Pharmacokinetics in children

A pharmacokinetic study of 8 adolescents (6-18 years) under steady state conditions at an average oral dose of 19 mg reported the following data  [Grothe 2000]:

Cmax (ng/ml)	Tmax (h)	t½ (h)	Cl (l/h)
115.6 ± 26.7	4.7 ± 3.7	37.2 ± 5.1	9.6 ± 2.4

The pharmacokinetics of olanzapine are similar between adolescents (13-17 years) and adults. In clinical studies, the mean olanzapine exposure in adolescents was approximately 27% higher. Demographic differences between adolescents and adults include lower mean body weight and fewer smokers among adolescents. Such factors may contribute to higher mean exposure in adolescents [SmPC Zyprexa].

A pop-PK study studied 45 children, with a median age of 3.8 years (range: 0.2–19.2 years) and a mean body weight of 14.1 kg (range: 4.2–111.7 kg). The children received olanzapine for schizophrenia (n = 1), anxiety (n = 10), and ‘other’ indications (n = 34). Following enteral administration (oral or via feeding tube) of olanzapine, the median dose was 0.1 mg/kg (range: 0.03–0.27 mg/kg). A parabolic relationship between olanzapine half-life and postnatal age was observed. Longer half-lives were observed in infants <5 months and children ≥6 years. Comparatively, shorter half-lives were observed for participants aged 6 months to <6 years. This pattern can be attributed to the ontogeny of physiological processes modulating olanzapine hepatic clearance, which have yet to reach full maturation in younger children. The reported parameters are described in the table below [Maharaj 2021].  

PNA (years)	N	Cl/F (L/h/kg)	Cl70kg/F (L/h)	Half-life (h)
<2 years	17	0.35 (0.14-1.41)	7.86 (2.32-31.39)	18.56 (4.65-46.65)
2-<6 years	10	0.50 (0.18-1.7)	15.16 (7.23-50.31)	13.36 (3.86-35.86)
6-<12 years	11	0.24 (0.15-0.78)	13.96 (6.34-44.71)	26.92 (8.42-42.72)
≥12 years	7	0.23 (0.12-0.47)	18.69 (8.74-34.01)	28.93 (14.11-56.44)
Overall	45	0.37 (0.12-1.7)	12.79 (2.32-50.31)	17.65 (3.86-56.44)

Data are expressed as median (min-max) 
PNA, postnatal age; CL/F, olanzapine apparent clearance; and CL70kg/F, olanzapine apparent clearance scaled to 70 kg.

Another popPK study reported the kinetic parameters summarized below. In this analysis, 151 children were included, with a median age of 15.34 ± 1.63 years (range 10–17) and a median body weight of 53.05 ± 12.75 kg (range 25–120). Participants received olanzapine at a median dose of 8.24 ± 4.27 mg (range 1.25–30). Various dosing regimens (5-20 mg) were simulated to achieve a target concentration of 20 ng/mL. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly [Xiao 2022].  

V/F (L)	322
t1/2 (h)	33
Steady state (days)	10
Cl/F (L/h)	15.4

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

Anorexia nervosa
Oral 9 years up to 18 years 2.5 - 12.5 mg/day in 1 dose Only limited clinical research has been carried out into the use of olanzapine in children with anorexia nervosa. Olanzapine should be prescribed by a specialist in child and youth psychiatry. The dosage should be set individually and the lowest possible dose should be used.

Intervention medication for acute psychotic crises

Intramuscular 12 years up to 18 years 5 - 10 mg/dose, once only. If necessary, repeat after 2 hours but not more than 3 times per 24 hours and not more than 3 days in a row. Maximum of 20 mg/day (oral plus intramuscular).. Only if oral medication is refused or does not have the desired effect. Olanzapine should be prescribed by a specialist in child and youth psychiatry. The dosage should be set individually and the lowest possible dose should be used.

Prevention and treatment of chemotherapy-induced nausea and vomiting (CINV)
Oral 2 years up to 18 years 0.14 mg/kg/day in 1 dose. Max: 10 mg/day. Round down to the nearest lower tablet strength  On day 1-4 of chemotherapy Preferably take dose in the evening Evidence for children <5 years is limited

State of arousal or motoric agitation in Autism spectrum disorder (ASD), mania and psychosis

Oral 12 years up to 18 years Initial dose: 2.5 mg/day in 1 dose Maintenance dose: should be titrated slowly (2.5 mg/week) depending on the effect and the side effects to a maximum of 20 mg/day in 1 dose Directions for administration: The dose should preferably be taken in the evening. Note: The maximum dose is 20 mg/day because sedation and extrapyramidal side effects occur at this dose. However, the drug already has strong metabolic side effects even at lower doses, which means that further increases in the daily dose must be weighed up carefully. Olanzapine should be prescribed by a specialist in child and youth psychiatry. The dosage should be set individually and the lowest possible dose should be used.

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

In adolescents (aged 13–17), some side effects occur more frequently than in adults, or different side effects may occur [SmPC Zyprexa]:

• Very common: weight gain, elevated triglyceride levels, increased appetite, sedation, elevated ALT and AST, decreased total bilirubin, increased γ-GT, elevated prolactin levels.
• Common: elevated cholesterol levels, dry mouth. [SmPC Zyprexa]

The following side effects are observed in paediatrics aged 2-17 years:  

• Very common (≥10%); weight gain (≥7% of baseline, cumulative with treatment duration), increased appetite, increased triglyceride levels, sedation, drowsiness, hypersomnia, lethargy, increases in hepatic transaminases (ALT/AST), decreased total bilirubin, increased GGT, increased plasma prolactin levels.   
• Common (≥1% and <10%): elevated cholesterol levels, dry mouth. In addition, dizziness, constipation [Moshayedi 2021; Sammadar 2017; Moothedath 2022], orthostatic hypotension, akathisia, extrapyramidal phenomena and elevated glucose concentrations occur.
• Furthermore, a number of cases of Malignant Neuroleptic Syndrome (NMS) have also been described in the literature [Croarkin 2008], ECG abnormalities, anxiety, headache, gastrointestinal side effects, hypersalivation, dry eyes and nose [Flank 2014], headache [Radhakrishnan 2020], feeling of tension and agitation [Fekete 2017]. 

Controlled data on efficacy in adolescents (aged 13 to 17 years) are limited to short-term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving fewer than 200 adolescents. Olanzapine was used in a flexible dosage starting at 2.5 mg/day and increasing to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight than adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides and prolactin was greater in adolescents than in adults. There is no controlled data on the maintenance of effect or on long-term safety. Information on long-term safety is mainly limited to open-label, uncontrolled data [SmPC Zyprexa]. 

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

Summary: Because of the strong metabolic side effects, only prescribe in exceptional circumstances. Follow up if the use is prolonged because of the potential for effects on the capacity to learn. Inform patients about the increase in bodyweight. Fasting glucose and lipid levels should be determined. Caution is recommended in cases of hepatic impairment, diabetes mellitus, convulsions, bone marrow depression and abnormal blood counts. Discontinue the treatment in hepatitis. Regular clinical checks of the endocrine status are recommended.

Because of the major metabolic side effects, olanzapine should only be prescribed under exceptional circumstances.

Sedation with olanzapine should be closely monitored in adolescents because there are potential consequences for their learning ability. Changing the moment of administration may possibly improve the impact of sedation on concentration for adolescents.

When prescribing olanzapine, the patient and parents should be warned about the increase in appetite and bodyweight. The baseline weight needs to be determined and monitored. It is recommended that recommendation on diet and exercise should be given. Caution is recommended in the presence of or with risk factors for diabetes mellitus, convulsions and bone marrow depression, and with a low leukocyte and/or neutrophil count, hypereosinophilia, myeloproliferative diseases.

The fasting glucose and lipid levels should be determined before and during treatment with olanzapine (e.g. after 1 month, 3 months and then every six months or every year).

Caution is needed in patients with hepatic function disorders or elevated liver transaminases (ALAT/ASAT). In cases of elevated ALAT and/or ASAT during treatment, this should be checked periodically and dose reduction considered. Treatment should be discontinued in cases where hepatitis has been diagnosed.
In particular, it is recommended that patients with diabetes and patients with risk factors for developing diabetes mellitus should be given appropriate clinical follow-up in which regular glucose monitoring is recommended. In addition, in patients with dyslipidaemia and risk factors for developing lipid disorders, lipid increases should be regulated in a clinically appropriate way. Regular monitoring for extrapyramidal symptoms and other motor disorders is also recommended.

Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation in adolescents, regular clinical monitoring of the endocrine status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual function and other possible effects of prolactin.

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
	Quetiapine Related Medicines Menu">	N05AH04

Lithium
	Lithium Related Medicines Menu">	N05AN01

Other antipsychotics
	Aripiprazole Related Medicines Menu">	N05AX12
	Paliperidon Related Medicines Menu">	N05AX13
	Risperidone Related Medicines Menu">	N05AX08

References

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11. Sikich L, Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study., Am J Psychiatry, 2008, Nov;165(11), 1420-31
12. Tohen M, et al, Olanzapine versus placebo in the treatment of adolescents with bipolar mania, Am J Psychiatry, 2007, 164, 1547-56
13. Fekete S et al, Therapeutic Drug Monitoring in Children and Adolescents Under Pharmacotherapy With Olanzapine in Daily Clinical Practice, Ther Drug Monit., 2017, Jun;39(3), 273-281
14. Flank J et al., The safety of olanzapine in young children: a systematic review and meta-analysis., Drug Saf, 2014, Oct;37(10), 791-804
15. Pisano S et al., Second generation antipsychotics in adolescent anorexia nervosa: a new hypothesis of eligibility criteria., J Child Adolesc Psychopharmacol., 2014, Jun;24(5), 293-5
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17. Leggero C et al., Low-dose olanzapine monotherapy in girls with anorexia nervosa, restricting subtype: focus on hyperactivity., J Child Adolesc Psychopharmacol., 2010, Apr;20(2), 127-33
18. Kenniscentrum Kind,- en Jeugdpsychiatrie, Ingrijpmedicatie protocol 2016. , www.kenniscentrum-kjp.nl
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20. Flank T. et al., Olanzapine for prevention of chemotherapy-induced nausea and vomiting in children and adolescents: a multi-center, feasibility study., Supportive Care in Cancer, 2018, 26(2), 549-55
21. Maharaj A.R., et al., Population pharmacokinetics of olanzapine in children., Br J Clin Pharmacol., 2021, 87(2), 542-54
22. Xiao T., et al., Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance., Clin Pharm Ther., 2022, 47(11), 1811-19
23. Moothedath A.W., et al., Efficacy and Safety of Olanzapine in Children Receiving Highly Emetogenic Chemotherapy: A Randomized, Double-blind Placebo-controlled Phase 3 Trial., Pediatr Hematol Oncol., 2022, 44(8), 446-53
24. Moshayedi M, et al., Efficacy and Safety of Adding Olanzapine to the Standard Preventive Regimen for Chemotherapy-induced Nausea and Vomiting in Children: A Randomized Double-blind Controlled Trial., Iran J Pharm Res., 2021, 20(1), 318-26
25. Naik, et al., Olanzapine for Prevention of Vomiting in Children and Adolescents Receiving Highly Emetogenic Chemotherapy: Investigator-Initiated, Randomized, Open-Label Trial., Journal of Clinical Oncology., 2020, 38(32), 3785-93
26. Radhakrishnan V., et al., Olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy–induced vomiting in children: An open‐label, randomized phase 3 trial., Pediatr Blood Cancer, 2020, 67(9)
27. Samaddar, et al., A prospective, pilot study on the use of olanzapine for optimum control of chemotherapy induced nausea and vomiting (CINV) in children with solid tumours receiving moderate/highly emetogenic chemotherapy at Tata Medical Center, Kolkata., Pediatric Hematology Oncology Journal., 2017, 2(2), S6-S7
28. Kenniscentrum Kind,- en Jeugdpsychiatrie, Ingrijpmedicatie protocol 2016., www.kenniscentrum-kjp.nl

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