Zonisamide

Usage

• Zonisamide is an anticonvulsant medication used as adjunctive therapy for the treatment of partial seizures, with or without secondary generalization, in adults and children 6 years of age and older. It is also sometimes used off-label for binge-eating disorder.
• Pharmacological Classification: Anticonvulsant.
• Zonisamide’s mechanism of action is not fully understood but is thought to involve multiple mechanisms, including blockade of voltage-gated sodium and T-type calcium channels, which reduces neuronal excitability and inhibits the spread of seizure activity.

Alternate Names

• Zonegran (brand name)
• Zonisade (brand name for oral suspension)

How It Works

• Pharmacodynamics: Zonisamide stabilizes neuronal membranes by blocking voltage-gated sodium and T-type calcium channels, decreasing neuronal excitability. It may also enhance the inhibitory effects of gamma-aminobutyric acid (GABA).

• Pharmacokinetics:

  • Absorption: Well-absorbed orally, with peak plasma concentrations reached within 2-6 hours. Food delays but does not affect overall absorption.
  • Metabolism: Primarily metabolized in the liver, mainly by CYP3A4.
  • Elimination: Excreted by the kidneys, with a half-life of approximately 63 hours.

• Mode of Action: Zonisamide blocks voltage-gated sodium channels, inhibiting repetitive neuronal firing. It also blocks T-type calcium channels, suppressing sustained high-frequency neuronal discharges. These actions decrease neuronal excitability. Zonisamide does not appear to enhance GABAergic transmission or affect glutamate receptors.

• Elimination Pathways: Primarily renal excretion, with a minor contribution from hepatic metabolism via CYP3A4.

Dosage

Standard Dosage

Adults:

• Initial dose: 100 mg orally once a day.
• Titration: Increase at 2-week intervals by 100 mg/day, up to a maximum of 600 mg/day. The dose may be divided twice daily.
• Usual maintenance dose: 300-400 mg/day.

Children (6 years and older):

• Initial dose: 1 mg/kg orally once a day.
• Titration: Increase weekly by 1 mg/kg/day, up to a maximum dose of 8 mg/kg/day or 500 mg/day, whichever is less.

Special Cases:

• Elderly Patients: Start at a lower dose and titrate more slowly due to potential age-related decline in renal and hepatic function.
• Patients with Renal Impairment: Titrate dose more slowly and frequently monitor renal function. Avoid use in patients with GFR < 50 mL/min.
• Patients with Hepatic Dysfunction: Titrate dose more slowly in patients with mild to moderate hepatic impairment. Not recommended for severe hepatic impairment.
• Patients with Comorbid Conditions: No specific dosage adjustments are routinely recommended for patients with diabetes or cardiovascular disease. However, monitor closely for adverse effects.

Clinical Use Cases

Zonisamide is not indicated for use in acute settings such as:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations (e.g., status epilepticus, cardiac arrest)

Dosage Adjustments

Adjustments may be needed for patients with renal or hepatic impairment. Titrate slowly and monitor closely. Drug interactions with CYP3A4 inducers (e.g., phenytoin, carbamazepine) may require a higher zonisamide dose, while CYP3A4 inhibitors (e.g., ketoconazole) necessitate a lower dose.

Side Effects

Common Side Effects:

• Drowsiness, fatigue, dizziness
• Loss of appetite, weight loss
• Nausea, abdominal pain
• Cognitive impairment (memory and concentration problems)
• Headache

Rare but Serious Side Effects:

• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Suicidal ideation, worsening depression
• Metabolic acidosis
• Kidney stones
• Blood dyscrasias
• Hyperammonemia

Long-Term Effects:

• Osteopenia (with chronic metabolic acidosis)
• Cognitive impairment
• Growth retardation in children

Adverse Drug Reactions (ADR):

• Angioedema, anaphylaxis
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Contraindications

• Hypersensitivity to zonisamide or sulfonamides
• Severe hepatic impairment

Drug Interactions

• CYP3A4 Inducers: (e.g., phenytoin, carbamazepine, rifampicin, St. John’s wort) may decrease zonisamide levels.
• CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin) may increase zonisamide levels.
• Carbonic Anhydrase Inhibitors: (e.g., acetazolamide) may increase the risk of metabolic acidosis.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C. Zonisamide should be avoided during pregnancy unless the potential benefit outweighs the risk to the fetus. There is a risk of fetal harm, including major congenital malformations and decreased fetal growth.
• Zonisamide is excreted in breast milk. Breastfeeding should not be resumed until one month after discontinuing zonisamide.

Drug Profile Summary

• Mechanism of Action: Blocks voltage-gated sodium and T-type calcium channels, decreasing neuronal excitability.
• Side Effects: Drowsiness, dizziness, fatigue, loss of appetite, cognitive impairment; rarely, severe skin reactions, suicidal ideation, metabolic acidosis.
• Contraindications: Hypersensitivity to zonisamide or sulfonamides; severe hepatic impairment.
• Drug Interactions: CYP3A4 inducers and inhibitors, carbonic anhydrase inhibitors.
• Pregnancy & Breastfeeding: Avoid during pregnancy and breastfeeding.
• Dosage: Adults: 100-600 mg/day; Children: 1-8 mg/kg/day or up to 500 mg/day.
• Monitoring Parameters: Renal function, liver function, serum bicarbonate, complete blood count, mental status, growth in children.

Popular Combinations

Zonisamide is often used in combination with other antiepileptic drugs (AEDs), such as levetiracetam, lamotrigine, or valproate, to achieve better seizure control.

Precautions

• General Precautions: Monitor for suicidal thoughts, skin reactions, metabolic acidosis, kidney stones, and blood dyscrasias. Monitor growth in children.
• Specific Populations:
  • Pregnant Women: Avoid if possible.
  • Breastfeeding Mothers: Discontinue breastfeeding or the drug.
  • Children & Elderly: Adjust dose based on age and renal/hepatic function.
• Lifestyle Considerations: Advise patients about potential drowsiness and cognitive impairment and their impact on driving and operating machinery. Advise patients to maintain adequate hydration to reduce the risk of kidney stones.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Zonisamide?

A: Adults: Initial dose is 100 mg/day, titrated up to 600 mg/day as needed. Children: 1-8 mg/kg/day or up to 500 mg/day.

Q2: What are the common side effects of Zonisamide?

A: Common side effects include drowsiness, dizziness, fatigue, loss of appetite, nausea, cognitive impairment, and headache.

Q3: How is Zonisamide metabolized?

A: Primarily by hepatic CYP3A4 enzymes.

Q4: What are the serious side effects of Zonisamide?

A: Serious side effects include severe skin reactions, suicidal ideation, metabolic acidosis, kidney stones, and blood dyscrasias.

Q5: Can Zonisamide be used during pregnancy?

A: Zonisamide is generally avoided during pregnancy due to the risk of fetal harm.

Q6: Can Zonisamide be used during breastfeeding?

A: It is recommended to discontinue breastfeeding while taking Zonisamide due to its excretion in breast milk.

Q7: What are the contraindications for Zonisamide?

A: Hypersensitivity to zonisamide or sulfonamides, severe hepatic impairment.

Q8: What should be monitored in patients taking Zonisamide?

A: Renal and hepatic function, serum bicarbonate, complete blood count, mental status, and growth in children.

Q9: How does Zonisamide interact with other antiepileptic drugs?

A: CYP3A4 inducers may decrease zonisamide levels, while CYP3A4 inhibitors may increase levels.