Zonisamide is a sulfonamide anticonvulsant. It is a derivative of a series of compounds known as benzisoxazoles. The pharmacological profile is similar to that of carbamazepine and phenytoin; however, no comparative double-blind trials have been published. Zonisamide showed a significant reduction in seizure frequency as compared to placebo. No less than 28% of patients achieved a >= 50% reduction in seizure frequency during three multicenter, placebo-controlled, double blind, 3-month clinical trials (two in the US, one in Europe). Zonisamide appears to possess more than one mechanism of action which may make it effective in a broader range of seizures. Central nervous system adverse reactions (e.g., ataxia, psychosis, speech impairment, etc.) are common and can limit the usefulness of the drug in some patients. Zonisamide is approved for adjunctive treatment of partial seizures in adults 16 years and older with epilepsy. Although not approved for use in children in the US, the drug is often used 'off-label' in children; the drug is approved for use in children in Japan where it has been marketed since 1989. FDA approval for zonisamide was granted in March 2000.
General Administration Information
-For storage information, see the specific product information within the How Supplied section.
-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.
Route-Specific 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.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, the following centrally-mediated (CNS) effects occurred in at least 2% of patients in the zonisamide group (zonisamide with current AED regimen) and more frequently than in patients in the control group (placebo with current AED regimen): headache (10% vs. 8%), insomnia (6% vs. 3%), dizziness (13% vs. 7%), ataxia (6% vs. 1%), nystagmus (4% vs. 2%), paresthesias (4% vs. 1%), drowsiness (17% vs. 7%), fatigue (8% vs. 6%), tiredness (7% vs. 5%), speech abnormalities (5% vs. 2%), difficulty with verbal expression (2% vs. less than 1%), difficulty concentrating (6% vs. 2%), memory impairment (6% vs. 2%), and mental slowing (4% vs. 2%). Psychomotor impairment and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech impairment tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Drowsiness and fatigue occurred most often within the first month of treatment and at doses of 300 to 500 mg/day. Adverse CNS effects reported in at least 1% of patients receiving zonisamide during other clinical trial evaluations included tremor, seizures, abnormal gait, hyperesthesia, and incoordination. Infrequently reported adverse effects (0.1% to 1%) included hypertonia, twitching, abnormal dreams, vertigo, libido decrease, peripheral neuropathy, hyperkinesis, movement disorder, dysarthria, stroke, hypotonia, peripheral neuritis, and hyperreflexia. Rare events (less than 0.1%) included dyskinesia, dystonic reaction (e.g., oculogyric crisis), facial paralysis, hypokinesia, and myoclonia. In controlled clinical trials, 1.1% of zonisamide-treated patients had an event labeled as status epilepticus compared to none of placebo-treated patients. Among patients treated with zonisamide across all epilepsy studies (controlled and uncontrolled), 1% of patients experienced status epilepticus. Advise patients to contact their prescriber immediately if their seizures worsen while taking zonisamide. In addition, due to the potential for significant drowsiness, advise patients to avoid driving or engaging in other tasks requiring mental alertness until they know how the drug affects them.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, the following psychiatric effects occurred in at least 2% of patients in the zonisamide group (zonisamide + current AED regimen) and more frequently than in patients in the control group (placebo + current AED regimen): confusion (6% vs. 3%), agitation/irritability (9% vs. 4%), depression (6% vs. 3%), anxiety (3% vs. 2%), nervousness (2% vs. 1%), and schizophrenic/schizophreniform behavior (2% vs. 0%). Approximately 2.2% of zonisamide-treated patients discontinued therapy or were hospitalized for depression compared to 0.4% of placebo patients. Among all zonisamide-treated epilepsy patients, 1.4% were taken off zonisamide therapy and 1% were hospitalized because of reported depression or suicide attempts. Psychosis caused 2.2% of patients to discontinue zonisamide compared to none on placebo. Among all zonisamide-treated epilepsy patients, 0.9% discontinued zonisamide therapy and 1.4% required hospitalization because of psychosis or related symptoms. Three cases of temporally-related zonisamide visual hallucinations have been reported in seizure patients. Hallucinations were not related to EEG patterns. Upon reduction in dose or discontinuation of zonisamide, all hallucinations resolved without recurrence. Euphoria was reported in 0.1% to 1% of patients during other clinical trial evaluations. Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation; however, these events could also occur in patients receiving the drug for a longer time period. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, the following adverse gastrointestinal (GI) effects occurred in at least 2% of patients in the zonisamide group (zonisamide + current AED regimen) and more frequently than in patients in the control group (placebo + current AED regimen): anorexia (13% vs. 6%), nausea (9% vs. 6%), diarrhea (5% vs. 2%), dyspepsia (3% vs .1%), constipation (2% vs. 1%), abdominal pain (6% vs. 3%), and xerostomia (2% vs. 1%). Vomiting was reported in at least 1% of patients receiving zonisamide during other clinical trial evaluations. Infrequently reported GI effects (0.1% to 1%) included flatulence, gingivitis, gingival hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, peptic ulcer, dysphagia, and gum hemorrhage. Rare events (less than 0.1%) included cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, and oral ulceration. Acute pancreatitis has been reported during postmarketing use; however, the frequency is unknown and causality to the drug has not been established.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, rash (unspecified) occurred in 3% of patients in the zonisamide group (zonisamide + current AED regimen) and 2% of patients in the control group (placebo + current AED regimen). Pruritus was reported in at least 1% of patients receiving zonisamide during other clinical trial evaluation. Infrequently reported effects (0.1% to 1%) included maculopapular rash, acne vulgaris, alopecia, xerosis, hyperhidrosis, atopic dermatitis, urticaria, hirsutism, pustular rash, and vesiculobullous rash. Similar to other sulfonamides, zonisamide can produce severe, possibly fatal, skin reactions such as toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). Once sensitization to sulfonamides has occurred, a recurrence can be precipitated by administration of sulfonamides by any route. The use of zonisamide should be discontinued if there is any sign of these reactions or a hypersensitivity reaction. In U.S. and European randomized controlled trials, about 2.2% of zonisamide-treated patients discontinued treatment because of rash (unspecified) compared to none on placebo. Rash usually developed early in treatment, with 85% reported within 16 weeks in the U.S. and European studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship between the dose and the occurrence of rash. Seven deaths from severe rash (i.e., SJS and TEN) were reported in the first 11 years of marketing in Japan. All of the patients were receiving other drugs concomitantly with zonisamide. In post-marketing reports in Japan, a total of 49 cases of SJS or TEN have been reported. There were no confirmed cases of SJS or TEN in the U.S., European, or Japanese development programs.
Cardiovascular (CV) adverse reactions were infrequently reported with zonisamide therapy during clinical trial evaluation. Adverse reactions reported in 0.1% to 1% of patients included hypertension, hypotension, palpitations, sinus bradycardia, sinus tachycardia, syncope, thrombophlebitis, and vascular insufficiency. Rare CV adverse reactions (less than 0.1%) included atrial fibrillation, heart failure, pulmonary embolism, and ventricular extrasystoles.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, the following adverse effects related to the special senses occurred in at least 2% of patients in the zonisamide group (zonisamide with current AED regimen) and more frequently than in patients in the control group (placebo with current AED regimen): diplopia (6% vs. 3%) and dysgeusia (2% vs. 0%). Adverse effects reported in at least 1% of patients receiving zonisamide during other clinical trial evaluations included amblyopia and tinnitus. Infrequently reported adverse effects (0.1% to 1%) included conjunctivitis, parosmia, hearing loss, glaucoma (ocular hypertension), and visual field defect. Rare events (less than 0.1%) included photophobia and iritis. Acute myopia associated and secondary closed-angle glaucoma have been reported in patients receiving zonisamide. Secondary closed-angle glaucoma associated with zonisamide has been reported in pediatric and adult patients. Symptoms include acute onset of visual impairment and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with ciliochoroidal effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month after starting zonisamide therapy. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated. The primary treatment to reverse symptoms is discontinuation of zonisamide as rapidly as possible, according to the judgment of the treating physician. Myopia and secondary angle closure glaucoma usually resolve or improve after discontinuation of zonisamide. Other measures in conjunction with discontinuation of zonisamide may be helpful.
Oligohidrosis and hyperthermia have been observed in association with zonisamide use, especially in pediatric patients. Although zonisamide is not approved for patients younger than 16 years in the U.S., 38 cases of oligohidrosis and hyperthermia were reported (mostly in patients age 1.6 to 17 years of age) in the first 11 years of marketing in Japan; 2 additional cases occurred in the first year of marketing in the U.S. in the same period. One case of heat stroke has occurred in an 18-year-old patient in the U.S. Heatstroke requiring hospitalization was diagnosed in some cases. While there were no cases of oligohidrosis in the U.S. and European development program, fewer than 100 patients participated in these trials. Anhidrosis is possible, but not specifically reported. The cases reported may be underestimates of the true incidence of these conditions because of the typical under-reporting of adverse reactions. Because decreased sweating may be accompanied by elevated body temperature, especially in the summer, all patients, but particularly pediatric patients, taking zonisamide should be monitored for evidence of heat intolerance, decreased sweating, and increased body temperature. Concurrent conditions that may predispose patients to heat-related disorders (e.g., exposure to high environmental temperatures, or the concurrent use of carbonic anhydrase inhibitors or antimuscarinic drugs), might aggravate heat intolerance.
In several clinical studies, statistically significant increases (8%) from baseline in serum creatinine and blood urea nitrogen (BUN) were reported in zonisamide-treated patients and no placebo-treated patients. These increases persisted over time but were not progressive which was interpreted as a decrease in glomerular filtration rate (GFR). Decreases in GFR appeared within the first 4 weeks of treatment and returned to baseline within 2 to 3 weeks of drug discontinuation. It is not known if these decreases in GFR are reversible following long-term use of zonisamide. Although there were no episodes of unexplained acute renal failure in clinical development in the U.S., Europe, or Japan, zonisamide should be discontinued in patients who develop acute renal failure (unspecified) or a clinically significant sustained increase in the creatinine/BUN concentration (azotemia).
As a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis. Zonisamide-induced metabolic acidosis generally develops early during treatment and appears to be more common and severe in children. The condition is more frequently associated with higher doses, but can occur at doses as low as 25 mg/day. Signs and symptoms may include hyperventilation, fatigue, anorexia, cardiac arrhythmias, stupor, or unconsciousness; however some patients may be asymptomatic. Conditions that may predispose to acidosis include renal disease, severe respiratory disorders, status epilepticus, diarrhea, and ketogenic diet. Decreases in serum bicarbonate concentrations in adults have primarily been mild to moderate (i.e., average 2 mEq/L), although decreases as much as 10 mEq/L below baseline have occurred. During studies of epilepsy in adults, persistent decreases in serum bicarbonate to less than 20 mEq/L occurred in 21% of patients treated with zonisamide 25 mg/day or 100 mg/day, and 43% of patients treated with 300 mg/day. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for patients treated with placebo, 29% for patients treated with 150 mg/day, and 34% for patients treated with 300 mg/day. There was a 2% or less incidence of persistent abnormally low serum bicarbonate for all doses studied in these trials. In an open label trial of zonisamide as adjunct treatment of epilepsy in pediatric patients 3 to 16 years of age, mean serum bicarbonate reductions ranged from about 2 to 4 mEq/L. In the same study, 52% of pediatric patients who received doses up to 100 mg/day and up to 90% of those who received a wider range of doses up to 600 mg/day experienced persistent decreases in serum bicarbonate to concentrations less than 20 mEq/L. The incidence of persistently low serum bicarbonate concentrations less than 17 mEq/L and with more than a 5 mEq/L decrease from baseline values of at least 20 mEq/L was as high as 18%. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis, nephrocalcinosis, osteomalacia, and osteoporosis. During clinical development of zonisamide, possible or confirmed nephrolithiasis was reported in 4% of adults; the diagnosis was confirmed by passage of a stone or definitive sonographic detection in about 25% of these patients. The stones consisted of calcium or urate salts. Nephrolithiasis was reported as an adverse effect in 3% of pediatric patients and was detected by renal ultrasound in 8% of pediatric patients who had at least one ultrasound performed prospectively during open-label treatment. In general, increased fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors, although it is uncertain if these measures reduce the risk of stone formation during zonisamide treatment. Zonisamide has also been associated with decreases in serum phosphorus and increases in serum alkaline phosphatase. According to the manufacturer, these changes may be related to metabolic acidosis and subsequent osteomalacia. Chronic, untreated metabolic acidosis may be associated with reduced growth rates in children; however, the effects of zonisamide on growth rates in children have not been systematically evaluated. Baseline and periodic serum bicarbonate measurements are recommended during zonisamide treatment. If metabolic acidosis develops and persists, a reduction in dose or discontinuation of treatment may be necessary.
Musculoskeletal adverse reactions and pain symptoms were infrequently associated with zonisamide during clinical trial evaluation. Reported adverse reactions in 0.1% to 1% of patients included arthralgia, muscle cramps (legs), myalgia, flank pain, and myasthenia. Accidental injury was reported in at least 1% of patients. Increased creatine phosphokinase and rhabdomyolysis have been reported during postmarketing use; however, the frequencies are unknown and causality to the drug has not been established.
Infrequently reported adverse reactions (0.1% to 1%) affecting the urogenital system in zonisamide-treated patients during clinical trial evaluation included amenorrhea, dysuria, hematuria, impotence (erectile dysfunction), nocturia, polyuria, increased urinary frequency, urinary incontinence, urinary retention, and urinary urgency. Rare adverse reactions (less than 0.1%) included albuminuria (proteinuria), enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, and menorrhagia.
During clinical trial evaluation of zonisamide, asthenia was reported in at least 1% of patients. Other general adverse effects reported in 0.1% to 1% of patients included chest pain (unspecified), malaise, allergic reaction, facial swelling, and neck rigidity. Lupus erythematosus (lupus-like symptoms) was reported rarely (less than 0.1%). Nine cases of sudden unexplained deaths occurred among 991 patients with epilepsy receiving zonisamide. Although the incidence rate exceeds that expected in a healthy population, it is within the range of estimated sudden unexplained deaths for patients with refractory epilepsy who are not receiving zonisamide.
During controlled trials assessing zonisamide as add-on therapy for epilepsy, the following adverse respiratory effects or infections occurred in at least 2% of patients in the zonisamide group (zonisamide + current AED regimen) and more frequently than in patients in the control group (placebo + current AED regimen): influenza (4% vs. 3%) and rhinitis (2% vs. 1%). Adverse respiratory effects reported during other clinical trial evaluations included pharyngitis (1% or more), increased cough (1% or more), dyspnea (0.1% to 1%), apnea (less than 0.1%), and hemoptysis (less than 0.1%).
During controlled trials assessing zonisamide as add-on therapy for epilepsy, ecchymosis was reported in 2% of patients in the zonisamide group (zonisamide + current AED regimen) and 1% of patients in the control group (placebo + current AED regimen). Leukopenia, anemia, immunodeficiency, and lymphadenopathy were reported in 0.1% to 1% of patients during other clinical trial evaluations. Rare events (less than 0.1%) included thrombocytopenia, microcytic anemia, and petechiae. Similar to other sulfonamides, zonisamide can produce severe, possibly fatal, reactions such as fulminant hepatic necrosis or agranulocytosis, aplastic anemia, and other blood dyscrasias. Once sensitization to sulfonamides has occurred, a recurrence can be precipitated by administration of sulfonamides by any route. Two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of use in Japan. There were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the U.S., European, or Japanese development programs. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. However, the use of zonisamide should be discontinued if there is any sign of these reactions.
Weight loss was the most frequently reported metabolic and nutritional adverse reaction in patients receiving zonisamide, occurring in 3% of patients receiving zonisamide as add-on therapy in epilepsy trials and 2% of patients in the control groups. Infrequent (0.1% to 1%) metabolic and nutritional adverse reactions included dehydration, edema, peripheral edema, thirst, and weight gain. Elevated hepatic enzymes, hypoglycemia, hyponatremia, and lactic dehydrogenase increase were rarely reported (less than 0.1%).
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has occurred in patients taking zonisamide. Some cases have been life-threatening or fatal. Although symptoms vary, DRESS may present with fever, rash, lymphadenopathy, and/or facial swelling with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Early signs of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of a rash. Patients should be instructed to promptly report potential signs of multiorgan hypersensitivity reactions to their healthcare provider. If DRESS is suspected, zonisamide should be discontinued.
Hyperammonemia and encephalopathy have been reported with zonisamide during postmarketing experience. Encephalopathy was reported in 0.1% to 1% of patients during clinical trials of zonisamide. Zonisamide may cause metabolic acidosis that is associated with an increased risk of developing hyperammonemia. Hyperammonemia resulting from zonisamide can also be asymptomatic. The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy (e.g., unexplained change in mental status, vomiting, or lethargy) occur. Hyperammonemia resulting from zonisamide resolves with zonisamide discontinuation. A reduction in zonisamide daily dose may resolve or decrease the severity of hyperammonemia.
Zonisamide showed teratogenesis when administered during the period of organogenesis in mice, rats, and dogs. It was also embryolethal in monkeys during this period. A variety of fetal abnormalities were observed in these animals at maternal plasma concentrations similar to or lower than therapeutic levels in humans. Zonisamide should be administered during pregnancy only when the potential benefit to the mother justifies the potential risk to the fetus.
Zonisamide is contraindicated in patients who have demonstrated zonisamide hypersensitivity or sulfonamide hypersensitivity. Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately.
Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving zonisamide closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups vs. none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.
Use zonisamide with caution in patients with hepatic dysfunction. Because zonisamide is metabolized in the liver, slower titration and more frequent monitoring may be needed in patients with hepatic disease.
Use zonisamide with caution in patients with renal impairment or renal failure. Because zonisamide is excreted by the kidneys, slower titration and more frequent monitoring may be needed in patients with renal disease. Zonisamide has been associated with a mean increase in the concentrations of serum creatinine and blood urea nitrogen (BUN). Consider monitoring renal function periodically.
Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis. Conditions or therapies that predispose to acidosis, such as renal disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or specific drugs, may be additive to the bicarbonate lowering effects of zonisamide. Measurement of baseline and periodic serum bicarbonate during zonisamide treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing zonisamide. If the decision is made to continue patients on zonisamide in the face of persistent acidosis, consider alkali treatment. Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg/day.
Neonates, infants, and children appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Monitor patients, especially pediatric patients, treated with zonisamide closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather (ambient temperature increase). Use caution when zonisamide is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and anticholinergic medications. Pediatric patients may also be more likely to develop metabolic acidosis. Conditions or therapies that predispose to acidosis, such as renal disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or specific drugs, may be additive to the bicarbonate lowering effects of zonisamide. Measurement of baseline and periodic serum bicarbonate during zonisamide treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing zonisamide. If the decision is made to continue patients on zonisamide in the face of persistent acidosis, consider alkali treatment. Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg/day.
Clinical studies of zonisamide did not include sufficient numbers of geriatric subjects 65 years and older to determine whether they respond differently from younger adults. Other reported clinical experience has not identified differences in responses. In general, initial dose selection for a geriatric individual should be cautious, usually starting at the low end of the dosing range. According to the Beers Criteria, anticonvulsants such as zonisamide are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If zonisamide must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
As with other antiepileptic drugs, abrupt discontinuation of zonisamide in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Gradually reduce the zonisamide dose to discontinue.
Zonisamide may produce drowsiness, especially at higher doses. Advise patients against driving or operating machinery until they have gained experience on zonisamide sufficient to determine whether it affects their performance.
Hyperammonemia and encephalopathy have been reported with zonisamide use. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity (mitochondrial disease) may be at an increased risk for hyperammonemia with or without encephalopathy, and this risk may be increased by zonisamide use. The risks of hyperammonemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonemia. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy (e.g., unexplained change in mental status, vomiting, or lethargy) occur. Hyperammonemia resulting from zonisamide resolves with zonisamide discontinuation. A reduction in zonisamide daily dose may resolve or decrease the severity of hyperammonemia.
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.
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. 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. 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.
Zonisamide may be associated with reproductive risk. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during treatment with zonisamide and for 1 month after discontinuation. Based on animal data, zonisamide can cause fetal harm and may cause infertility in females.
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.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Amphetamine: (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.
Amphetamine; Dextroamphetamine: (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.
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.
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.
Benzphetamine: (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.
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.
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.
Bictegravir; Emtricitabine; 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.
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.
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.
Darunavir; Cobicistat; Emtricitabine; 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.
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.
Dextroamphetamine: (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.
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 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.
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 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.
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 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.
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.
Encorafenib: (Moderate) Monitor for decreased efficacy of zonisamide when coadministered with encorafenib; adjust the dose of zonisamide as clinically appropriate. Zonisamide is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with other strong CYP3A 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 encorafenib is added, dose adjusted, or withdrawn from zonisamide therapy.
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.
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.
Lisdexamfetamine: (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.
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; 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.
Methamphetamine: (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.
Methazolamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with other carbonic anhydrase inhibitors. Concomitant use of zonisamide with another carbonic anhydrase inhibitor may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
Methohexital: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Barbiturates are inducers of CYP3A4 and can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
Methscopolamine: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
Mitotane: (Major) Use caution if mitotane and zonisamide are used concomitantly, and monitor for decreased efficacy of zonisamide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and zonisamide is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of zonisamide. Concomitant administration of other strong CYP3A inducerse, phenytoin and carbamazepine, increase zonisamide plasma clearance from 0.30 to 0.35 mL/min/kg to 0.35 to 0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant. In addition, zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.
Monoamine oxidase inhibitors: (Moderate) Additive CNS depression is possible if MAOIs and zonisamide are coadministered. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient with epilepsy is required.
Morphine: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and morphine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
Morphine; Naltrexone: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and morphine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid 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.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with zonisamide due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a 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 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.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied.
Renal Impairment
After administration of a single zonisamide 300 mg dose to subjects with CrCl of 70 to 152 mL/minute, subjects with CrCl of 14.5 to 59 mL/minute, and subjects with CrCl of 10 to 20 mL/minute, zonisamide clearance decreased with decreasing renal function (3.42, 2.50, and 2.23 mL/minute, respectively). Zonisamide AUC increased 35% in subjects with CrCl less than 20 mL/minute.
Geriatric
The pharmacokinetics of zonisamide were similar in subjects with a mean age of 69 years and younger subjects with a mean age of 28 years after a single zonisamide 300 mg dose.