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

Interactions
PK
Renal impairment
References

Clozapine

Generic name
Clozapine
Brand name
ATC Code
N05AH02

Pharmacokinetics in children

Metabolization: primarily via CYP1A2 and to a lesser extent via CYP3A4, CYP2C19 and CYP2D6. Norclozapine is the most important (active) metabolite.

Children (n=6, 9-16 years) have an average clearance of 1.7 l/kg/hour.

 

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

No information is present at this moment.

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Available formulations

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Dosages

Therapy-resistant psychosis
  • Oral
    • 12 years up to 18 years
      • Initial dose: 12.5 - 25 mg/day in 1 - 2 doses.
      • Maintenance dose: depending on the effect and side effects, the starting dose can be increased after a few days by steps of 25-50 mg over 2-3 weeks to a maximum of 25 - 300 mg/day in 2 - 3 doses.
      • Directions for administration:

        The total daily dose can be administered in different amounts, with the largest part in the evening. When the daily dose is not greater than 200 mg, a single administration in the evening is sufficient.

      • After that, increase the daily dose if necessary up to the effective dosage (usually 200-450 mg/day distributed over multiple doses), occasionally up to a maximum of 900 mg/day.

        Because of the risk of acute withdrawal symptoms (cholinergic rebound), the treatment should be stopped gradually.
        After reaching a maximum therapeutic effect, many patients can be adjusted effectively to a lower dose. Careful downward titration to a quantity of 150 to 300 mg/day is recommended.

        Clozapine should be prescribed by a child and youth psychiatry specialist. The dose should be determined individually and the lowest possible dose should be used.

         

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

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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

Children seem to be more sensitive to the dose-dependent side effects such as leukopenia and agranulocytosis. In addition to granulocytopenia and agranulocytosis, the following side effects also occur: sedation, akinesia, dyslipidaemia.

 

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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

Myeloproliferative conditions, severe kidney or heart diseases (such as myocarditis or cardiomyopathy induced by clozapine in the previous history) and an extended QTc interval. If there is a previous history of granulocytopenia or agranulocytosis caused by other medication, treatment with clozapine can be considered under careful monitoring of the leukocytes, e.g. twice weekly.

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

Summary: Because of the risk of neutropenia, be aware of signs of infection. The blood counts should also be checked. Making an EEG is recommended. Discontinue cardiomyopathy treatment in cases of myocarditis. Checking the weight is necessary. It is also recommended that blood pressure, fasting glucose levels, glucose 2 hours after a normal breakfast and fasting total cholesterol should be monitored.

Prescribing doctors should follow the requisite safety precautions strictly. On every visit, patients receiving clozapine should be reminded to contact the treating physician immediately if an infection of any kind whatsoever starts developing. Special attention should be paid to flu-like complaints such as fever or a sore throat and other signs of infection that could indicate neutropenia. Neutropenia occurs more often in children than in adults (Maher 2013)

The white blood cell counts (numbers and differentiation) are to be determined prior to treatment with clozapine. After the start of the treatment, the blood count should be checked weekly during the first 18 weeks. Afterwards, the blood count should be checked at least once every month for the duration of the treatment.

Making an EEG before starting medication is also recommended when using clozapine due to the epileptogenic side effects and the associated EEG changes. Clozapine is also associated with an elevated risk of myocarditis. If myocarditis or cardiomyopathy is suspected, the treatment should be stopped immediately and the patient referred to a cardiologist.

Due to the significant chance of weight gain (with an increased risk of developing diabetes and an elevated level of triglycerides in the blood), checking the weight is necessary. It is also recommended that monitor blood pressure, fasting glucose levels, glucose 2 hours after a normal breakfast and fasting total cholesterol (if elevated: also HDL, LDL and triglycerides) should be monitored before starting the medication, after 3 months and then yearly.

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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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Phenothiazines with aliphatic side-chain
N05AA02
Butyrophenone derivatives
N05AD01
N05AD05
Indole derivatives
N05AE05
N05AE04
Diphenylbutylpiperidine derivatives
N05AG02
Diazepines, oxazepines, thiazepines and oxepines
N05AH03
N05AH04
Lithium
N05AN01
Other antipsychotics
N05AX12
N05AX13
N05AX08

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References

  1. Findling RL, et al, Is there a role for clozapine in the treatment of children and adolescents?, J Am Acad Child Adolesc Psychiatry, 2007, 46, 423-8
  2. Fleischhaker C, et al, Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone., J Neural Transm., 2008, 115, 1599-608
  3. Fleischhaker C, et al, Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics, J Child Adolesc Psychopharmacol., 2006, 16, 308-16
  4. Frazier JA, et al, Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia, J Clin Psychopharmacol, 2003, 23, 87-91.
  5. Gerbino-Rosen G, et al, Hematological adverse events in clozapine-treated children and adolescents, J Am Acad Child Adolesc Psychiatry, 2005, 44, 1024-31
  6. Jacobsen LK, et al, Clozapine in the treatment of a young adolescent with schizophrenia., J Am Acad Child Adolesc Psychiatry, 1994, 33, 645-50
  7. Kumra S, et al, Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison., Arch Gen Psychiatry., 1996, 53, 1090-7
  8. Kumra S, et al, Clozapine and \"high-dose\" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison, Biol Psychiatry, 2008, 63, 524-9
  9. Shaw P, et al, Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison., Arch Gen Psychiatry, 2006, 63, 721-30
  10. Sporn AL, et al, Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome., J Am Acad Child Adolesc Psychiatry., 2007, 46, 1349-56
  11. Maher KN et al. , Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia. , J Child Adolesc Psychopharmacol., 2013, Mar;23(2), 110-6
  12. Mylan Healthcare, SmPC Leponex® 25 mg/100 mg Tabletten (6499028.00.00), 04/2019
  13. Mylan Healthcare, SmPC Leponex® 50 mg Tabletten ( 3000702.00.00), 04/2019
  14. neuraxpharm, SmPC Clozapin-neuraxpharm® 25 mg/ 50 mg/ 100 mg/ 200 mg (41376.00.00), 01/2017
  15. neuraxpharm, SmPC Clozapin-neuraxpharm® 50 mg/ml Suspension zum Einnehmen (73495.00.00), 02/2018
  16. Gelbe Liste Online, https://www.gelbe-liste.de/, aufgerufen 02/2020
  17. Gerlach M, Mehler-Wex C, Walitza S, Warnke A, Wewetzer C., Neuro-/Psychopharmaka im Kindes- und Jugendalter: Grundlagen und Therapie, 3. Auflage. Springer-Verlag Berlin Heidelberg., 2016
  18. Maher KN et al., Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia., J Child Adolesc Psychopharmacol., 2013, Mar;23(2), 110-6
  19. Gelbe Liste Online, https://www.gelbe-liste.de/, aufgerufen 02/2020

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Changes

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