all of the patients were receiving other drugs in addition to zonisamide. in post-marketing experience from japan, a total of 49 cases of sjs or ten have been reported, a reporting rate of 46 per million patient-years of exposure. although this rate is greater than background, it is probably an underestimate of the true incidence because of under-reporting. there were no confirmed cases of sjs or ten in the us, european, or japanese development programs. in the us and european randomized controlled trials, 6 of 269 (2.2%) zonisamide patients discontinued treatment because of rash compared to none on placebo. across all trials during the us and european development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12 events per 1000 patient-years of exposure). during japanese development, serious rash or rash that led to study drug discontinuation was reported in 2% of patients (27.8 events per 1000 patient years). rash usually occurred early in treatment, with 85% reported within 16 weeks in the us and european studies and 90% reported within two weeks in the japanese studies. there was no apparent relationship of dose to the occurrence of rash. serious hematologic events two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of marketing in japan, rates greater than generally accepted background rates. there were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the us, european, or japanese development programs. there is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. oligohidrosis and hyperthermia in pediatric patients oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients. during the pre-approval development program in japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. while there were no cases reported in the us or european development programs, fewer than 100 pediatric patients participated in these trials. in the first 11 years of marketing in japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. in the first year of marketing in the us, 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. these rates are underestimates of the true incidence because of under-reporting. there has also been one report of heat stroke in an 18-year-old patient in the us. decreased sweating and an elevation in body temperature above normal characterized these cases. many cases were reported after exposure to elevated environmental temperatures. heat stroke, requiring hospitalization, was diagnosed in some cases. there have been no reported deaths. pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. patients, especially pediatric patients, treated with zonisamide should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. caution should be used 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 drugs with anticholinergic activity. the practitioner should be aware that the safety and effectiveness of zonisamide in pediatric patients have not been established, and that zonisamide is not approved for use in pediatric patients.

re is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted. the initial dose of zonisamide capsules should be 100 mg daily. after two weeks, the dose may be increased to 200 mg/day for at least two weeks. it can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. evidence from controlled trials suggests that zonisamide doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day (see clinical pharmacology, clinical studies subsection). there is little experience with doses greater than 600 mg/day. patients with renal or hepatic disease because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring (see clinical pharmacology and precautions ).

olled clinical trials table 4 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with zonisamide in controlled clinical trials that were numerically more common in the zonisamide group. in these studies, either zonisamide or placebo was added to the patient's current aed therapy. adverse events were usually mild or moderate in intensity. the prescriber should be aware that these figures, obtained when zonisamide was added to concurrent aed therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. an inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. table 4. incidence (%) of treatment-emergent adverse events in placebo-controlled, add-on trials (events that occurred in at least 2% of zonisamide-treated patients and occurred more frequently in zonisamide-treated than placebo-treated patients) body system / preferred term zonisamide placebo ( n = 269) (n = 230) % % body as a whole headache 10 8 abdominal pain 6 3 flu syndrome 4 3 digestive anorexia 13 6 nausea 9 6 diarrhea 5 2 dyspepsia 3 1 constipation 2 1 dry mouth 2 1 hematologic and lymphatic ecchymosis 2 1 metabolic and nutritional weight loss 3 2 nervous system dizziness 13 7 ataxia 6 1 nystagmus 4 2 paresthesia 4 1 neuropsychiatric and cognitive dysfunction-altered cognitive function confusion 6 3 difficulty concentrating 6 2 difficulty with memory 6 2 mental slowing 4 2 neuropsychiatric and cognitive dysfunction-behavioral abnormalities (non-psychosis related) agitation / irritability 9 4 depression 6 3 insomnia 6 3 anxiety 3 2 nervousness 2 1 neuropsychiatric and cognitive dysfunction-behavioral abnormalities (psychosis related) schizophrenic / schizophreniform behavior 2 0 neuropsychiatric and cognitive dysfunction-cns depression somnolence 17 7 fatigue 8 6 tiredness 7 5 neuropsychiatric and cognitive dysfunction-speech and language abnormalities speech abnormalities 5 2 difficulties in verbal expression 2 less than 1 respiratory rhinitis 2 1 skin and appendages rash 3 2 special senses diplopia 6 3 taste perversion 2 0

channels and reduces voltage-dependent, transient inward currents (t-type ca 2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. in vitro binding studies have demonstrated that zonisamide binds to the gaba/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. other in vitro studies have demonstrated that zonisamide (10 to 30 mcg/ml) suppresses synaptically-driven electrical activity without affecting postsynaptic gaba or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [ 3 h]-gaba (rat hippocampal slices). thus, zonisamide does not appear to potentiate the synaptic activity of gaba. in vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. zonisamide is a carbonic anhydrase inhibitor. the contribution of this pharmacological action to the therapeutic effects of zonisamide is unknown. however, as a carbonic anhydrase inhibitor, zonisamide may cause metabolic acidosis (see warnings, metabolic acidosis subsection). pharmacokinetics following a 200 to 400 mg oral zonisamide dose, peak plasma concentrations (range: 2 to 5 mcg/ml) in normal volunteers occur within 2 to 6 hours. in the presence of food, the time to maximum concentration is delayed, occurring at 4 to 6 hours, but food has no effect on the bioavailability of zonisamide. zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (rbc) than in plasma. the pharmacokinetics of zonisamide are dose proportional in the range of 200 to 400 mg, but the c max and auc increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to rbc. once a stable dose is reached, steady state is achieved within 14 days. the elimination half-life of zonisamide in plasma is about 63 hours. the elimination half-life of zonisamide in rbc is approximately 105 hours. the apparent volume of distribution (v/f) of zonisamide is about 1.45 l/kg following a 400 mg oral dose. zonisamide, at concentrations of 1 to 7 mcg/ml, is approximately 40% bound to human plasma proteins. protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. metabolism and excretion following oral administration of 14 c-zonisamide to healthy volunteers, only zonisamide was detected in plasma. zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. following multiple dosing, 62% of the 14 c dose was recovered in the urine, with 3% in the feces by day 10. zonisamide undergoes acetylation to form n-acetyl zonisamide and reduction to form the open ring metabolite, 2–sulfamoylacetyl phenol (smap). of the excreted dose, 35% was recovered as zonisamide, 15% as n-acetyl zonisamide, and 50% as the glucuronide of smap. reduction of zonisamide to smap is mediated by cytochrome p450 isozyme 3a4 (cyp3a4). zonisamide does not induce its own metabolism. plasma clearance of zonisamide is approximately 0.3 to 0.35 ml/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (aeds). the clearance of zonisamide is increased to 0.5 ml/min/kg in patients concurrently on enzyme-inducing aeds. renal clearance is about 3.5 ml/min. the clearance of an oral dose of zonisamide from rbc is 2 ml/min. special populations renal insufficiency single 300 mg zonisamide doses were administered to three groups of volunteers. group 1 was a healthy group with a creatinine clearance ranging from 70 to 152 ml/min. group 2 and group 3 had creatinine clearances ranging from 14.5 to 59 ml/min and 10 to 20 ml/min, respectively. zonisamide renal clearance decreased with decreasing renal function (3.42, 2.5, 2.23 ml/min, respectively). marked renal impairment (creatinine clearance less than 20 ml/min) was associated with an increase in zonisamide auc of 35% (see dosage and administration section). hepatic disease the pharmacokinetics of zonisamide in patients with impaired liver function have not been studied (see dosage and administration section). age the pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years). gender and race information on the effect of gender and race on the pharmacokinetics of zonisamide is not available. interactions of zonisamide with other antiepilepsy drugs (aeds) concurrent medication with drugs that either induce or inhibit cyp3a4 may alter serum concentrations of zonisamide. concomitant administration of phenytoin and carbamazepine increases zonisamide plasma clearance from 0.3 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. plasma protein binding of phenytoin and carbamazepine was not affected by zonisamide administration (see precautions, drug interactions subsection). interactions of zonisamide with other carbonic anhydrase inhibitors: concomitant use of zonisamide , a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (see precautions, drug interactions subsection). clinical studies the effectiveness of zonisamide as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one european) in 499 patients with refractory partial onset seizures with or without secondary generalization. each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. the 499 patients (209 women, 290 men) ranged in age from 13 to 68 years with a mean age of about 35 years. in the two us studies, over 80% of patients were caucasian; 100% of patients in the european study were caucasian. zonisamide or placebo was added to the existing therapy. the primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. the secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). the results described below are for all partial seizures in the intent-to-treat populations. in the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. this design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. the total daily dose was given as twice a day dosing. statistically significant treatment differences favoring zonisamide were seen for doses of 100, 200, and 400 mg/day. in the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide for three months. zonisamide was introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/ml. in the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. the average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. both studies demonstrated statistically significant differences favoring zonisamide for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide at doses between 100 and 400 mg/day. the primary comparison in both trials was for any dose over weeks 5 to 12. table 1. median % reduction in all partial seizures and % responders in primary efficacy analyses: intent-to-treat analysis study median % reduction in partial seizures % responders zonisamide placebo zonisamide placebo study 1: n = 98 n = 72 n = 98 n = 72 weeks 8 to 12 40.5 %* 9% 41.8% * 22.2% study 2: n = 69 n = 72 n = 69 n = 72 weeks 5 to 12 29.6% - 3.2% 29% 15% study 3: n = 67 n = 66 n = 67 n = 66 weeks 5 to 12 27.2% - 1.1% 28 % * 12% * p less than 0.05 compared to placebo table 2. median % reduction in all partial seizures and % responders for dose analyses in study 1: intent-to-treat analysis dose group median % reduction in partial seizures % responders zonisamide placebo zonisamide placebo 100 to 400 mg / day: n = 112 n = 83 n = 112 n = 83 weeks 1 to 12: 32.3% * 5.6% 32.1% * 9.6% 100 mg / day: n = 56 n = 80 n = 56 n = 80 weeks 1 to 5: 24.7% * 8.3% 25% * 11.3% 200 mg / day: n = 55 n = 82 n = 55 n = 82 weeks 2 to 6: 20.4% * 4 % 25.5% * 9.8 % * p less than 0.05 compared to placebo

rs). the results described below are for all partial seizures in the intent-to-treat populations. in the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. this design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. the total daily dose was given as twice a day dosing. statistically significant treatment differences favoring zonisamide were seen for doses of 100, 200, and 400 mg/day. in the second (n = 152) and third (n = 138) studies, patients had a 2 to 3 month baseline, then were randomly assigned to placebo or zonisamide for three months. zonisamide was introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/ml. in the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. the average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. both studies demonstrated statistically significant differences favoring zonisamide for doses of 400 to 600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide at doses between 100 and 400 mg/day. the primary comparison in both trials was for any dose over weeks 5 to 12. table 1. median % reduction in all partial seizures and % responders in primary efficacy analyses: intent-to-treat analysis study median % reduction in partial seizures % responders zonisamide placebo zonisamide placebo study 1: n = 98 n = 72 n = 98 n = 72 weeks 8 to 12 40.5 %* 9% 41.8% * 22.2% study 2: n = 69 n = 72 n = 69 n = 72 weeks 5 to 12 29.6% - 3.2% 29% 15% study 3: n = 67 n = 66 n = 67 n = 66 weeks 5 to 12 27.2% - 1.1% 28 % * 12% * p less than 0.05 compared to placebo table 2. median % reduction in all partial seizures and % responders for dose analyses in study 1: intent-to-treat analysis dose group median % reduction in partial seizures % responders zonisamide placebo zonisamide placebo 100 to 400 mg / day: n = 112 n = 83 n = 112 n = 83 weeks 1 to 12: 32.3% * 5.6% 32.1% * 9.6% 100 mg / day: n = 56 n = 80 n = 56 n = 80 weeks 1 to 5: 24.7% * 8.3% 25% * 11.3% 200 mg / day: n = 55 n = 82 n = 55 n = 82 weeks 2 to 6: 20.4% * 4 % 25.5% * 9.8 % * p less than 0.05 compared to placebo

, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones. patients should contact their physician immediately if a child has been taking zonisamide and is not sweating as usual with or without a fever. because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising. suicidal thinking and behavior - patients, their caregivers, and families should be counseled that aeds, including zonisamide, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. behaviors of concern should be reported immediately to healthcare providers. patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations (possible manifestations of metabolic acidosis). as with other aeds, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide therapy. patients should notify their physician if they intend to breast-feed or are breast-feeding an infant. patients should be encouraged to enroll in the north american antiepileptic drug (naaed) pregnancy registry if they become pregnant. this registry is collecting information about the safety of antiepileptic drugs during pregnancy. to enroll, patients can call the toll free number 1-888-233-2334 (see precautions, pregnancy subsection). laboratory tests in several clinical studies, zonisamide was associated with a mean increase in the concentration of serum creatinine and blood urea nitrogen (bun) of approximately 8% over the baseline measurement. consideration should be given to monitoring renal function periodically (see precautions, effect on renal function subsection). zonisamide increases serum chloride and alkaline phosphatase and decreases serum bicarbonate (see warnings, metabolic acidosis subsection), phosphorus, calcium, and albumin. drug interactions effects of zonisamide on the pharmacokinetics of other antiepilepsy drugs (aeds) zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome p450), as measured in human liver microsomal preparations, in vitro . zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome p450 isozymes. effects of other drugs on zonisamide pharmacokinetics drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. the half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing aeds such as phenytoin, carbamazepine, or phenobarbital was between 27 and 38 hours; the half-life of zonisamide in patients concurrently on the non-enzyme inducing aed, valproate, was 46 hours. concurrent medication with drugs that either induce or inhibit cyp3a4 would be expected to alter serum concentrations of zonisamide. interaction with cimetidine zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days). drug interactions with cns depressants concomitant administration of zonisamide and alcohol or other cns depressant drugs has not been evaluated in clinical studies. because of the potential of zonisamide to cause cns depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other cns depressants. other carbonic anhydrase inhibitors concomitant use of zonisamide , a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (see clinical pharmacology, interactions of zonisamide with other carbonic anhydrase inhibitors subsection). carcinogenicity, mutagenesis, impairment of fertility no evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. in mice, this dose is approximately equivalent to the maximum recommended human dose (mrhd) of 400 mg/day on a mg/m 2 basis. in rats, this dose is 1 to 2 times the mrhd on a mg/m 2 basis. zonisamide was mutagenic in an in vitro chromosomal aberration assay in chl cells. zonisamide was not mutagenic or clastogenic in other in vitro assays (ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the in vivo rat bone marrow cytogenetics assay. rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses. the low dose in this study is approximately 0.5 times the maximum recommended human dose (mrhd) on a mg/m 2 basis. pregnancy pregnancy category c (see warnings, teratogenicity subsection): zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data. zonisamide was teratogenic in multiple animal species. zonisamide treatment causes metabolic acidosis in humans. the effect of zonisamide-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) may be associated with decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. (see warnings, metabolic acidosis subsection.) newborns of mothers treated with zonisamide should be monitored for metabolic acidosis because of transfer of zonisamide to the fetus and possible occurrence of transient metabolic acidosis following birth. transient metabolic acidosis has been reported in neonates born to mothers treated during pregnancy with a different carbonic anhydrase inhibitor. zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. a variety of external, visceral, and skeletal malformations was produced in animals by prenatal exposure to zonisamide. cardiovascular defects were prominent in both rats and dogs. following administration of zonisamide (10, 30, or 60 mg/kg/day) to pregnant dogs during organogenesis, increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, various valvular and arterial anomalies) were found at doses of 30 mg/kg/day or greater. the low effect dose for malformations produced peak maternal plasma zonisamide levels (25 mcg/ml) about 0.5 times the highest plasma levels measured in patients receiving the maximum recommended human dose (mrhd) of 400 mg/day. in dogs, cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose, which was associated with maternal plasma levels (44 mcg/ml) approximately equal to the highest levels measured in humans receiving the mrhd. incidences of skeletal malformations were also increased at the high dose, and fetal growth retardation and increased frequencies of skeletal variations were seen at all doses in this study. the low dose produced maternal plasma levels (12 mcg/ml) about 0.25 times the highest human levels. in cynomolgus monkeys, administration of zonisamide (10 or 20 mg/kg/day) to pregnant animals during organogenesis resulted in embryo-fetal deaths at both doses. the possibility that these deaths were due to malformations cannot be ruled out. the lowest embryolethal dose in monkeys was associated with peak maternal plasma zonisamide levels (5 mcg/ml) approximately 0.1 times the highest levels measured in patients at the mrhd. in a mouse embryo-fetal development study, treatment of pregnant animals with zonisamide (125, 250, or 500 mg/kg/day) during the period of organogenesis resulted in increased incidences of fetal malformations (skeletal and/or craniofacial defects) at all doses tested. the low dose in this study is approximately 1.5 times the mrhd on a mg/m 2 basis. in rats, increased frequencies of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) were observed among the offspring of dams treated with zonisamide (20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. the low effect dose is approximately 0.5 times the mrhd on a mg/m 2 basis. perinatal death was increased among the offspring of rats treated with zonisamide (10, 30, or 60 mg/kg/day) from the latter part of gestation up to weaning at the high dose, or approximately 1.4 times the mrhd on a mg/m 2 basis. the no effect level of 30 mg/kg/day is approximately 0.7 times the mrhd on a mg/m 2 basis. there are no adequate and well-controlled studies in pregnant women. zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. to provide information regarding the effects of in utero exposure to zonisamide, physicians are advised to recommend that pregnant patients taking zonisamide capsules enroll in the naaed pregnancy registry. this can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. labor and delivery the effects of zonisamide on labor and delivery in humans are unknown. use in nursing mothers zonisamide is excreted in human milk. because of the potential for serious adverse reactions in nursing infants from zonisamide, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother. pediatric use the safety and effectiveness of zonisamide in children under age 16 have not been established. cases of oligohidrosis and hyperpyrexia have been reported (see warnings, oligohidrosis and hyperthermia in pediatric patients subsection). zonisamide commonly causes metabolic acidosis in pediatric patients (see warnings, metabolic acidosis subsection). chronic untreated metabolic acidosis in pediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially resulting in rickets), and may reduce growth rates. a reduction in growth rate may eventually decrease the maximal height achieved. the effect of zonisamide on growth and bone-related sequelae has not been systematically investigated. geriatric use single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers (see clinical pharmacology, special populations subsection). clinical studies of zonisamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.