Zonisamide

Uses

Zonisamide is used for adjunctive therapy in the treatment of partial seizures in adults with epilepsy.

Zonisamide is also used to associated treatment for these conditions: Partial-Onset Seizures

How Zonisamide works

Zonisamide binds to sodium channels and voltage sensitive calcium channels, which suppresses neuronal depolarization and hypersynchronization. Zonisamide also inhibits carbonic anhydrase to a weaker extent, but such an effect is not thought to contribute substantially to the drug's anticonvulsant activity.

Dosage

Zonisamide dosage

Zonisamideis recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide should be administered once or twice daily, using 25 mg or 100 mg capsules. Zonisamide is given orally and can be taken with or without food. Capsules should be swallowed whole.Adults Over Age 16: The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100-200 mg/day, the increase appears small and formal dose-response studies have not been conducted.The initial dose of Zonisamide 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 100-600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day. There is little experience with doses greater than 600 mg/day.

Side Effects

The most common adverse reactions with Zonisamide (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration.In controlled clinical trials, 12% of patients receiving Zonisamide as adjunctive therapy discontinued due to an adverse reaction compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received Zonisamide in clinical studies discontinued treatment because of an adverse reaction. The most common adverse reactions leading to discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse reactions were doserelated

Toxicity

Symptoms of overdose include diminished breathing, loss of consciousness, low blood pressure, and slow heartbeat.

Precaution

Somnolence is commonly reported, especially at higher doses of Zonisamide. Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering Zonisamide to patients with hepatic and renal dysfunction

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase drowsiness and dizziness.
• Take with or without food.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Zonisamide Drug Interaction

Major: diphenhydramine, topiramateModerate: duloxetine, levetiracetam, lamotrigine, escitalopram, pregabalin, alprazolam, sertraline, cetirizineUnknown: omega-3 polyunsaturated fatty acids, polyethylene glycol 3350, albuterol, montelukast, levothyroxine, lacosamide, cyanocobalamin, ascorbic acid, cholecalciferol, ondansetron

Zonisamide Disease Interaction

Major: bone marrow depression/blood dyscrasias, oligohidrosis/hyperthermia, severe liver disease, hematologic toxicity, hypersensitivity reactions, depressionModerate: suicidal tendency, renal dysfunction, metabolic acidosis, nephrolithiasis, seizures

Volume of Distribution

• 1.45 L/kg

Elimination Route

The absorption is rapid with a time to peak concentration of 2.8-3.9 hours. Food has not effect on bioavailability.

Half Life

63 hours

Clearance

• 0.30 - 0.35 mL/min/kg [patients not receiving enzyme-inducing antiepilepsy drugs (AEDs)]
• 0.35 - 0.5 mL/min/kg [Concomitant administration of phenytoin and carbamazepine]

Elimination Route

Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite.

Pregnancy & Breastfeeding use

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's ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the non-pregnant state. 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.

Contraindication

Zonisamide is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.

Special Warning

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 monitoringPediatric Use: The safety and effectiveness of Zonisamide in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported. Zonisamide commonly causes metabolic acidosis in pediatric patients. 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 bonerelated sequelae has not been systematically investigated.Geriatric Use: Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. 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.

Acute Overdose

Human Experience: Experience with Zonisamide daily doses over 800 mg/day is limited. During Zonisamide clinical development, three patients ingested unknown amounts of Zonisamide as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1 μg/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later.Management: No specific antidotes for Zonisamide overdosage are available. Following a suspected recent overdose, emesis should be induced or gastriclavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation.Zonisamide has a long half-life. Due to the low protein binding of zonisamide (40%), renal dialysis may be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of Zonisamide overdosage.

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