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Lamotrigine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as zonisamide. Concomitant use of zonisamide with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
    Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and clarithromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with zonisamide is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    L-Asparaginase Escherichia coli: (Moderate) Concomitant use of zonisamide with asparaginase may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Ledipasvir; Sofosbuvir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ledipasvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with zonisamide as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and zonisamide is a P-gp inhibitor.
    Levonorgestrel; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Linagliptin; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with zonisamide, a mild in vitro inhibitor of P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with zonisamide, a mild in vitro inhibitor of P-gp. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Loxapine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may significantly decrease the systemic exposure and therapeutic efficacy of zonisamide, particularly if lumacaftor; ivacaftor is added to existing zonisamide therapy. If concomitant use is necessary, monitor the patient closely and adjust the zonisamide dosage as appropriate. If lumacaftor; ivacaftor is subsequently discontinued it may be necessary to reduce the zonisamide dose. Zonisamide is primarily metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may significantly decrease the systemic exposure and therapeutic efficacy of zonisamide, particularly if lumacaftor; ivacaftor is added to existing zonisamide therapy. If concomitant use is necessary, monitor the patient closely and adjust the zonisamide dosage as appropriate. If lumacaftor; ivacaftor is subsequently discontinued it may be necessary to reduce the zonisamide dose. Zonisamide is primarily metabolized by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Lumateperone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Lurasidone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    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.
    Maraviroc: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and maraviroc is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    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, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Some, but not all anticonvulsants, induce CYP3A4 and may increase the metabolism of mefloquine. Use of enzyme-inducing anticonvulsants can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
    Mepenzolate: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Meperidine; Promethazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Mephobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Metformin; Repaglinide: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Metformin; Rosiglitazone: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Metformin; Saxagliptin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Metformin; Sitagliptin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Methadone: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and methadone is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Methazolamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with other carbonic anhydrase inhibitors. Concomitant use of zonisamide with another carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Methohexital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Methscopolamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Mitotane: (Major) Use caution if mitotane and zonisamide are used concomitantly, and monitor for decreased efficacy of zonisamide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zonisamide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zonisamide. Concomitant administration of other strong CYP3A inducerse, phenytoin and carbamazepine, increase zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant. In addition, zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Monoamine oxidase inhibitors: (Moderate) Additive CNS depression is possible if MAOIs and zonisamide are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    Morphine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and morphine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Morphine; Naltrexone: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and morphine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with zonisamide as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and zonisamide is a P-gp inhibitor.
    Nelfinavir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and nelfinavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Nevirapine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as nevirapine, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Norethindrone; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Norgestimate; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Olanzapine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Olanzapine; Fluoxetine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Olanzapine; Samidorphan: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as rifabutin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Ondansetron: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ondansetron is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Oritavancin: (Moderate) Zonisamide is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of zonisamide may be reduced if these drugs are administered concurrently.
    Oxybutynin: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Paclitaxel: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and paclitaxel is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Paliperidone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Panobinostat: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and panobinostat is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Pazopanib: (Moderate) Coadministration of pazopanib and zonisamide may result in increased concentrations of both drugs. Pazopanib is a weak inhibitor of CYP3A4 and a substrate of P-glycoprotein (P-gp). Zonisamide is a weak inhibitor of P-gp and a substrate of CYP3A4. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when administering these drugs concomitantly.
    Pegaspargase: (Moderate) Concomitant use of zonisamide with pegaspargase may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Pemoline: (Moderate) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents.
    Pentobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Perphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Phenelzine: (Moderate) Additive CNS depression is possible if MAOIs and zonisamide are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
    Phenobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug. (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Phentermine; Topiramate: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with topiramate. Concomitant use of zonisamide with another carbonic anhydrase inhibitor, like topiramate, may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Phenytoin: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as phenytoin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Pimozide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Pioglitazone; Metformin: (Moderate) Carbonic anhydrase inhibitors such as zonisamide frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Use of zonisamide with metformin may increase the risk for lactic acidosis; consider more frequent monitoring. Carbonic anhydrase inhibitors may also alter blood sugar; both hyperglycemia and hypoglycemia have been described. Monitor blood glucose and for changes in glycemic control and be alert for evidence of an interaction.
    Posaconazole: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and posaconazole is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Primidone: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Probenecid; Colchicine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and colchicine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Promethazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Promethazine; Dextromethorphan: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Promethazine; Phenylephrine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Propantheline: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Quetiapine: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Quinidine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and quinidine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Quinine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and quinine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Rabeprazole: (Moderate) Concomitant use of zonisamide with rabeprazole may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Ranolazine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ranolazine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Relugolix: (Major) Avoid concomitant use of relugolix and zonisamide. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer zonisamide at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and zonisamide. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer zonisamide at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor.
    Rifabutin: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as rifabutin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Rifampin: (Major) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4 (CYP3A4). Inducers of CYP3A4, such as rifampin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug. Coadminister these drugs with caution.
    Rifapentine: (Moderate) Monitor for decreased efficacy of zonisamide when coadministered with rifapentine; adjust the dose of zonisamide as clinically appropriate. Zonisamide is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the zonisamide half-life by 8 to 19 hours. These effects are unlikely to be of clinical significance when zonisamide is added to rifapentine therapy; however, changes in zonisamide concentrations may occur if rifapentine is added, dose adjusted, or withdrawn from zonisamide therapy.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with zonisamide; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and zonisamide is a P-gp inhibitor.
    Riociguat: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and riociguat is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Risperidone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Ritonavir: (Moderate) Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and rivaroxaban is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Romidepsin: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and romidepsin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Rufinamide: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as zonisamide, may occur during concurrent use with rufinamide.
    Saquinavir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and saquinavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Scopolamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Secobarbital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ethinyl estradiol is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Selexipag: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and selexipag is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of zonisamide, which is a CYP3A4 substrate. Monitor patients for adverse effects of zonisamide.
    Sirolimus: (Major) Avoid coadministration of sirolimus with zonisamide as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and zonisamide is a P-gp inhibitor.
    Sofosbuvir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with zonisamide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); zonisamide is a weak in vitro inhibitor of P-gp. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with zonisamide. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); zonisamide is a weak in vitro inhibitor of P-gp. (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and sofosbuvir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    St. John's Wort, Hypericum perforatum: (Major) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, including St. John's wort, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with zonisamide is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering zonisamide with telaprevir due to an increased potential for zonisamide-related adverse events. If zonisamide 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 zonisamide. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated zonisamide plasma concentrations.
    Telithromycin: (Minor) Telithromycin, a ketolide antibiotic, can compete with zonisamide for metabolism by CYP3A4. This can result in increased concentrations of zonisamide if the two drugs are coadministered.
    Temsirolimus: (Minor) Monitor for an increase in temsirolimus-related adverse reactions when starting or stopping therapy with zonisamide, or when changing the dose of zonisamide. Temsirolimus is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. There is a theoretical potential for zonisamide to affect the pharmacokinetics of drugs which are P-gp substrates.
    Teniposide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and teniposide is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Tenofovir Alafenamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
    Thiethylperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Thiopental: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Thiothixene: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Ticagrelor: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ticagrelor is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Tipranavir: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and tipranavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
    Topiramate: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with topiramate. Concomitant use of zonisamide with another carbonic anhydrase inhibitor, like topiramate, may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Topotecan: (Major) Avoid coadministration of zonisamide with oral topotecan due to increased topotecan exposure; zonisamide may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and zonisamide is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Trandolapril; Verapamil: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and verapamil is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs that are P-gp substrates.
    Tranylcypromine: (Moderate) Additive CNS depression is possible if MAOIs and zonisamide 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 CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. Zonisamide may also cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotic phenothiazines. Monitor patients for decreased efficacy of the anticonvulsant, heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
    Trihexyphenidyl: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Trospium: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution with other drugs that may also predispose patients to heat-related disorders like anticholiinergics.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with zonisamide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; zonisamide is a P-gp inhibitor.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant use of zonisamide with valproic acid may increase the risks of hyperammonemia and encephalopathy. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
    Vemurafenib: (Moderate) Coadministration of vemurafenib and zonisamide may result in decreased zonisamide concentrations and increased vemurafenib concentrations. Vemurafenib is an inducer of CYP3A4 and a substrate of P-glycoprotein (P-gp). Zonisamide is a weak inhibitor of P-glycoprotein (P-gp) and a substrate of CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with zonisamide due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of zonisamide. Venetoclax is a P-glycoprotein (P-gp) substrate; zonisamide is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and verapamil is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs that are P-gp substrates.
    Zafirlukast: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 isoenzyme 3A4. Zafirlukast is an inhibitor of this enzyme and may decrease the clearance of zonisamide.
    Ziprasidone: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Use zonisamide during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies with zonisamide in pregnant women. Zonisamide was teratogenic in multiple animal species. Fetal abnormalities or embryofetal deaths occurred in animals at zonisamide dosage and maternal plasma concentrations similar to or lower than therapeutic concentrations in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent. The effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy due to other causes may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus's ability to tolerate labor. Monitor pregnant patients for metabolic acidosis and treat as in the non-pregnant state. Monitor newborns of mothers treated with zonisamide for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis after birth. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to zonisamide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28843]

    Zonisamide is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue breast-feeding or discontinue zonisamide, taking into account the importance of the drug to the mother.[28843] In a case report of a mother who was breast-feeding her infant while receiving 300 mg/day of zonisamide, the mean milk to plasma concentration ratio was 0.93 +/- 0.09 (range: 0.81 to 1.03) based on 4 pairs of milk/plasma samples collected between days 3 and 30 after delivery. The sampling times were 1.5 to 2.5 hours after zonisamide ingestion. No behavioral problems were observed in the nursing infant during the study.[40275] In a separate case in which the breast-feeding mother had received zonisamide 400 mg/day, carbamazepine 1,000 mg/day, and clonazepam 1 mg/day throughout pregnancy and after birth, the concentrations of zonisamide in maternal serum and cord blood at the time of delivery were 15.7 mcg/mL and 14.4 mcg/mL, respectively, resulting in a placental transfer rate at the time of delivery of 92%. It appears that the maternal zonisamide dose was unchanged during the breast-feeding period, and the infant's plasma zonisamide concentration decreased from a concentration approximating the maternal plasma concentration at birth to 3.9 mcg/mL by day 24.[40274]

    MECHANISM OF ACTION

    The exact mechanism(s) by which zonisamide exerts its anticonvulsant effect is unknown. It appears that zonisamide exhibits a dual mechanism of action as an anticonvulsant. Zonisamide a) stops the spread of seizures and b) suppresses their focus. The drug may produce these effects by acting at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type calcium currents), thereby stabilizing neuronal membranes and suppressing neuronal hypersynchronization. It does not affect GABA pathways. Zonisamide also has weak carbonic anhydrase inhibiting activity, but this pharmacologic effect is not thought to be a major contributing factor in the antiseizure activity of zonisamide. It should be noted, however, that the carbonic anhydrase inhibiting effects of zonisamide may cause metabolic acidosis through renal bicarbonate loss (see Adverse Reactions). Augmentation of dopaminergic and serotonergic transmission occurs; however the clinical significance is unknown. In animal models, zonisamide has a profile of activity similar to carbamazepine and phenytoin and is more active against the tonic phase than the clonic phase.

    PHARMACOKINETICS

    Zonisamide is administered orally. Once in the systemic circulation, it is extensively bound to erythrocytes, resulting in an 8-fold higher concentration in red blood cells (RBC) than in plasma. Zonisamide is approximately 40% bound to human plasma proteins. Protein binding is unaffected in the presence of therapeutic concentrations of carbamazepine, phenobarbital, or phenytoin. Dose proportional pharmacokinetics are observed in the range of 200—400 mg, but the Cmax and AUC increase disproportionately at 800 mg, possibly due to saturable binding to RBC. Once a stable dose is reached, steady state is achieved within 14 days. The half-life in RBC is approximately 105 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT, P-gp
    Zonisamide is metabolized by acetylation and reduction. It undergoes acetylation to form N-acetyl zonisamide and reduction to form 2-sulfamoylacetyl phenol (SMAP), an open ring metabolite. Reduction to SMAP is mediated by the hepatic cytochrome P450 3A4 isozyme. Zonisamide is also metabolized by UGT (UDP-glucuronosyltransferase). In vitro data suggest that it does not inhibit or induce cytochrome P450 enzymes or UGT and is not likely to interfere with the hepatic metabolic clearance of drugs metabolized by these enzyme systems. Zonisamide does not induce its own metabolism. Zonisamide is a weak inhibitor of P-gp. It is excreted primarily in the urine as parent drug and as the glucuronide of SMAP. The elimination half-life in plasma is about 63 hours during monotherapy but can decrease to 27—38 hrs during combination therapy with other anticonvulsants.

    Oral Route

    Following oral administration, peak plasma concentrations are achieved within 2—6 hours. Food delays the time to maximum concentration, but has no effect on the bioavailability of zonisamide.