Summary Of Exposure |
A) USES: Zonisamide is a sulfonamide antiepileptic agent primarily used for treatment of partial seizure disorders. It is also used off-label as an adjunct in Parkinson's disease.
B) PHARMACOLOGY: Zonisamide blocks voltage-gated sodium and calcium channels. It increases dopamine effects in the brain. In addition, the agent is a reversible monoamine oxidase-B (MAO-B) inhibitor. The agent may have carbonic anhydrase inhibitor action.
C) TOXICOLOGY: At high doses, zonisamide inhibits dopamine function, leading to CNS depression.
D) EPIDEMIOLOGY: Both adverse effects from therapeutic use and toxicity from overdose are uncommon. Severe toxicity is rare.
E) WITH THERAPEUTIC USE
1) The most common adverse effects associated with therapeutic administration of zonisamide include somnolence, fatigue/ataxia (6%), difficulty concentrating (2%), and nausea and vomiting (2%). Dermal hypersensitivity reactions, likely due to the sulfa moiety, have been reported in 1% to 2% of patients. Nephrolithiasis has also been reported following long-term therapy with zonisamide. Severe adverse effects are rare and include anhydrosis and subsequent hyperthermia, seizure aggravation, aplastic anemia, metabolic acidosis, and psychosis. Severe skin rashes following zonisamide therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred with fatalities reported.
F) WITH POISONING/EXPOSURE
1) OVERDOSE: Very limited data is available regarding toxicity of zonisamide in overdose.
2) MILD TO MODERATE TOXICITY: Most patients that ingest this agent in overdose experience only mild or moderate effects. The primary manifestation is CNS depression, somnolence, ataxia, and nausea and vomiting.
3) SEVERE TOXICITY: Due to the long half-life of the agent, prolonged CNS depression and coma are possible with large overdoses. Bradycardia, hypotension, and respiratory depression have occurred following an overdose ingestion of an unknown amount of zonisamide. Multiple seizures, cardiac arrest, and wide complex tachycardia have been reported in an adult after an overdose. Based upon the pharmacologic mechanism of action causing sodium channel blockade, wide complex cardiac dysrhythmias may be possible.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) HYPERTHERMIA a) Hyperthermia and oligohidrosis, often resulting in heat stroke, have been reported among pediatric patients, following therapeutic administration of zonisamide (Prod Info ZONEGRAN(R) oral capsules, 2016).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Nystagmus and diplopia may infrequently occur as adverse effects with higher therapeutic administration (Prod Info ZONEGRAN(R) oral capsules, 2016; Leppik et al, 1993; Sackellares et al, 1985).
B) WITH POISONING/EXPOSURE 1) NYSTAGMUS was reported following a zonisamide overdose (Naito et al, 1988).
2) BLURRED VISION was reported following zonisamide overdose (Wightman et al, 2011).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CONDUCTION DISORDER OF THE HEART 1) WITH POISONING/EXPOSURE a) Bradycardia was reported in a 26-year-old woman who became comatose after ingesting an unknown amount of zonisamide in a suicide attempt. The zonisamide plasma level was 100.1 mcg/mL 31 hours post-ingestion (Naito et al, 1988). The patient had also ingested unknown amounts of clonazepam and carbamazepine.
b) CASE REPORT: A 25-year-old woman with depression and a history of seizures treated with zonisamide, clobazam, and lacosamide intentionally ingested 12.6 g of zonisamide (therapeutic dose 300 mg/day). She presented to the emergency department 8 hours after ingestion with a Glasgow Coma Scale (GCS) score of 9, mild hypotension, temperature 36.8 degrees C, and repeated episodes of vomiting. Mild QT prolongation (QTc 506 msec) and QRS widening (102 msec) were observed on ECG. She was intubated and received a single dose of activated charcoal. Her condition improved quickly and she was extubated 8 hours later; however, somnolence persisted for another 50 hours. Arterial blood gas analysis 28 hours after admission showed metabolic acidosis, which resolved with supportive treatment only over a 3-day period. ECG showed a normal QTc (398 msec) and QRS (85 msec) 3 days after admission(Hofer et al, 2011).
c) CASE REPORT: Multiple generalized tonic-clonic seizures and cardiac arrest occurred in an 18-year-old woman after a single drug ingestion of 4.8 grams of zonisamide in a suicide attempt. The patient converted to a perfusing wide complex tachycardia following cardioresuscitative measures; but developed severe cerebral edema and brain death likely secondary to anoxia (Huang et al, 2002).
B) HYPOTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) Hypotension developed in a patient who ingested an unknown amount of zonisamide (Naito et al, 1988). The patient had also ingested unknown amounts of clonazepam and carbamazepine.
b) CASE REPORT: A 25-year-old woman with a history of seizures treated with multiple antiepileptic drugs presented with mild hypotension (103/54 mmHg) 8 hours after intentionally ingesting 12.6 g of zonisamide (therapeutic dose 300 mg/day). Upon admission, ECG showed mild QT prolongation and QRS widening, and Glasgow Coma Scale (GCS) score of 9. She was intubated but improved quickly and was extubated 8 hours later. She was discharged 7 days after admission with polyuria (Hofer et al, 2011).
C) CHEST PAIN 1) WITH POISONING/EXPOSURE a) Diffuse chest pain has been reported with zonisamide overdose (Wightman et al, 2011).
3.5.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) HYPOTENSION a) DOGS: In a study conducted by Nakatsuji et al (1987), zonisamide, administered intravenously to anesthetized dogs at a dose of 30 mg/kg, transiently lowered blood pressure and decreased blood flow in the carotid and femoral arteries(Nakatsuji et al, 1987).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) ACUTE RESPIRATORY INSUFFICIENCY 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 26-year-old woman developed respiratory depression following an overdose ingestion of an unknown amount of zonisamide, clonazepam, and carbamazepine (Naito et al, 1988).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM DEFICIT 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 25-year-old woman with depression and a history of seizures treated with zonisamide, clobazam, and lacosamide intentionally ingested 12.6 g of zonisamide (therapeutic dose 300 mg/day). She presented to the emergency department 8 hours after ingestion with a Glasgow Coma Scale (GCS) score of 9. She was intubated and received a single dose of activated charcoal. Eight hours after admission her condition improved and she was extubated. Somnolence persisted for 50 hours after extubation and she experienced transient episodes of generalized myoclonus and diplopia. She was discharged 7 days after admission with polyuria (Hofer et al, 2011).
B) DROWSY 1) WITH THERAPEUTIC USE a) Somnolence and fatigue are common occurrences following therapeutic administration of zonisamide and appear to be dose-related, occurring most frequently at doses of 300 to 500 mg/day (Prod Info ZONEGRAN(R) oral capsules, 2016; Walker & Sander, 1994; Seino et al, 1991; Shimizu et al, 1987).
C) COMA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 26-year-old woman became comatose, and subsequently developed hypotension, bradycardia, and respiratory depression, after ingesting an unknown amount of zonisamide in a suicide attempt. The patient's zonisamide serum level was 100.1 mcg/mL 31 hours postingestion. The patient recovered 5 days later (Naito et al, 1988). The patient had also ingested a large amount of clonazepam which may have contributed to her CNS depression.
D) DIZZINESS 1) WITH POISONING/EXPOSURE a) Dizziness has been reported with zonisamide overdose (Wightman et al, 2011).
E) HEADACHE 1) WITH POISONING/EXPOSURE a) Mild headache has been reported with zonisamide overdose (Wightman et al, 2011).
F) ATAXIA 1) WITH THERAPEUTIC USE a) Fatigue/ataxia has been reported in 6% of patients following zonisamide therapy (Prod Info ZONEGRAN(R) oral capsules, 2016; Oommen & Mathews, 1999; Walker & Sander, 1994; Seino et al, 1991) and may occur with high-dose therapy (Wilensky et al, 1985).
G) ALTERED MENTAL STATUS 1) WITH THERAPEUTIC USE a) Difficulty concentrating has been reported in 2% of patients following zonisamide therapy (Prod Info ZONEGRAN(R) oral capsules, 2016).
b) Mental status changes, including mental slowing, lack of concentration, decreased short-term memory, and speech slowing, have been reported with zonisamide therapy. These symptoms may be dose-related (Prod Info ZONEGRAN(R) oral capsules, 2016; Seino et al, 1991; Shimizu et al, 1987; Wilensky et al, 1985) .
H) SEIZURE 1) WITH THERAPEUTIC USE a) Abrupt withdrawal of zonisamide therapy may result in an increase in seizure frequency or in the development of status epilepticus (Prod Info ZONEGRAN(R) oral capsules, 2016). Status epilepticus has also been reported during zonisamide therapy.
b) INCIDENCE: In controlled trials, status epilepticus occurred in 1.1% of patients receiving zonisamide therapy as compared to none of the patients receiving placebo (Prod Info ZONEGRAN(R) oral capsules, 2016). It is unclear if the status epilepticus is related to zonisamide or the poorly controlled underlying seizure disorders of the enrolled patients.
2) WITH POISONING/EXPOSURE a) In the setting of acute overdose, zonisamide may cause seizures (Wightman et al, 2011; Huang et al, 2002).
b) CASE REPORT: Multiple generalized tonic-clonic seizures and cardiac arrest occurred in an 18-year-old woman after a single drug ingestion of 4.8 grams of zonisamide in a suicide attempt. The patient converted to a perfusing wide complex tachycardia following resuscitation efforts; however, she developed severe cerebral edema and brain death likely secondary to anoxia (Huang et al, 2002).
I) EXTRAPYRAMIDAL DISEASE 1) WITH THERAPEUTIC USE a) A 2-year-old mentally retarded boy with seizures treated with carbamazepine, phenytoin, phenobarbital and clonazepam was begun on zonisamide 5 milligrams/kilogram/day. He developed a fever of 40 C two days after beginning zonisamide therapy, which persisted for 12 days. Zonisamide dose was gradually increased to 15 mg/kg/day over two weeks, and the child's temperature increased to 42 C. Chorea-like involuntary movements, resting tremor, cog-wheel rigidity, and decreased sweating also developed and his serum creatine kinase level was elevated at 380 IU/l (normal range is 7 to 80 IU/L). The involuntary movements subsided with sodium dantrolene, amantadine, levodopa and biperiden administration, however the tremor and rigidity did not completely resolve for 2 months (Shimizu et al, 1997). It is not clear if this case represents an incomplete neuroleptic malignant syndrome.
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea and vomiting have been reported in 2% of patients following zonisamide therapy (Prod Info ZONEGRAN(R) oral capsules, 2016; Shimizu et al, 1987; Wilensky et al, 1985).
2) WITH POISONING/EXPOSURE a) Nausea and vomiting have been reported with zonisamide overdose (Wightman et al, 2011).
b) CASE REPORT: A 25-year-old woman treated with multiple antiepileptic drugs presented to the emergency department with repeated episodes of vomiting 8 hours after intentionally ingesting 12.6 g of zonisamide (therapeutic dose 300 mg/day). Upon admission, ECG showed mild QT prolongation and QRS widening, and Glasgow Coma Scale (GCS) score of 9. She was intubated but improved quickly and was extubated 8 hours later. She was discharged 7 days after admission with polyuria (Hofer et al, 2011).
B) LOSS OF APPETITE 1) WITH THERAPEUTIC USE a) Anorexia may occur following therapeutic administration of zonisamide (Prod Info ZONEGRAN(R) oral capsules, 2016; Seino et al, 1991; Shimizu et al, 1987).
b) INCIDENCE: In clinical trials, 13% of patients receiving zonisamide therapy (n=269) reported anorexia as compared to 6% of patients receiving placebo (n=230) (Prod Info ZONEGRAN(R) oral capsules, 2016).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Transient elevations of hepatic enzyme levels may infrequently occur with zonisamide therapy (Prod Info ZONEGRAN(R) oral capsules, 2016; Wilensky et al, 1985).
3.9.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) HEPATOCELLULAR DAMAGE a) DOGS: elevated liver enzyme levels, dark brown discoloration of the liver, and concentric lamellar bodies in the cytoplasm of hepatocytes, were reported in dogs given zonisamide for 1 year at doses of 75 mg/kg/day, which is approximately 6 times the maximum recommended human dose of 400 mg/day on a mg/m(2) basis (Prod Info zonisamide oral capsules, 2006).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) KIDNEY STONE 1) WITH THERAPEUTIC USE a) Kidney stones have been reported in some patients following therapy with zonisamide (Prod Info ZONEGRAN(R) oral capsules, 2016; Leppik et al, 1993; Seino et al, 1991).
b) INCIDENCE: Thirteen of 700 patients (1.9%), who received zonisamide during European and American clinical trials, reported the occurrence of renal calculi (Oommen & Mathews, 1999).
B) ABNORMAL RENAL FUNCTION 1) WITH THERAPEUTIC USE a) Transient elevations of serum creatinine and BUN levels may occur with zonisamide therapy. The increase in levels appeared to be persistent but was not progressive. At the time of this review, there were no episodes of unexplained acute renal failure (Prod Info ZONEGRAN(R) oral capsules, 2016).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) METABOLIC ACIDOSIS 1) WITH THERAPEUTIC USE a) Metabolic acidosis has been reported in some patients receiving therapeutic doses of zonisamide. There is an increased risk for metabolic acidosis in patients with conditions or on therapies that predispose them to acidosis (eg, renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or other drugs). Patients on a higher dose of zonisamide have a higher risk for the development of zonisamide-induced metabolic acidosis, however, metabolic acidosis can occur with doses as low as 25 mg/day. Metabolic acidosis generally occurs early in zonisamide treatment, but may occur at any time during treatment. Zonisamide-induced metabolic acidosis may be more frequent and severe in younger patients (US Food and Drugs Administration, 2009). 1) CHILDREN: During an open-label, uncontrolled, adjunctive treatment trial of 3 to 16-year-old patients with partial epilepsy, the incidence of a persistent decrease in serum bicarbonate levels to less than 20 mEq/L was up to 90%, and increased with higher doses. The incidence of abnormally low serum bicarbonate levels (less than 17 mEq/L and more than 5 mEq/L decrease from a pretreatment value of at least 20 mEq/L) was up to 18% and increased with higher doses (US Food and Drugs Administration, 2009).
2) ADULTS: Adult patients treated with various doses of zonisamide may experience mild to moderate decreases in serum bicarbonate levels (average decrease of approximately 2 mEq/L). However, severe serum bicarbonate decreases of as much as 10 mEq/L below baseline have been reported in some adult patients. In placebo-controlled studies of adults treated with zonisamide, the incidences of serum bicarbonate of less than 20 mEq/L were 21% in patients on 25 mg/day and 43% in patients on 300 mg/day. Persistent and abnormally low serum bicarbonate occurred in up to 2% of patients (US Food and Drugs Administration, 2009).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 25-year-old woman treated with multiple antiepileptic drugs developed non-anion gap metabolic acidosis after intentionally ingesting 12.6 g of zonisamide (therapeutic dose 300 mg/day). She presented to the emergency department 8 hours after ingestion with a Glasgow Coma Scale (GCS) score of 8, mild hypotension, and repeated episodes of vomiting. She was intubated but improved quickly and was extubated 8 hours later. Arterial blood gas (ABG) analysis after intubation showed lactic acidosis with pH 7.28, pCO2 5.19 kPa, PO2 20.1 kPa, bicarbonate 28.4 mmol/L, base excess -7.3 mmol/L, lactate 5.5 mmol/L. ABG analysis 28 hours after admission showed metabolic acidosis with pH 7.34, pCO2 3.7 kPa, pO2 13 kPa, bicarbonate 17 mmol/L, base excess -9.7 mmol/L, lactate 0.5 mmol/L, chloride 117 mmol/L, sodium 136 mmol/L. Bicarbonate infusion was not required as the acidosis resolved gradually within 3 days(Hofer et al, 2011).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Leukopenia may infrequently occur with zonisamide therapy (Prod Info ZONEGRAN(R) oral capsules, 2016; Shimizu et al, 1987; Wilensky et al, 1985) and has been reported as a reason for discontinuing zonisamide therapy during clinical trials (Seino et al, 1991).
B) APLASTIC ANEMIA 1) WITH THERAPEUTIC USE a) Two cases of aplastic anemia and one case of agranulocytosis were reported in patients following zonisamide therapy during the first 11 years of marketing in Japan (Prod Info ZONEGRAN(R) oral capsules, 2016).
C) NORMOCYTIC HYPOCHROMIC ANEMIA 1) WITH THERAPEUTIC USE a) Hypochromic anemia was reported in two patients following therapeutic administration of zonisamide (Shimizu et al, 1987).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) Severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, were reported in patients receiving zonisamide therapy in clinical trials during the first eleven years of marketing in Japan, with 7 deaths reported (Prod Info ZONEGRAN(R) oral capsules, 2016). All of the affected patients were also receiving other drugs in addition to zonisamide. b) In all European and US clinical trials, skin rashes led to discontinuation of zonisamide therapy in approximately 1.4% of the patients. During Japanese development of zonisamide, skin rashes led to discontinuation of zonisamide therapy in 2% of patients (Prod Info ZONEGRAN(R) oral capsules, 2016). 1) Approximately 85% of the patients reported that rash occurred within the first two weeks of initiation of zonisamide therapy in US and European trials, and 90% of patients reported rash within 2 weeks of beginning zonisamide therapy in Japanese trials. The rash does not appear to be dose-related (Prod Info ZONEGRAN(R) oral capsules, 2016).
B) ANHIDROSIS 1) WITH THERAPEUTIC USE a) Oligohidrosis has been reported in pediatric patients following therapeutic administration of zonisamide (Oommen & Mathews, 1999) and may be associated with the development of hyperthermia in these patients; heatstroke may occur(Prod Info ZONEGRAN(R) oral capsules, 2016; Shimizu et al, 1997). The patients recovered following discontinuation of zonisamide.
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH THERAPEUTIC USE a) CASE REPORT: A 26-year-old man developed a hypersensitivity reaction, characterized by generalized maculopapular erythema, bilateral lymphadenopathy, hepatomegaly, elevated liver enzyme levels, and eosinophilia, approximately 6 weeks after beginning zonisamide therapy. The patient recovered after discontinuation of the medication. Upon rechallenge with zonisamide, the patient again developed erythema, bilateral inguinal lymphadenopathy, elevated liver enzyme levels, and eosinophilia 3 days after restarting the medication (Sakamoto et al, 1994).
B) DECREASED IMMUNOGLOBULIN 1) WITH THERAPEUTIC USE a) CASE REPORT: The IgA and IgG2 levels in a 2-year-old child were shown to be decreased four months after beginning zonisamide therapy, as determined by a turbidimetric immunoassay. Three weeks after discontinuation of zonisamide therapy, the patient's IgA levels returned to normal; however, low IgG2 levels persisted for 7 months after cessation of zonisamide administration (Maeoka et al, 1997).
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Reproductive |
3.20.1) SUMMARY
A) Zonisamide is classified as FDA pregnancy category C. There are no adequate or well-controlled studies of zonisamide in pregnant women; however, it may cause serious adverse fetal effects. Metabolic acidosis may develop in patients taking zonisamide. Metabolic acidosis during pregnancy (due to other causes) may result in decreased fetal growth, decreased fetal oxygenation, and fetal death. Zonisamide is transferred to the fetus and may cause transient metabolic acidosis in the newborn following birth. Anencephaly and atrial septal defects occurred after first trimester exposure to zonisamide and other anticonvulsant agents, although it is not clear if zonisamide is the direct cause. Cardiovascular defects and embryolethal effects in animals have also been reported. Therefore, it is recommended that zonisamide be used in a pregnant woman only if the potential benefit to the mother justifies the potential risks to the fetus. Pregnant women taking zonisamide are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry available at 1-888-233-2334.
B) Compared with other antiepileptic drugs, zonisamide is more readily distributed into breast milk.
3.20.2) TERATOGENICITY
A) BIRTH DEFECTS 1) Anencephaly and an atrial septal defect occurred in 2 fetuses, respectively, following first trimester exposure to zonisamide and other anticonvulsant agents. Maternal zonisamide serum concentrations were 6.1 mcg/mL and 6.3 mcg/mL, respectively, which are both below the therapeutic concentration range of zonisamide. It is not clear if zonisamide was the direct cause of the malformations (Kondo et al, 1996).
B) ANIMAL STUDIES 1) RATS: Increased cardiovascular defects, persistent cords of thymic tissue, and decreased skeletal ossification were reported in rat offspring of dams treated with zonisamide throughout organogenesis at doses of 20, 60, or 200 mg/kg/day. The 20 mg/kg/day dose is about 0.5 times the MRHD on a mg/m(2) basis. Increased perinatal death was seen in offspring of rats treated with zonisamide at doses of 60 mg/kg/day (approximately 1.4 times the MRHD on a mg/m(2) basis) from the latter part of gestation up to weaning (Prod Info ZONEGRAN(R) oral capsules, 2012).
2) MICE: Craniofacial defects and skeletal abnormalities were reported in mouse fetuses following maternal ingestion of 125, 250, or 500 mg/kg/day of zonisamide during organogenesis. The 125 mg/kg/day dose is about 1.5 times the maximum recommended human dose (MRHD) on a mg/m(2) basis (Prod Info ZONEGRAN(R) oral capsules, 2012).
3) DOGS: Ventricular septal defects, cardiomegaly, and various valvular and arterial anomalies were reported in dog fetuses following maternal ingestion of 30 mg/kg (about 0.5 times the exposure at the MRHD) of 400 mg/day) of zonisamide during organogenesis. Incidences of skeletal malformations were increased following maternal ingestion of 60 mg/kg of zonisamide (approximately equal to the exposure at the MRHD). Fetal growth retardation and increased frequencies of skeletal variations were observed at doses greater than or equal to 10 mg/kg/day (about 0.25 times to approximately equal to the exposure at the MRHD). (Prod Info ZONEGRAN(R) oral capsules, 2012).
4) MONKEYS: Embryofetal deaths were reported in cynomolgus monkeys following maternal administration of zonisamide at doses about 0.1 times the exposure at the MRHD during organogenesis (Prod Info ZONEGRAN(R) oral capsules, 2012).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Zonisamide is classified as FDA pregnancy category C (Prod Info ZONEGRAN(R) oral capsules, 2012).
B) METABOLIC ACIDOSIS 1) Metabolic acidosis may develop in patients taking zonisamide. Metabolic acidosis during pregnancy (due to other causes) may result in decreased fetal growth, decreased fetal oxygenation, and fetal death. Monitor all pregnant women for metabolic acidosis during zonisamide therapy. Zonisamide is transferred to the fetus and may cause transient metabolic acidosis in the newborn following birth. Monitor all newborns of mothers taking zonisamide for metabolic acidosis (Prod Info ZONEGRAN(R) oral capsules, 2012).
2) It is recommended that zonisamide be used in a pregnant woman only if the potential benefit to the mother justifies the potential risks to the fetus. Pregnant women taking zonisamide are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry available at 1-888-233-2334 (Prod Info ZONEGRAN(R) oral capsules, 2012).
C) DECREASED FETAL GROWTH 1) One study found a decrease in mean birth weight and birth length among neonates exposed to topiramate or zonisamide in utero compared with neonates exposed to lamotrigine and unexposed group. Data of women (mean gestational length of 39 weeks) who were enrolled from the North American Antiepileptic Drug Pregnancy Registry between 1997 to 2012 showed that the mean birthweight was 3,200 g for zonisamide (n=98), 3181 g for topiramate (n=347), 3402 g for lamotrigine (n=1,548), and 3458 g for the unexposed group (n=457) (P less than 0.01). Mean length at birth was 49.9 cm for zonisamide, 49.8 cm for topiramate, 50.9 cm for lamotrigine, and 51.2 cm for the unexposed group (P less than 0.01). Overall the prevalence of small for gestation age for lamotrigine, topiramate, and zonisamide were 6.8%, 17.9% (relative risk (RR): 2.4, 95% confidence interval (CI): 1.8 to 3.3), and 12.2% (relative risk (RR): 1.6, 95% CI 0.9 to 2.8), respectively (Hernandez-Diaz et al, 2014).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) Compared with other antiepileptic drugs, zonisamide is more readily distributed into breast milk. In a nursing mother monitored using a solid-phase extraction high performance liquid chromatography (HPLC) method, the milk-to-plasma concentration ratio was 0.93. The average concentration of zonisamide in breast milk was 9.41 +/-0.95 mcg/L, following maternal ingestion of 300 mg/day in three divided doses (Shimoyama et al, 1999). Because zonisamide is excreted in human milk and the potential for serious adverse effects in the nursing infant exists, consideration should be given to either discontinuing zonisamide or discontinuing breastfeeding, taking into account the importance of the drug to the mother (Prod Info ZONEGRAN(R) oral capsules, 2012).
2) Two nursing mothers who were taking zonisamide, partially breastfed their infants, supplementing with formula, with no apparent adverse reactions resulting in the infants. The first patient was treated with zonisamide monotherapy 300 mg/day, starting 2 months before conception and continuing throughout pregnancy and after delivery. The zonisamide concentration in milk and relative infant dose were 18 mcg/mL and 44%, respectively, at 5 days after delivery. Starting on day 9 after delivery, the mother partially breastfed, reducing the breastfeeding to twice a day and giving formula 7 to 8 times/day. The serum concentrations of zonisamide in the infant taken on day 34 after delivery was below the limit of detection (less than 0.5 mcg/mL). The second patient was treated with zonisamide 100 mg/day for more than a decade since before conception; treatment continued throughout pregnancy and after delivery. The zonisamide concentration in her milk and relative infant dose were 5.1 mcg/mL and 36%, respectively, at 5 days after delivery. It was recommended that she breastfeed partially; however, she stopped breastfeeding 2 weeks after delivery due to insufficient milk production. No adverse effect was observed in either neonate. The authors suggest that while significant caution should be exercised, mothers treated with zonisamide should be able to safely breastfeed their infants in reduced amounts (ie, not exclusively) (Ando et al, 2014).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) Studies in female rats receiving zonisamide at doses of 20, 60, and 200 mg/kg (the low end of the dosing range corresponds to approximately 0.5 times the MRHD on a mg/m(2) basis), before mating and during the initial phase of gestation, exhibited signs of reproductive toxicity as indicated by decreases in corpora lutea, implantations, and live fetuses. These effects were observed at all doses (Prod Info ZONEGRAN(R) oral capsules, 2012).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) Zonisamide was not carcinogenic to mice or rats administered zonisamide at doses up to 80 mg/kg/day for 2 years. In rats, this dose is approximately equivalent to a maximum recommended human dose of 400 mg/day on a mg/m(2) day basis and, in mice, this dose is 1 to 2 times the maximum recommended human dose on a mg/m(2) day basis (Prod Info ZONEGRAN(R) oral capsules, 2012).
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