Zonegran

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Zonegran

Classes

Anticonvulsants, Miscellaneous

Administration

A MedGuide that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications will be available.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

Oral Administration

May be administered with or without food.

Oral Solid Formulations

Swallow capsules whole.

Oral Liquid Formulations

Oral suspension (20 mg/mL)
Shake well prior to administration.
Measure dose with a calibrated measuring device.
Storage: Discard any unused suspension remaining after 30 days of first opening the bottle.

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
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known

Moderate

ataxia / Delayed / 6.0-6.0
memory impairment / 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
hypotonia / Delayed / 0.1-1.0
peripheral neuropathy / Delayed / 0.1-1.0
hypertonia / Delayed / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
hyperreflexia / Delayed / 0.1-1.0
neuritis / Delayed / 0.1-1.0
euphoria / Early / 0.1-1.0
gingival hyperplasia / Delayed / 0.1-1.0
cholelithiasis / Delayed / 0.1-1.0
glossitis / Early / 0.1-1.0
dysphagia / Delayed / 0.1-1.0
gastritis / Delayed / 0.1-1.0
melena / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
atopic dermatitis / Delayed / 0.1-1.0
hypertension / Early / 0.1-1.0
palpitations / Early / 0.1-1.0
sinus tachycardia / Rapid / 0.1-1.0
hypotension / Rapid / 0.1-1.0
conjunctivitis / Delayed / 0.1-1.0
flank pain / Delayed / 0.1-1.0
myasthenia / Delayed / 0.1-1.0
urinary retention / Early / 0.1-1.0
hematuria / Delayed / 0.1-1.0
dysuria / 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
leukopenia / Delayed / 0.1-1.0
lymphadenopathy / Delayed / 0.1-1.0
anemia / Delayed / 0.1-1.0
peripheral edema / Delayed / 0.1-1.0
dehydration / Delayed / 0.1-1.0
edema / Delayed / 0.1-1.0
encephalopathy / Delayed / 0.1-1.0
dystonic reaction / Delayed / 0-0.1
myoclonia / Delayed / 0-0.1
dyskinesia / Delayed / 0-0.1
fecal incontinence / Early / 0-0.1
jaundice / Delayed / 0-0.1
cholangitis / Delayed / 0-0.1
esophagitis / Delayed / 0-0.1
colitis / Delayed / 0-0.1
oral ulceration / 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
psychosis / Early / Incidence not known
hallucinations / Early / Incidence not known
myopia / Delayed / Incidence not known
heat intolerance / Early / Incidence not known
anhidrosis / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known
metabolic acidosis / Delayed / Incidence not known
osteomalacia / 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
agitation / Early / 9.0-9.0
irritability / Delayed / 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
hyperkinesis / Delayed / 0.1-1.0
vertigo / Early / 0.1-1.0
libido decrease / Delayed / 0.1-1.0
flatulence / Early / 0.1-1.0
gingivitis / Delayed / 0.1-1.0
alopecia / Delayed / 0.1-1.0
hirsutism / Delayed / 0.1-1.0
acne vulgaris / Delayed / 0.1-1.0
maculopapular rash / Early / 0.1-1.0
urticaria / Rapid / 0.1-1.0
hyperhidrosis / Delayed / 0.1-1.0
xerosis / Delayed / 0.1-1.0
syncope / Early / 0.1-1.0
parosmia / Delayed / 0.1-1.0
myalgia / Early / 0.1-1.0
arthralgia / Delayed / 0.1-1.0
muscle cramps / Delayed / 0.1-1.0
increased urinary frequency / Early / 0.1-1.0
polyuria / Early / 0.1-1.0
amenorrhea / Delayed / 0.1-1.0
nocturia / Early / 0.1-1.0
urinary urgency / Early / 0.1-1.0
malaise / Early / 0.1-1.0
weight gain / Delayed / 0.1-1.0
gynecomastia / Delayed / 0-0.1
menorrhagia / 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
cough / Delayed / 1.0
pharyngitis / Delayed / 1.0
oligohidrosis / Delayed / Incidence not known

Common Brand Names

Zonegran, ZONISADE

Dea Class

Rx

Description

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

Dosage And Indications
For the treatment of partial seizures as adjunct therapy. Oral dosage Adults

100 mg/day PO in 1 or 2 divided doses, initially. May increase the dose by 100 mg/day every 2 weeks as needed. Max: 600 mg/day; however, data shows no suggestion of increasing response above 400 mg/day.

Adolescents 16 to 17 years

100 mg/day PO in 1 or 2 divided doses, initially. May increase the dose by 100 mg/day every 2 weeks as needed. Max: 600 mg/day; however, data shows no suggestion of increasing response above 400 mg/day.

Children and Adolescents 1 to 15 years†

1 to 2 mg/kg/day PO in 1 to 2 divided doses, initially. May increase the dose by 1 to 2 mg/kg/day every 1 to 2 weeks. Usual dose range: 4 to 8 mg/kg/day. Max: 12 mg/kg/day.

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.

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.
Albuterol; 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.
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; 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.
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: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with zonisamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; zonisamide is a P-gp inhibitor.
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.
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.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with zonisamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; zonisamide is a P-gp inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with zonisamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; zonisamide is a P-gp inhibitor.
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; 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.
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; 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.
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.
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.
Butalbital; Aspirin; 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: (Major) Avoid concomitant use of colchicine and zonisamide due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and zonisamide is a P-gp inhibitor.
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.
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.
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.
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; 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.
Efavirenz; 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.
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.
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.
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.
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.
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.
Levonorgestrel; 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.
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) 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), if coadministered with zonisamide. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) 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), if coadministered with zonisamide. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
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.
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 c

learance 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 concomitant use of sirolimus and zonisamide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. 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.
Neostigmine; 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.
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.
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.
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: (Major) Avoid coadministration of pazopanib and zonisamide due to the potential for increased pazopanib exposure. Pazopanib is a P-gp substrate; zonsiamide is a P-gp inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp.
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.
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.
Pralsetinib: (Major) Avoid concomitant use of zonisamide with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
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: (Major) Avoid concomitant use of colchicine and zonisamide due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and zonisamide is a P-gp inhibitor.
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.
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.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with zonisamide is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and zonisamide is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
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.
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.
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.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of zonisamide. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. 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-gp substrate and zonisamide is a P-gp inhibitor.
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 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.
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.
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.
Vonoprazan; 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.
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.

How Supplied

Zonegran/Zonisamide Oral Cap: 25mg, 50mg, 100mg
ZONISADE Oral Susp: 1mL, 20mg

Maximum Dosage
Adults

600 mg/day PO.

Geriatric

600 mg/day PO.

Adolescents

16 to 17 years: 600 mg/day PO.
1 to 15 years: Safety and efficacy have not been established; 12 mg/kg/day PO has been suggested.

Children

Safety and efficacy have not been established; 12 mg/kg/day PO has been suggested.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

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. The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg after a 400 mg oral dose. 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 to 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. Zonisamide is metabolized by N-acetyl-transferases to form N-acetyl zonisamide and by CYP3A4 to form 2-sulfamoylacetylphenol (SMAP). Zonisamide is excreted primarily in the urine as parent drug and as the glucuronide of SMAP. After multiple dosing, approximately 62% and 3% of a dose were recovered in urine and feces, respectively, by day 10. Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Plasma clearance of zonisamide is approximately 0.3 to 0.35 mL/minute/kg in patients not receiving enzyme-inducing antiepileptic drugs (AEDs) and 0.5 mL/minute/kg in patients concurrently receiving enzyme-inducing AEDs. After single dose administration, renal clearance of zonisamide is approximately 3.5 mL/minute. The elimination half-life of zonisamide in plasma is approximately 63 hours. The elimination half-life of zonisamide in RBC is approximately 105 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp, UGT
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 UDP-glucuronosyltransferase (UGT). 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.

Oral Route

After oral administration, peak plasma concentrations are achieved within 2 to 6 hours for the capsules and 0.5 to 5 hours for the oral suspension. Dose proportional pharmacokinetics are observed in the range of 200 to 400 mg; however, 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. Food delays the time to maximum concentration from 4 to 6 hours and 3.5 to 7.5 hours for capsules and oral suspension, respectively, but it has no effect on the bioavailability of zonisamide.

Pregnancy And Lactation
Pregnancy

Use zonisamide during pregnancy only if the potential benefit justifies the potential risk to the fetus. Monitor pregnant persons 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. Physiological changes during pregnancy may affect zonisamide concentrations and/or therapeutic effect; dosage adjustments may be necessary to maintain clinical response. There have been reports of decreased zonisamide concentrations during pregnancy and restoration of prepartum concentrations after delivery. There are no adequate and well-controlled studies with zonisamide in pregnant women. Available data from the NAAED Pregnancy Registry have not identified a drug-associated risk of major birth defects (1.4%) in over 200 first trimester pregnancies exposed to zonisamide monotherapy use. Data from the United Kingdom and Ireland Epilepsy Pregnancy Registry (UKIEPR) reported an increased rate of major birth defects (13%) in 26 first trimester pregnancies exposed to zonisamide monotherapy; however, the study has methodological limitations, including a small sample size and inability to account for potential confounders. Prospective cohort studies, including data from NAAED Pregnancy Registry and UKIEPR, have reported increased rates of small for gestational age infants in those exposed to zonisamide during pregnancy compared to lamotrigine-exposed pregnancies and the unexposed general population. There are no reports of metabolic acidosis with use of zonisamide in pregnancy; however, the increased rate of small for gestational age infants in pregnancies exposed to zonisamide may be associated with metabolic acidosis. 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. The available published data describing the use of zonisamide during pregnancy are insufficient to evaluate for a drug-associated risk of miscarriage. 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 were produced in animals by prenatal exposure to zonisamide. Cardiovascular defects were prominent. Signs of reproductive toxicity, including decreased corpora lutea, implantations, and live fetuses, occurred in rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase. The low dose is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to zonisamide during pregnancy. Health care providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-888-233-2334 or visiting www.aedpregnancyregistry.org.[28843]

Zonisamide is excreted in human milk with a reported milk-to-plasma ratio of 0.7 to 0.9. There are no data on the effects of zonisamide on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for zonisamide and any potential adverse effects on the breast-fed infant from zonisamide or the underlying maternal condition. Monitor infants exposed to zonisamide during breast-feeding for poor feeding, weight loss, excess sedation, decreased muscle tone, and elevated temperature. Zonisamide has been associated with metabolic acidosis and hyperthermia in pediatric patients.[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 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]