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Zonisamide

AEMPS

Antiepileptic with multiple mechanisms

ATC code: N03AX15

Updated · Methodology

Indications

A

Focal epilepsy

Second line

Second-line in focal epilepsy in adults and children over 6, as monotherapy or combination per ILAE 2017 and SEN 2024. First-line is lamotrigine, levetiracetam, lacosamide. Starting dose 50 mg once daily, titrated to 300–500 mg daily. Long half-life provides stable concentration.

Sources

  1. Epilepsia: Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. (2013)
  2. AEMPS: Ficha técnica de Zonisamida (2024)
  3. Cochrane Database Syst Rev: Zonisamide add-on therapy for focal epilepsy. (2020)
  4. Lancet Neurol: Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. (2012)
  5. The Lancet: The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial (2021)

ICD-10: G40.2 · ICD-11: 8A60

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

F

Weight loss

Not recommended

Zonisamide is a sulfonamide-class antiepileptic. It is prescribed for focal epilepsy and Lennox-Gastaut syndrome ( 2018, AEMPS Ficha Técnica). Zonisamide is used off-label for weight loss based on the weight-loss side effect. In people without epilepsy, zonisamide is not approved for weight loss. The drug has serious risks: severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), nephrolithiasis (kidney stones), metabolic acidosis, oligohidrosis with heat stroke risk, cognitive disturbances, depression, and suicidal ideation. If zonisamide was prescribed for weight loss, consider seeking a second opinion.

Sources

  1. AEMPS: Ficha técnica de Zonisamida (2024)
  2. Cochrane: Green tea for weight loss and weight maintenance in overweight or obese adults (2012)
How to read tiers A–F
  • AStrong evidence – first or second line in international guidelines
  • BRecommended in selected cases
  • CStudy data contradict each other
  • DBenefit not proven, no documented harm
  • FDocumented harm, or risk without benefit

Mechanism of action

A sulfonamide derivative with multiple mechanisms: voltage-gated sodium channel and T-type calcium channel blockade, weak carbonic anhydrase inhibition. Also modulates GABAergic and dopaminergic transmission. Compared with other antiepileptics, has a long half-life (60 hours) allowing once or twice daily dosing. CYP3A4-metabolized.

Safety

Contraindications

  • Hypersensitivity to zonisamide or sulfonamides
  • Severe hepatic or renal impairment
  • Pregnancy – with caution
  • Age under 6

Serious adverse effects

  • Severe cutaneous reactions (Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS)
  • Metabolic acidosis
  • Kidney stones
  • Oligohidrosis and hyperthermia in children
  • Acute angle-closure glaucoma
  • Psychotic disorders
  • Suicidal thoughts

Common adverse effects

  • Drowsiness
  • Dizziness
  • Ataxia
  • Anorexia and weight loss
  • Paraesthesia
  • Cognitive impairment

Pregnancy: can you take Zonisamide?

T1 use raises malformation risk (cleft lip/palate, cardiac defects) 2–3 fold. In pregnant epilepsy patients, decisions are made with an epileptologist; switch to lamotrigine or levetiracetam.

Breastfeeding: can you take Zonisamide?

High milk concentrations. Use during lactation cautiously with monitoring of infant sedation and weight gain.

Calculate RIDFull profile on NIH LactMed ↗

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Timing and administration

Take once or twice daily, with or without food. Adequate hydration is important – carbonic anhydrase inhibition raises kidney stone risk by 4% with long-term use. In patients allergic to sulfonamides (thiazide diuretics, co-trimoxazole), cross-allergy risk is increased. Exclude heat-instability risk factors in children before start.
Label mentions19 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

  • MajorTopiramate
    «Inhibidores de la anhidrasa carbónica: Zonisamida no se debe utilizar concomitantemente con otros inhibidores de la anhidrasa carbónica tales como topiramato y acetazolamida en pacientes pediátricos…»

    AEMPS, section 4.5 · Open on CIMA

  • ModerateCarbamazepine
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inducción enzimática: La exposición a la zonisamida es inferior en los pacientes epilépticos que reciben agentes inductores…»

    AEMPS, section 4.5 · Open on CIMA

  • ModerateCNS depressantsclass named in the label
    «Drug Interactions: Drug Interactions with CNS Depressants: Concomitant administration of zonisamide and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of…»

    FDA, section 7 · Open on DailyMed

  • ModerateDigoxin
    «Sustrato de la P-gp: Un estudio in vitro demuestra que la zonisamida es un inhibidor débil de la P-gp (MDR1) con una CI 50 de 267 μmol/l, y en teoría existe el potencial de que la zonisamida afecte a…»

    AEMPS, section 4.5 · Open on CIMA

  • Moderateinductores del CYP3A4class named in the label
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inducción enzimática: La exposición a la zonisamida es inferior en los pacientes epilépticos que reciben agentes inductores…»

    AEMPS, section 4.5 · Open on CIMA

  • ModeratePhenobarbital
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inducción enzimática: La exposición a la zonisamida es inferior en los pacientes epilépticos que reciben agentes inductores…»

    AEMPS, section 4.5 · Open on CIMA

  • ModeratePhenytoin
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inducción enzimática: La exposición a la zonisamida es inferior en los pacientes epilépticos que reciben agentes inductores…»

    AEMPS, section 4.5 · Open on CIMA

  • ModerateQuinidine
    «Sustrato de la P-gp: Un estudio in vitro demuestra que la zonisamida es un inhibidor débil de la P-gp (MDR1) con una CI 50 de 267 μmol/l, y en teoría existe el potencial de que la zonisamida afecte a…»

    AEMPS, section 4.5 · Open on CIMA

  • ModerateRifampicin
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inducción enzimática: La exposición a la zonisamida es inferior en los pacientes epilépticos que reciben agentes inductores…»

    AEMPS, section 4.5 · Open on CIMA

  • ModerateTopiramate
    «Drug Interactions: Other Carbonic Anhydrase Inhibitors: Concomitant use of zonisamide, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or…»

    FDA, section 7 · Open on DailyMed

  • MinorLamotrigine
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: En estudios clínicos, la coadministración de lamotrigina no tuvo ningún efecto aparente en la farmacocinética de la zonisamida…»

    AEMPS, section 4.5 · Open on CIMA

  • Ethinylestradiol
    «Los estudios in vitro que utilizan microsomas de hígado humano muestran una inhibición pequeña o nula (<25 %) de las isoenzimas 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 o 3A4 del citocromo P450 con…»

    AEMPS, section 4.5 · Open on CIMA

  • inhibidores del CYP3A4class named in the label
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inhibición de CYP3A4: En función de los datos clínicos, los inhibidores de CYP3A4 específicos y no específicos conocidos no…»

    AEMPS, section 4.5 · Open on CIMA

  • Ketoconazole
    «Posibles interacciones con otros medicamentos que afecten a Zonisamida: - Inhibición de CYP3A4: En función de los datos clínicos, los inhibidores de CYP3A4 específicos y no específicos conocidos no…»

    AEMPS, section 4.5 · Open on CIMA

  • Norethisterone
    «Anticonceptivos orales: En estudios clínicos con sujetos sanos, la administración en estado estacionario con zonisamida no afectó a las concentraciones séricas del etinilestradiol ni de la…»

    AEMPS, section 4.5 · Open on CIMA

From other drugs’ labels

  • ModerateTopiramate
    «Other Carbonic Anhydrase Inhibitors: Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the…»

    FDA, section 7 · Open on DailyMed

  • Carbamazepine
    «Fármacos que pueden disminuir los niveles plasmáticos de carbamazepina: Antiepilépticos: clobazam, lamotrigina, eslicarbazepina, tiagabina, topiramato, clonazepam, etosuximida, primidona, ácido…»

    AEMPS, section 4.5 · Open on CIMA

  • Lamotrigine
    «Fármacos que tienen poco o ningún efecto en la concentración de lamotrigina: Zonisamida»

    AEMPS, section 4.5 · Open on CIMA

  • Metformin
    «DRUG INTERACTIONS: Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.»

    FDA, section 7 · Open on DailyMed

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Frequently asked

What is Zonisamide used for?

Zonisamide is evaluated for the following indications with varying evidence strength: Focal epilepsy (evidence tier A), Weight loss (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Zonisamide?

Common side effects of Zonisamide (≥ 1 in 100): Drowsiness, Dizziness, Ataxia, Anorexia and weight loss, Paraesthesia, Cognitive impairment. See the Safety section for uncommon and serious reactions.

Is Zonisamide safe during pregnancy?

T1 use raises malformation risk (cleft lip/palate, cardiac defects) 2–3 fold. In pregnant epilepsy patients, decisions are made with an epileptologist; switch to lamotrigine or levetiracetam.

Is Zonisamide compatible with breastfeeding?

High milk concentrations. Use during lactation cautiously with monitoring of infant sedation and weight gain.

Who should not take Zonisamide?

Zonisamide is contraindicated in: Hypersensitivity to zonisamide or sulfonamides; Severe hepatic or renal impairment; Pregnancy – with caution; Age under 6. Full list in the Safety section.

Official sources

Direct links to regulator labels. Open in a new tab.

Other drugs in this group

Carbamazepine, Eslicarbazepine acetate, Gabapentin, Lacosamide, Phenobarbital, Pregabalin, Lamotrigine, Levetiracetam