Aripiprazole

Generic name
Aripiprazole
Brand name
ATC Code
N05AX12
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Aripiprazole

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

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Metabolization: extensively via the liver, especially via CYP3A4 and CYP2D6 inter alia to the active metabolite dehydroaripiprazole.

The following kinetic parameters were found after oral administration in children aged 10-17 years (Findling RL et al. 2008):

Aripiprazole

Dose 20 mg/day (n=6) 25 mg/day (n=5) 30 mg/day (n=6)
Cmax (ng/ml) 435 ± 137 529 ± 341 653 ± 213
Tmax (h) 2.00 (1.00-24.08) 2.05 (1.00-4.02) 2.00 (1.00-8.00)
Cl (ml/h/kg) 51.7 ± 22.0 50.4 ± 25.9 58.8 ± 27.7

Dehydroaripiprazole

Dose 20 mg/day (n=6) 25 mg/day (n=5) 30 mg/day (n=6)
Cmax (ng/ml) 100 ± 38 141 ± 51 202 ± 64
Tmax (h) 2.51 (1.00-24.08) 4.02 (1.00-24.03) 2.00 (0.00-8.00)

This study found that aripiprazole has linear pharmacokinetics. It also showed that the pharmacokinetic parameters of aripiprazole in children (10-17 years) are comparable to those in adults.

Pharmacodynamic data
study by Gründer et al. (2003) shows that the dopamine receptor occupancy (mixed antagonism and agonism) increases very quickly between 0 and 5 mg. For non-psychotic problems it is therefore justifiable to find the right dose from 1 mg/day upwards and to remain below 6 mg in general.

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

Tics, behavioural disorders and autism
  • Oral
    • 5 years up to 18 years
      • Initial dose: 1 mg/day in 1 dose
      • Maintenance dose: Depending on the effect, increase the initial dose by 1 mg every 1 to 2 weeks until the desired effect is achieved, which is usually at 1 - 5 mg/day in 1 dose

      • Doses of up to 20 mg/day have been used in the literature.

        Aripiprazole should be prescribed by a specialist in child and youth psychiatry. The dosage should be determined individually; the lowest effective dosage should be maintained.
Schizophrenia (psychoses); manic episodes with bipolar disorder (type I)
  • Oral
    • 10 years up to 18 years
      • Initial dose: 2 mg/day in 1 dose
      • Maintenance dose: depending on the effect, increase the initial dose by 2 mg every 1 to 2 weeks until the desired effect is achieved; this is usually at 10 mg/day in 1 dose. Max: 30 mg/day.

      • In individual cases, increase in steps of 5 mg/day to a maximum of 30 mg/day. In psychosis, doses of > 10 mg/day are not necessarily more effective.

        Aripiprazole should be prescribed by a specialist in child and youth psychiatry. The dosage should be determined individually; the lowest effective dosage should be maintained.

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.

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

Weight gain and weight loss: weight loss was reported more often in young people with schizophrenia and weight gain was reported more often in young people with mania [SPC Abilify].

Additionally, cases of MNS (malignant neuroleptic syndrome) have been reported in clinical studies [Croarkin 2008].

There is a higher risk of side effects in young people, especially with mania. Very common (> 10%): sleeplessness, sedation, extrapyramidal symptoms, akathisia, fatigue, low serum prolactin levels. Common (1-10%): pain in the upper abdomen, increased heart rate, weight gain, dry mouth, increased appetite, orthostatic hypotension, muscle twitches and dyskinesia.

 

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

If severe side effects occur of if there is no effect, it is possible that the metabolization of the drug may be different. CYP2D6 can determine the variation in response. Genotyping can be considered.

Treatment with aripiprazole should not be discontinued suddenly: the dosage should be gradually decreased. Aripiprazole should not be discontinued suddenly when switching from aripiprazole to another drug. Aripiprazole should be gradually decreased while the other drug is gradually increased. As with other antipsychotics, when using aripiprazole you should be aware of the occurrence of what is known as ‘malignant neuroleptic syndrome’, in which hyperthermia, extreme muscle rigidity and autonomic instability are key.

It can take days to weeks before there is improvement in the clinical condition. Patients should be strictly monitored during this period.

There is evidence that the risk of suicide lasts longer than the first 4 weeks of treatment in young people aged < 18 years.

Check for weight gain in children and adolescents; consider lowering the dose in the event of relevant weight gain.

If extrapyramidal symptoms occur, consider dose reduction and clinical monitoring.

If serious side effects occur or if the effect fails, there may be an abnormal drug metabolism. Cyp2D6 can explain the variation in response. Genotyping can be considered.

Interactions

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

ANTIPSYCHOTICS

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

Phenothiazines with aliphatic side-chain
N05AA02
Butyrophenone derivatives
N05AD01
N05AD05
Indole derivatives
N05AE05
N05AE04
Diphenylbutylpiperidine derivatives
N05AG02
Diazepines, oxazepines, thiazepines and oxepines
N05AH02
N05AH03
N05AH04
Lithium
N05AN01
Other antipsychotics
N05AX13
N05AX08

References

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  2. Biederman J, et al, Aripiprazole in the treatment of pediatric bipolar disorder: a systematic chart review, CNS Spectr, 2005, 10, 141-8
  3. Chang KD., The use of atypical antipsychotics in pediatric bipolar disorder., J Clin Psychiatry., 2008, 69 Suppl 4, 4-8
  4. Croarkin PE, et al, Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases, J Clin Psychiatry., 2008, 69, 1157-65
  5. Findling RL, et al., Tolerability and pharmacokinetics of aripiprazole in children and adolescents with psychiatric disorders: an open-label, dose-escalation study, J Clin Psychopharmacol., 2008, 28, 441-6
  6. Gibson AP, et al., Effectiveness and tolerability of aripiprazole in child and adolescent inpatients: a retrospective evaluation., Int Clin Psychopharmacol., 2007, 22, 101-5
  7. McDougle CJ, et al, Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders, J Clin Psychiatry, 2008, 69, 15-20
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  9. Yoo HK, et al, An open-label study of the efficacy and tolerability of aripiprazole for children and adolescents with tic disorders, J Clin Psychiatry, 2007, 68, 1088-93
  10. Ercan ES et al. , A promising preliminary study of aripiprazole for treatment-resistant childhood obsessive-compulsive disorder. , J Child Adolesc Psychopharmacol , 2015, 25(7), 580-4
  11. Gründer G et al., Mechanism of new antipsychotic medications: occupancy is not just antagonism., Arch Gen Psychiatry., 2003, Oct;60(10), 974-7
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  15. Findling RL et al., A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder., J Clin Psychiatry. , 2014, 75, 22-30
  16. Ghanizadeh A et al., A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial., Child Psychiatry Hum Dev., 2014, 45, 185–192.
  17. Yoo HK et al., An open-label study of the efficacy and tolerability of aripiprazole for children and adolescents with tic disorders,, J Clin Psychiatry, 2007, 68, 1088-93
  18. Yoo HK et al., A multicenter, randomized, double-blind, placebo-controlled study of aripiprazole in children and adolescents with Tourette’s disorder., J Clin Psychiatry, 2013, 74, e772–780.
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  20. Yoo HK et al. , Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders. , Eur Child Adolesc Psychiatry. , 2011, 20(3), 127-35
  21. Findling RL et al., A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia., Am J Psychiatry., 2008, 165, 1432-1441.
  22. Savitz AJ et al, Efficacy and safety of paliperidone extended release in adolescents with schizophrenia: a randomized,double-blind study. , J Am Acad Child Adolesc Psychiatry, 2015 , Feb;54(2), 126-137.e1.
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  24. Findling RL et al, Double-blind, randomized, placebo-controlled long-term maintenance study of aripiprazole in children with bipolar disorder., J Clin Psychiatry, 2012, Jan;73(1), 57-63
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  33. Yoo HK, Joung YS, Lee JS, Song DH, Lee YS, Kim JW, et al., A multicenter, randomized, double-blind, placebo-controlled study of aripiprazole in children and adolescents with Tourette's disorder, The Journal of clinical psychiatry., 2013, 74(8), 772-80
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  37. Bristol Meyers Squibb, SPC Abilify EU/1/04/276/001-011, Geraadpleegd op 5 februari 2009
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  39. Otsuka Pharma, SmPC ABILIFY® 1 mg/ml Lösung zum Einnehmen, 03/2018
  40. Neuraxpharm Arzneimittel, SmPC Aripiprazol-neuraxpharm ® 1mg/ml Lösung zum Einnehmen Saft, 07/2017
  41. Hexal, SmPC AripiHEXAL Tabletten, 11/2016
  42. Otsuka Pharma, SmPC Abilify Tabletten, 03/2018
  43. Otsuka Pharma, SmPC Abilify 5 mg, 10 mg, 15 mg, 30 mg Tabletten, 04/2015
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  45. Otsuka Pharma, SmPC ABILIFY® Schmelztabletten, 10/2016
  46. Silva RR, Munoz DM, Alpert M, Perlmutter IR, Diaz J., Neuroleptic malignant syndrome in children and adolescents., Journal of the American Academy of Child and Adolescent Psychiatry., 1999, 38(2), 187-94
  47. Ghanizadeh A, Haghighi A., Aripiprazole versus risperidone for treating children and adolescents with tic disorder: a randomized double blind clinical trial., Child psychiatry and human development., 2014, 45(5), 596-603.
  48. Findling RL et al., A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder., J Clin Psychiatry., 2014, 75, 22-30
  49. Ercan ES et al., A promising preliminary study of aripiprazole for treatment-resistant childhood obsessive-compulsive disorder., J Child Adolesc Psychopharmacol, 2015, 25(7), 580-4
  50. Ghanizadeh A et al., Aripiprazole versus risperidone for treating children and adolescents with tic disorder: A randomized double blind clinical trial., Child Psychiatry Hum Dev, 2014., 45, 596–603
  51. Yoo HK et al., Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders., Eur Child Adolesc Psychiatry., 2011, 20(3), 127-35
  52. Savitz AJ et al, Efficacy and safety of paliperidone extended release in adolescents with schizophrenia: a randomized,double-blind study., J Am Acad Child Adolesc Psychiatry, 2015, Feb;54(2), 126-137.e1.
  53. Findling RL et al., Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-week, randomized, placebo-controlled study., Bipolar Disord., 2013, Mar;15(2), 138-49

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