Clonazepam

Generic name
Clonazepam
Brand name
ATC Code
N03AE01
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Clonazepam

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

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

t½ and the Cl in neonates are similar to those in adults (SmPC). Children generally metabolize benzodiazepine agonists faster than juveniles and adults.

The following kinetic parameters have been found after intravenous administration in neonates [Andre]:

  Vd (l/kg) Cl (l/h/kg) t1/2 (h)
PNA 0.5-40 days; 
Dose 0.1 mg/kg (n=8)		 1,5-11,0 PNA 0,5-2,5 days (n=5): 0,03-0,06

PNA 25 days;40 dagen (n=2): 0,14 resp 0,15		 19,4-140
PNA 0,5-6 days; 
Dose 0.2 mg/kg
(n=9)		 1,8-4,4 0,04-0,07 22,5-74
PNA 44 days; 
Dose 0.2 mg/kg
(n=1)		 5,0 0,153 22,5-74

The following pharmacokinetic data in children were found after oral administration:

Age n= Dose Cl (ml/hour/kg) t1/2 (hour) Reference
2-18 years 10 0,01-0,085 mg/kg/day in 3-4 doses 7-64
(mean 25±19)		 - Walson et al. 1996
6-13 years 4 0,028-0,083 mg/kg/day in 3 doses - 22,1-32,7 (mean 28,7) Dreifuss et al. 1975

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

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Epilepsy
  • Oral
    • 1 month up to 18 years and < 30 kg
      • Initial dose: 0.03 mg/kg/day in 2 - 3 doses.
      • Maintenance dose: Gradually increase the initial dose by max 0.5 mg in 3 days to 0.05 - 0.1 mg/kg/day a single dose in the evening or split into 2 or 3 doses with the biggest dose in the evening. Max: 0.3 mg/kg/day.

      • Do not suddenly discontinue treatment, but taper off slowly

    • 1 month up to 18 years and ≥ 30 kg
      • Initial dose: 1 - 2 mg/day in 2 - 3 doses.
      • Maintenance dose: Gradually increase the initial dose by max 0.5 mg in 3 days to 1.5 - 4 mg/day a single dose in the evening or split into 2 or 3 doses with the biggest dose in the evening. Max: 10 mg/day.

      • Do not suddenly discontinue treatment, but taper off slowly
Status epilepticus
  • Intravenous
    • 1 month up to 18 years
      • 0.5 mg/dose Repeat if needed..

      • Antagonist: Flumazenil <include hyperlink to monograph URL>
Acute anxiety (short use)
  • Oral
    • 6 years up to 18 years
      • 0.02 - 0.1 mg/kg/day in 2 - 3 doses.
        • Start with a low initial dose and slowly increase, depending on the clinical picture.
        • Avoid administering directly into the mouth from the dropper bottle at all times! Always mix the drops with water, tea or juice and administer using a spoon.
        • Do not suddenly discontinue treatment, but taper off slowly

Renal impaiment in children > 3 months

There are no known data on dose adjustment in renal impairment. According to the manufacturer, renal impairment in adults does not affect the pharmacokinetics of clonazepam and does not require dose adjustment.

 

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

Drowsiness and hypotonia.

In infants and young children: increased salivation and bronchial hypersecretion.

Especially in children, paradoxical reactions occur with restlessness, agitation, irritability, aggression, nervousness, hostility, anxiety, sleep disturbances, delusions, anger, nightmares, abnormal dreams, hallucinations, psychoses, hyperactivity, inappropriate behavior and other behavioral disturbances. Solated cases of reversible development of preterm secondary sexual characteristics in children (incomplete pubertas praecox) have been reported (SmPC).
In neonates and particularly in preterm infants, benzyl alcohol (component of the solution for injection of Rivotril) has been associated with permanent neuropsychiatric abnormalities and multi-organ failure (SmPC).

Undiluted administration of the drip solution may cause irritation and blue discoloration of the oral mucosa.

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

Contra-indications

No information available on specific contra indications in children.

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

Intravenous administration under respiratory and blood pressure monitoring (SmPC).

In infants and toddlers, because of increased salivation and bronchial hypersecretion, adequate monitoring is required to ensure that the airways remain clear (SPC).

In these patients, very careful dose adjustment, generally dose reduction, and great care in use are required (SPC).
Slowly taper off over at least 2 weeks.

Avoid administering directly from the dropper bottle into the mouth to prevent incorrect dosing (e.g., overdose).Preferably mix the drops with water, tea, or juice and administer with a spoon.

In infants and children < 3 years of age, the benzyl alcohol in the injection may cause toxic and anaphylactoid reactions (SPC).

Rivotril drops contain propylene glycol. co-administration with an alcohol dehydrogenase substrate, such as ethanol, may cause adverse reactions in children less than 5 years of age.

Interactions

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

ANTIEPILEPTICS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Barbiturates and derivatives
N03AA02
N03AA03
Hydantoin derivatives
N03AB02
Succinimide derivatives
N03AD01
Carboxamide derivatives
N03AF01
N03AF02
N03AF03
Fatty acid derivatives
N03AG01
N03AG04
Other antiepileptics
N03AX23
N03AX24
N03AX10
N03AX26
N03AX18
N03AX09
N03AX14
N03AX22
N03AX16
N03AX17
N03AX03
N03AX11
N03AX15

References

  1. Rademaker C.M.A. et al, Geneesmiddelen formularium voor Kinderen, 2007
  2. Landelijk Kenniscentrum Kind-enJeugdpsychiatrie (Ketelaars), Anxiolytica/hypnotica - geraadpleegd dec 2018
  3. Smit LS et al. , Richtlijnen voor behandeling van neonatale epileptische aanvallen. , Nederlands Vlaamse Werkgroep Neonatale Neurologie van de sectie Neonatologie van de NVK en van de Nederlandse Vereniging voor Kinderneurologie , Nieuwe aangepaste versie juni 2012
  4. Waardenburg van DA, et al., Richtlijn status epilepticus kinderen ouder dan één maand., Nederlandse Vereniging voor Kindergeneeskunde, Augustus 2005
  5. DAZ.online, Individuell für Kinder: Einige Besonderheiten der paediatrischen Rezeptur. , Accessed May 18, 2018
  6. Roche, SmPC Rivotril 1 mg/ml Konzentrat zur Hersellung einer Injektionslösung und Lösungsmittel (6246327.00.000), 08/2017
  7. Roche, Rivotril 0,5 mg/2 mg Tabletten und 2,5 mg/ml Tropfen zum Einnehmen, Lösung (6246267.01.00, 6246267.00.00, 6246327.00.01), 11/2017
  8. Neuraxpharm, SmPC Clonazepam 2,5 mg/ml Tropfen zum Einnehmen,Lösung (84842.00.00), 07/2015
  9. Desitin, SmPC Antelepsin 0,5 mg/2 mg (45191.00.00-01.00), 06/2017
  10. Kutcher SP et al. , Successful clonazepam treatment of adolescents with panic disorder. , J Clin Psychopharmacol, 1988, 8(4), 299-301
  11. Graae F et al., Clonazepam in childhood anxiety disorders, J Am Acad Child Adolesc Psychiatry, 1994, 33(3), 372-6
  12. Roche Nederland B.V., SPC Rivotril (RVG 06870-3) 31-05-2018, www.geneesmiddeleninformatiebank.nl
  13. Bensch J. et al., A double-blind study of clonazepam in the treatment of therapy-resistant epilepsy in children, Dev Med Chil Neurol, 1977, 19, 335-42
  14. Ishikawa A. et al., Clonazepam monotherapy for epilepsy in childhood, Brain Dev, 1985, 7, 610
  15. Sugai K. et al., Seizures with clonazepam: discontinuation and suggestions for safe discontinuation rates in children, Epilepsia, 1993, 34, 1089-97
  16. Mikkelsen B. et al., Clonazepam in the treatment of epilepsy. A controlled clinical trial in simple absences, bilateral massive epileptic myoclonus, and atonic seizures., , Arch Neurol, 1976, 33, 322-5
  17. André M. et al., Clonazepam pharmacokinetics and therapeutic efficacy in neonatal seizures, Eur J Clin Pharmacol, 1986, 30, 585-9
  18. Walson PD et al., Clonazepam disposition in pediatric patients, Ther Drug Monit, 1996, 18(1), 1-5
  19. Dreifuss FE et al., Serum clonazepam concentrations in children with absence seizures, Neurology, 1975, 25(3), 255-8
  20. Breitkreutz J BJ., Paediatric and geriatric drug delivery. Expert opinion on drug delivery., 2007, 4, 37-45
  21. Mikkelsen B. et al., Clonazepam in the treatment of epilepsy. A controlled clinical trial in simple absences, bilateral massive epileptic myoclonus, and atonic seizures.,, Arch Neurol, 1976, 33, 322-5
  22. Roche, Rivotril 0,5 mg/2 mg Tabletten und 2,5 mg/ml Tropfen zum Einnehmen, Lösung (6246267.01.00, 6246267.00.00, 6246327.00.01), 11/2017
  23. DAZ.online, Individuell für Kinder: Einige Besonderheiten der paediatrischen Rezeptur., Accessed May 18, 2018
  24. Desitin, SmPC Antelepsin 0,5 mg/2 mg (45191.00.00-01.00), 06/2017
  25. Smit LS et al., Richtlijnen voor behandeling van neonatale epileptische aanvallen., Nederlands Vlaamse Werkgroep Neonatale Neurologie van de sectie Neonatologie van de NVK en van de Nederlandse Vereniging voor Kinderneurologie, Nieuwe aangepaste versie juni 2012
  26. Kutcher SP et al., Successful clonazepam treatment of adolescents with panic disorder., J Clin Psychopharmacol, 1988, 8(4), 299-301

Changes

Therapeutic Drug Monitoring


Overdose