Zonisade (zonisamide)

The initial dosage of zonisamide as adjunctive therapy for partial seizures in adults and children older than 16 years of age is 100 mg daily. After 2 weeks, the dosage may be increased to 200 mg daily for at least 2 weeks. Dosage can further be increased to 300 and 400 mg daily with at least 2 weeks between dosage changes to achieve steady state at each dosage level. Results of controlled clinical trials suggest that zonisamide dosages of 100-600 mg daily are effective; however, dosages exceeding 400 mg daily may not be associated with increased therapeutic benefit. There is only limited experience with zonisamide dosages exceeding 600 mg daily. The manufacturer states that although this dosage regimen has been shown to be tolerated, some clinicians may prefer to administer lower dosages of zonisamide for longer periods in order to fully assess safety of zonisamide at steady state, since adverse effects occur more frequently at dosages of 300 mg daily and higher.

Zonisamide is administered orally once or twice daily (except the initial daily dosage of 100 mg, which is administered once daily), without regard to meals. The capsules should be swallowed intact. Patients should be encouraged to drink plenty of fluids while taking the drug to reduce the risk of kidney stones.

Zonisamide therapy should not be discontinued abruptly; dosage reduction or discontinuance of the drug should be done gradually.

Patients currently receiving or beginning therapy with zonisamide and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Zonisamide/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zonisamide is a carbonic anhydrase inhibitor and can induce renal bicarbonate loss, resulting in metabolic acidosis. It can also reduce urinary citrate excretion and increase urinary pH, posing a risk for nephrolithiasis. As well, carbonic anhydrase inhibitors can cause decreased sweating and elevated body temperature, predisposing patients to heat-related disorders. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may result in an additive risk of all these effects.(1-2)

CLINICAL EFFECTS: The concurrent use of zonisamide with another carbonic anhydrase inhibitor may increase the risk of metabolic acidosis and kidney stone formation.(1) Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.(1) Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other carbonic anhydrase inhibitors.(1-2) Pediatric and adolescent patients must not take carbonic anhydrase inhibitors concurrently with zonisamide.(1) Check serum bicarbonate at baseline and periodically during treatment. Monitor for signs and symptoms of metabolic acidosis: hyperventilation, fatigue, anorexia, arrhythmias, stupor. Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis, or elevated body temperature occur, a decreased dose or discontinuation of zonisamide should be considered.

DISCUSSION: Zonisamide is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary citrate excretion and increase urinary pH. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the risk of metabolic acidosis and kidney stone formation and should therefore be avoided.(1) Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Carbonic Anhydrase Inhibitors/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1)

CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1)

DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1)

Zonisamide/Anticholinergics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zonisamide can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of zonisamide with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity.(1-2) Pediatric and adolescent patients must not take anticholinergic agents (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Known hypersensitivity to zonisamide, sulfonamides, or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Agranulocytosis
• Aplastic anemia
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Dehydration
• Disease of liver
• Fever
• Metabolic acidosis
• Suicidal ideation

• Depression
• Diarrhea
• Invasive surgical procedure
• Severe chronic obstructive pulmonary disease

Abdominal pain, anorexia, diarrhea, nausea, dyspepsia, constipation, dry mouth, taste perversion, headache, dizziness, ataxia, nystagmus, paresthesia, confusion, difficulty concentrating, impaired memory, mental slowing, speech abnormalities, difficulty in verbal expression, agitation and/or irritability, depression, insomnia, anxiety, nervousness, schizophrenic and/or schizophreniform behavior, somnolence, fatigue, tiredness, flu-like syndrome, ecchymosis, rhinitis, weight loss, rash, and diplopia were reported in 2% or more patients in clinical studies in which zonisamide was administered in conjunction with other anticonvulsants.

More Frequent

• Ataxia

Less Frequent

• Acute cognitive impairment
• Depression
• Ecchymosis
• Kidney stone
• Simple schizophrenia
• Skin rash

Rare or Very Rare

• Abnormal ECG
• Abnormal hepatic function tests
• Accidental fall
• Accidental injury
• Agranulocytosis
• Anemia
• Aplastic anemia
• Apnea
• Biliary calculus
• Cholecystitis
• Colitis
• Decreased sweating
• Dehydration
• DRESS syndrome
• Drug-induced psychosis
• Dyskinesia
• Dyspnea
• Encephalopathy
• Eosinophilia
• Fever
• Gastroenteritis
• Gingival hyperplasia
• Hemoptysis
• Hepatic necrosis
• Hyperammonemia
• Hyponatremia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Maculopapular rash
• Metabolic acidosis
• Oculogyric crisis
• Pancreatitis
• Rectal bleeding
• Rhabdomyolysis
• Secondary angle-closure glaucoma
• Stevens-johnson syndrome
• Suicidal ideation
• Systemic lupus erythematosus
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Agitation
• Anorexia
• Dizziness
• Drowsy
• Headache disorder
• Nausea

Less Frequent

• Acute abdominal pain
• Altered mental status
• Concentration difficulty
• Constipation
• Diarrhea
• Diplopia
• Dysarthria
• Dysgeusia
• Dyspepsia
• Fatigue
• Flu-like symptoms
• Insomnia
• Memory impairment
• Nervousness
• Nystagmus
• Paresthesia
• Rhinitis
• Symptoms of anxiety
• Vomiting
• Weight loss
• Xerostomia

Rare or Very Rare

• Aphasia
• Arthralgia
• Behavioral disorders
• Chest pain
• Conjunctivitis
• Cough
• Cramps in legs
• Dysphagia
• Edema
• Flatulence
• Gait abnormality
• General weakness
• Gynecomastia
• Hearing loss
• Hirsutism
• Hyperesthesia
• Hypoglycemic disorder
• Increased creatine kinase level
• Increased urinary frequency
• Lymphadenopathy
• Malaise
• Menstrual disorder
• Muscle weakness
• Myalgia
• Myopia
• Neck stiffness
• Palpitations
• Parosmia
• Petechiae
• Pharyngitis
• Pruritus of skin
• Stomatitis
• Syncope
• Thrombophlebitis
• Tinnitus
• Toxic amblyopia
• Urinary retention

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Safety and efficacy of zonisamide in children younger than 16 years of age have not been established. However, the drug has been used for the treatment of epilepsy in some pediatric patients+; studies conducted with pediatric patients indicate that the frequency of some adverse effects (e.g., metabolic acidosis, oligohidrosis and hyperthermia) may be increased compared with adults.

Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, have been reported in pediatric patients (1.6-17 years of age) receiving zonisamide and have sometimes resulted in heat stroke and hospitalization. (See Oligohidrosis and Hyperthermia under Warnings/Precautions: Warnings, in Cautions.) As of December 31, 2001, there were 40 reported cases of oligohidrosis and hyperthermia in patients receiving zonisamide, including 38 in the first 11 years of marketing in Japan (approximately one case per 10,000 patient-years of exposure) and 2 in the first year of marketing in the US (approximately 12 cases per 10,000 patient-years of exposure). However, it generally is recognized that postmarketing data are subject to underreporting. In many of the reported cases, oligohidrosis and hyperthermia occurred after exposure to elevated environmental temperatures; in some cases, heat stroke requiring hospitalization resulted. There have been no reported deaths associated with these adverse effects thus far.

If zonisamide is used in pediatric patients (not an FDA-labeled population), they should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather or when other drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors) are used concomitantly. (See Drug Interactions: Drugs Predisposing to Heat-related Disorders.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis and the condition may be more severe in younger patients. In an open-label trial evaluating adjunctive zonisamide therapy in pediatric patients 3-16 years of age with partial epilepsy, the incidence of a persistent decrease in serum bicarbonate to levels less than 20 mEq/L was up to 90% and generally increased with higher dosages. The incidence of persistent and abnormally low serum bicarbonate values (less than 17 mEq/L and more than 5 mEq/L decrease from pretreatment value of at least 20 mEq/L) was as high as 18% and appeared to increase with higher dosages. Although the specific effects of zonisamide on growth and bone have not been studied, chronic metabolic acidosis in pediatric patients can reduce growth rates, resulting in a reduction in the maximal height achieved. (See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions and see also Advice to Patients.)

Zonisamide may cause fetal harm; the drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should be advised to use effective contraception during zonisamide therapy. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Women who are pregnant while receiving zonisamide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; patients can enroll by calling 888-233-2334. Information on the registry also can be found on the website https://www.aedpregnancyregistry.org.

Zonisamide therapy can cause metabolic acidosis. (See Metabolic Acidosis under Warnings/Precautions: Warnings, in Cautions.) The effect of zonisamide-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor. Therefore, pregnant women receiving zonisamide should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients. In addition, neonates born to women treated with zonisamide should be monitored for metabolic acidosis because of possible drug transfer to the fetus and possible occurrence of transient metabolic acidosis following birth.

Some clinicians recommend closely monitoring plasma zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.

Zonisamide is distributed into milk. Because of the potential for serious adverse reactions to zonisamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Clinical studies of zonisamide did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adults. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies. (See Dosage and Administration: Special Populations.)