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

Phenothiazines with aliphatic side-chain
	Levomepromazin Related Medicines Menu">	N05AA02

Butyrophenone derivatives
	Haloperidol Related Medicines Menu">	N05AD01
	Pipamperone (as the hydrochloride) Related Medicines Menu">	N05AD05

Indole derivatives
	Lurasidon Related Medicines Menu">	N05AE05
	Ziprasidon Related Medicines Menu">	N05AE04

Diphenylbutylpiperidine derivatives
	Pimozide Related Medicines Menu">	N05AG02

Diazepines, oxazepines, thiazepines and oxepines
	Clozapine Related Medicines Menu">	N05AH02
	Olanzapine Related Medicines Menu">	N05AH03
	Quetiapine Related Medicines Menu">	N05AH04

Lithium
	Lithium Related Medicines Menu">	N05AN01

Other antipsychotics
	Paliperidon Related Medicines Menu">	N05AX13
	Risperidone Related Medicines Menu">	N05AX08

References

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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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