Zonisamide

Pronunciation: zoe-NIS-a-MIDE
Class: Anticonvulsant, Sulfonamide

Trade Names

Zonegran
- Capsules, oral 25 mg
- Capsules, oral 100 mg

Zonisamide
- Capsules, oral 50 mg

Pharmacology

Unknown; however, may produce anticonvulsant effects through action at sodium and calcium channels.

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Pharmacokinetics

Absorption

The C _max is 2 to 5 mcg/mL and T _max is 2 to 6 h. Steady state is achieved within 14 days. T _max is delayed to 4 to 6 h in the presence of food.

Distribution

The apparent Vd is approximately 1.45 L/kg. It is approximately 40% bound to plasma proteins and extensively binds to erythrocytes, resulting in an 8-fold higher concentration in RBCs than plasma.

Metabolism

Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2-sulfamoylacetyl phenol (SMAP).

Elimination

Renal Cl is approximately 3.5 mL/min. Elimination half-life is approximately 63 h. Excreted primarily in urine as parent drug and as glucuronide metabolite. Approximately 62% is recovered in urine and approximately 3% in feces by day 10. Plasma Cl is approximately 0.3 to 0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs.

Special Populations

Renal Cl decreases with decreased renal function. Marked renal impairment (CrCl less than 20 mL/min) was associated with an increase in AUC of 35%.

The pharmacokinetics in patients with impaired liver function have not been studied.

The pharmacokinetics were similar in younger and elderly subjects.

Information on the effect of gender on the pharmacokinetics is not available.

Information on the effect of race on the pharmacokinetics is not available.

Indications and Usage

Adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Unlabeled Uses

Binge eating disorder; weight gain or obesity; use in children to treat infantile spasms and/or partial generalized seizures.

Contraindications

Hypersensitivity to sulfonamides or zonisamide.

Dosage and Administration

PO 100 mg/day initially, may increase dosage by 100 mg/day every 2 wk to the usual effective dosage range of 100 to 600 mg/day (no additional benefit has been demonstrated with dosages above 400 mg/day).

General Advice

• Administer capsules once or twice daily with or without food.
• Capsules should be swallowed whole.
• Dose reduction or discontinuation should be done gradually.

Storage/Stability

Store between 59° and 86°F. Protect from moisture and light.

Drug Interactions

Concomitant use may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Monitor closely.

Additive CNS depression as well as other cognitive and/or neuropsychiatric adverse events may occur. Use with caution.

May increase the metabolism and Cl and decrease the half-life of zonisamide.

Adverse Reactions

CNS

Somnolence (17%); dizziness (13%); headache (10%); agitation/irritability (9%); fatigue (8%); tiredness (7%); ataxia, confusion, depression, difficulty concentrating, difficulty with memory, insomnia (6%); speech abnormalities (5%); mental slowing, nystagmus, paresthesia (4%); anxiety (3%); difficulty in verbal expression, nervousness, schizophrenic/schizophreniform behavior (2%); abnormal gait, asthenia, convulsion, hyperesthesia, incoordination, tremor (at least 1%).

Dermatologic

Rash (3%); pruritus (at least 1%).

EENT

Diplopia (6%); amblyopia, tinnitus (at least 1%).

GI

Anorexia (13%); nausea (9%); abdominal pain (6%); diarrhea (5%); dyspepsia (3%); constipation, dry mouth, taste perversion (2%); vomiting (at least 1%).

Respiratory

Rhinitis (2%); increased cough, pharyngitis (at least 1%).

Miscellaneous

Flu syndrome (4%); weight loss (3%); ecchymosis (2%); accidental injury (at least 1%).

Precautions

Pregnancy

Category C . Zonisamide may cause serious adverse fetal effects, based on clinical and nonclinical data.

Lactation

Excreted in breast milk.

Children

Safety and efficacy in children younger than 16 y not established.

Elderly

Select dose with caution and start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of comorbidity.

Hypersensitivity

May present as fatal or severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

Renal Function

Do not use in patients with renal failure (if glomerular filtration rate is less than 50 mL/min).

Hepatic Function

Use with caution.

Hazardous Tasks

May cause drowsiness and fatigue, which may impair the ability to perform tasks such as driving or operating machinery.

CNS effects

Frequent CNS adverse reactions, including depression, psychosis, psychomotor slowing, somnolence, fatigue, and difficulty with concentration, speech, or language, have occurred.

Creatine kinase elevations/pancreatitis

Have been reported. Discontinue zonisamide if myopathy or pancreatitis is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

Hematologic effects

Aplastic anemia and agranulocytosis have been reported.

Kidney stones

May occur.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (ie, decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) may occur.

Oligohidrosis and hyperthermia

Oligohidrosis, sometimes resulting in heat stroke and hospitalization, has been reported in pediatric patients.

Renal effects

Increases in serum creatinine and BUN have occurred. Discontinue in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration.

Serious skin reactions

Severe rash (eg, Stevens-Johnson syndrome, TEN) has occurred. Consider discontinuing zonisamide in patients who develop an unexplained rash.

Status epilepticus

Has been reported.

Sudden unexplained death in epilepsy

Has occurred.

Suicidal behavior and ideation

May increase the risk of suicidal thoughts or behavior.

Withdrawal seizures

Abrupt withdrawal may precipitate increased seizure frequency or status epilepticus; gradually discontinue or decrease dose.

Overdosage

Symptoms

Bradycardia, CNS symptoms, coma, hypotension, respiratory depression.

Patient Information

• Advise patient to read the Medication Guide before starting therapy and with each refill.
• Advise patient to increase fluid intake (6 to 8 glasses of water per day) to reduce the risk of kidney stone formation.
• Advise patient that if medication needs to be discontinued it will be slowly withdrawn over a period of weeks unless safety concerns (eg, rash) require a more rapid withdrawal.
• Caution patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise women of childbearing potential to use effective contraception during treatment with zonisamide.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding.
• Instruct patient to contact health care provider immediately if a skin rash, sudden back pain, abdominal pain, blood in urine, fever, sore throat, oral ulcers, easy bruising, depression, unusual thoughts, speech or language problems, decreased sweating, or rise in body temperature develop.
• Instruct parent or caregiver to contact health care provider immediately if a child taking zonisamide is not sweating as usual with or without a fever.
• Instruct patient to inform health care provider if seizures become worse or if new types of seizures occur.
• Tell patients to contact their health care provider if they develop severe muscle pain and/or weakness.
• Advise patients to contact their health care provider immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heartbeat or palpitations, which are possible manifestations of metabolic acidosis.
• Counsel patients, their caregivers, and families that antiepileptic drugs, including zonisamide, may increase the risk of suicidal thoughts, behavior, or thoughts about self harm. Behaviors of concern should immediately be reported to their health care provider.

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