Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Zonisamide

Generic name
Zonisamide
Brand name
ATC Code
N03AX15

Pharmacokinetics in children

The limited data that is available shows that the pharmacokinetics in children and adolescents dosed to a steady state at 1, 7 or 12 mg/kg per day in divided doses are in line with those seen for adults after adjustment for the bodyweight. A population pharmacokinetic study of Hashimoto 1994 shows a Vd of 1,27 L/kg.

Suzuki 1997, Yanai 1999, Suzuki 2001 and Suzuki 2002 indicate a therapeutic range of 10-30 µg/ml. These studies and the studies of Kawawaki 1999, Lotze 2004 and Yanagaki 2005 show a Cmax of 5.2-38.9 µg/ml with a dose of 4-22 mg/kg/day.

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

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Available formulations

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Dosages

Epilepsy, adjuvant therapy: WITHOUT CYP3A4-inducing substances
  • Oral
    • 1 month up to 18 years
      • Initial dose: 1 mg/kg/day in 1 dose During the first 2 weeks.
      • Maintenance dose: then increase the starting dose based on the clinical effect at two-weekly intervals in steps of 1 mg/kg/day to 2 - 8 mg/kg/day in 1 dose. Max: 500 mg/day.

      • The usual maintenance dose is 6-8 mg/kg/day.
        When discontinuing, reduce gradually in weekly steps of 2 mg/kg

    • 1 month up to 18 years
      [1] [3] [4] [7] [10] [11] [12] [15] [17] [19] [20] [22] [23]
      • Initial dose: 1 mg/kg/day in 1 dose During the first 2 weeks.
      • Maintenance dose: then increase the starting dose based on the clinical effect at two-weekly intervals in steps of 1 mg/kg/day to 2 - 8 mg/kg/day in 1 dose. Max: 500 mg/day.

      • The usual maintenance dose is 6-8 mg/kg/day.
        When discontinuing, reduce gradually in weekly steps of 2 mg/kg
West’s syndrome
  • Oral
    • 1 month up to 18 years and < 25 kg
      • Initial dose: 1 - 3 mg/kg/day in 1 dose during 2-4 days..
      • Maintenance dose: then increase the starting dose based on the clinical effect every 2-4 days in steps of 1 mg/kg/day to 2 - 20 mg/kg/day in 1 dose

      • When discontinuing, reduce gradually in weekly steps of 2 mg/kg
        Dose may be administerred in two divided doses when side effects occur

    • 1 month up to 18 years and ≥ 25 kg
      • Initial dose: 1 - 3 mg/kg/day in 1 dose during 2-4 days..
      • Maintenance dose: then increase the starting dose based on the clinical effect every 2-4 days in steps of 1 mg/kg/day to max 500 mg/day in 1 dose

      • When discontinuing, reduce gradually in weekly steps of 2 mg/kg
        Dose may be administerred in two divided doses when side effects occur

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
Dose adjustment not needed
GFR 30-50 ml/min/1.73 m2
Consider slower uptitration of dose
GFR 10-30 ml/min/1.73 m2
Consider slower uptitration of dose
GFR < 10 ml/min/1.73 m2
A general recommendation for dose adjustment is not provided
Clinical consequences

Renal clearance of zonisamide decreases in patients with renal impairment. This increases the risk of side effects.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Zonegran can cause weight loss, which can potentially be more severe in children. Additionally: pneumonia, dehydration, reduced transpiration, abnormal hepatic function test results, middle ear inflammation, pharyngitis, sinusitis and infection of the upper respiratory tract, coughing, epistaxis and rhinitis, abdominal pain, vomiting, rashes and eczema and fever are reported more often than in adults; amnesia, elevated creatinine levels, lymphadenopathy and thrombocytopenia are reported less often.
 

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

Underweight

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Early in the treatment, there is a risk of hyperchloraemic non-anion gap metabolic acidosis; metabolic acidosis occurs more often in children and younger patients in particular and it is more severe. In children and if there are indications of metabolic acidosis or risk factors for it, the bicarbonate level should be monitored.

Because of the risk of heat stroke and dehydration, which can lead to brain damage and death in children, the following precautions should be taken with children: keep the child cool in very warm weather and avoid physical exercise; get the child to drink plenty of cold water; avoid use of carbonic anhydrase inhibitors and anticholinergic drugs. If the child feels hot with little or no transpiration, or if the child becomes confused or gets muscle cramps, or if the heart rate or respiration rate is elevated: move the child to a cool place, cool the skin with water and give them cold water to drink.

Do not use in children whose weight is too low (as defined by the WHO in the age-adjusted BMI categories) or if the appetite is reduced. The effect of weight loss in children or of low bicarbonate levels on growth and development in the long term is not known.In a placebo-controlled study in children, the number of patients with impaired cognition in the zonisamide group was higher compared to the placebo group.

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Barbiturates and derivatives
N03AA02
N03AA03
Hydantoin derivatives
N03AB02
Succinimide derivatives
N03AD01
Benzodiazepine derivatives
N03AE01
Carboxamide derivatives
N03AF01
N03AF02
N03AF03
Fatty acid derivatives
N03AG01
N03AG04
Other antiepileptics
N03AX23
N03AX24
N03AX10
N03AX26
N03AX18
N03AX09
N03AX14
N03AX22
N03AX16
N03AX17
N03AX03
N03AX11

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References

  1. Eisai Limited, SmPC Zonegran (EU/1/04/307/001-021) 10-05-2019, www.ema.europa.eu
  2. Hashimoto, Y., et al, Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients, Biol Pharm Bull, 1994, 17 (2), 323-6
  3. Lee, Y. J., et al, Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy, Brain Dev, 2010, 32(3), 208-12
  4. Santos, C. C., et al, Use of zonisamide in pediatric patients, Pediatr Neurol, 2005, 33(1), 12-4
  5. Suzuki, Y. et al, Zonisamide monotherapy in newly diagnosed infantile spasms, Epilepsia, 1997, 38(9), 1035-8
  6. Yum, M. S., et al, Zonisamide in West syndrome: an open label study, Epileptic Disord, 2009, 11(4), 339-44
  7. You, S. J., et al, Clinical efficacy of zonisamide in Lennox-Gastaut syndrome: Korean multicentric experience., Brain Dev, 2008, 30(4), 287-90
  8. Yanai, S., et al, Treatment of infantile spasms with zonisamide, Brain Dev, 1999, 21(3), 157-61
  9. Yanagaki, S., et al, Zonisamide for West syndrome: a comparison of clinical responses among different titration rate., Brain Dev, 2005, 27(4), 286-90
  10. Wilfong, A., et al, Zonisamide for absence seizures, Epilepsy Res, 2005, 64(1-2), 31-4
  11. Thampratankul, L., et al, Efficacy and safety of zonisamide in Thai children and adolescents with intractable seizures., J Child Neurol, 2015, 30(4), 527-31
  12. Tan, H. J., et al, Effectiveness and tolerability of zonisamide in children with epilepsy: a retrospective review., Seizure, 2010, 19(1), 31-5
  13. Suzuki, Y., Long-term response to zonisamide in patients with West syndrome., Neurology, 2002, 58(10), 1556-9
  14. Suzuki, Y., Zonisamide in West syndrome, Brain Dev, 2001, 23(7), 658-61
  15. Shinnar, S., et al, Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy., Eur J Paediatr Neurol, 2009, 13(1), 3-9
  16. Ohtahara, S, Zonisamide in the management of epilepsy--Japanese experience., Epilepsy Res, 2006, 68 Suppl 2, S25-33
  17. Mandelbaum, D. E., et al, Broad-spectrum efficacy of zonisamide at 12 months in children with intractable epilepsy., J Child Neurol, 2005, 20(7), 594-7
  18. Lotze, T. E., et al, Zonisamide treatment for symptomatic infantile spasms., Neurology, 2004, 62(2), 296-8
  19. Kluger, G. et al, Long-term use of zonisamide in refractory childhood-onset epilepsy., Eur J Paediatr Neurol, 2008, 12(1), 12-23
  20. Kim, H. L., et al, Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center, J Child Neurol, 2005, 20(3), 212-9
  21. Kawawaki, H. et al, Efficacy of zonisamide in West syndrome, No To Hattatsu, 1999, 31(3), 263-7
  22. Iinuma, K., et al, Clinical efficacy of zonisamide in childhood epilepsy after long-term treatment: a postmarketing, multi-institutional survey.", Seizure, 2004, 13 Suppl 1, S34-9; discussion S40
  23. Coppola, G., et al, Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study, Epilepsy Res, 2009, 83 (2-3), 112-6
  24. Angappan, D. et al, Safety, tolerability, and effectiveness of oral zonisamide therapy in comparison with intramuscular adrenocorticotropic hormone therapy in infants with West syndrome, Eur J Paediatr Neurol, 2019, 23(1), 136-42

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Changes

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