Pharmacokinetics in children

The following mean pharmacokinetic parameters were observed in 83 children aged 6 months -5 years with malaria (Obua et al 2008) and in 20 children of 5-10 years of age (Karunajeewa 2008). 

	6-24 months      (75 mg)	2-5 years       (150 mg)	5-10 years (n=20 30 mg/kg) median (IQR)
Cmax (mg/l) mean	0,79 ± 0.12	1,43 ± 0,24	-
Tmax (hours) mean	6,5 ± 1,2	6,9 ± 1,5	-
t1/2 (hours)	-	-	233 (206-298)
Cl	2,84 (5,4% RSE) (l/h)	2,84 (5,4% RSE) (l/h)	0,8 (0.52-0.96) (l/h/kg)
Vd	230 (7,8% RSE) (l)	230 (7,8% RSE) (l)	154 (101-210) (l/kg)

RSE: Relative Standard Error
IQR: Inter Quartile Range

In addition, some studies show that children <5 years of age achieve lower chloroquine levels than older children; up to half as much (Ursing et al. 2014, Ursing et al. 2016). (Zhao et al. 2014) also shows that the clearance of children <5 years is greater than children 5 years and older.

Kadam (2016) studied the effect of nourishing status on PK parameters, but did not observe a significant difference between well nourished and malnourished children (n=25, aged 5-12 years). 

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

Prophylaxis for malaria

Oral 10 up to 45 kg [1] [2] Initial dose: (Chloroquine) On days 1 and 2 before you depart to the endemic area: 5 mg/kg/day in 1 dose Maintenance dose: 5 mg/kg/dose 1 x per week. Duration of treatment: Prophylaxis should be continued at least 4-8 weeks after leaving a malaria area. Directions for administration: Take during or after a meal ≥ 45 kg [1] [2] Initial dose: (Chloroquine) On days 1 and 2 before you depart to the endemic area: 300 mg/day in 1 dose Maintenance dose: 300 mg/dose 1 x per week. Duration of treatment: Prophylaxis should be continued at least 4-8 weeks after leaving a malaria area. Directions for administration: Take during or after a meal

Treatment of uncomplicated malaria
Oral ≥ 10 kg [1] [2] Initial dose: (Chloroquine) 10 mg/kg/dose, once only. Maintenance dose: 6 hours after initial dose and then for 2 days: 5 mg/kg/day in 1 dose Then switch to prophylactic dosage (5 mg/kg/dose once a week).

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment not necessary

GFR 30-50 ml/min/1.73 m2

Adjustment not necessary

GFR 10-30 ml/min/1.73 m2

Generalized recommendations cannot be given. The risk of toxicity should be weighed up against the intended result.

GFR < 10 ml/min/1.73 m2

Generalized recommendations cannot be given.

Clinical consequences

The half-life of chloroquine is lengthened in cases of reduced renal function. Chloroquine can cause severe side effects, especially in long-term use.

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

Especially young children are sensitive to 4-aminoquinoline compounds and relatively small doses can lead to very serious intoxications (such as fatal respiratory and circulatory disorders) (SmPC).

In the study by Chandra (2015), vomiting and pruritus were reported as the most frequent side effects.

Studies by Ursing (2009,2016 and 2020) show that chloroquine is well tolerated in children even in high doses up to a total dose of 70 mg/kg.

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

Young children are particularly sensitive to 4-aminoquinoline derivatives and relatively small doses can cause very severe intoxication (such as fatal respiratory and circulatory insufficiency).

Choroquine may prolong the QT interval: the magnitude of the QT prolongation may increase with increasing concentration of chloroquine. Preform an ECG before starting treatment and monitor prolongation of the QTc time daily after start of treatment. Be cautious in congenitally or documented acquired QT prolongation and / or known risk factors for QT prolongation.

Bloodglucose levels should monitored as hypoglycemia can occur.

Dose-related side effects are especially expected in the first days when a higher  dose is given. The main and most serious symptoms of overdose are convulsions, coma, prolongation of the QRS interval on the ECG with arrhythmias (ventricular arrhythmias), bradyarrhythmias, a nodal heart rhythm, an extended QT time, an AV block, ventricular tachycardia, torsade de pointes and ventricular fibrillation, hypotension, cardiac arrest and respiratory failure with respiratory arrest. Severe hypokalemia can occur.

TO BE ADDED TO YOUR LOCAL AVAILABLE FORMULATIONS SECTION:

A solution can be prepared from the tablets. click here to access guidance form the PaedForm workinggroup.

Interactions

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

Aminoquinolines
	Hydroxychloroquine Related Medicines Menu">	P01BA02

Biguanides
	Proguanil Related Medicines Menu">	P01BB01

Methanolquinolines
	Mefloquine Related Medicines Menu">	P01BC02
	Quinine Related Medicines Menu">	P01BC01

Diaminopyrimidines
	Pyrimethamine Related Medicines Menu">	P01BD01

Artemisinin and derivatives, plain
	Artesunate Related Medicines Menu">	P01BE03

Artemisinin and derivatives, combinations
	Artemether + lumefantrine Related Medicines Menu">	P01BF01

References

1. ACE Pharmaceuticals, SmPC ACQ-100 (RVG 106659) 19 oktober 2018, www.geneesmiddeleninformatiebank.nl
2. LCR, Malaria protocol, 2018, maart
3. SWAB in collaboration with CIB, NVZA, NVMM, NVII and NVIC, Medicamenteuze behandelopties bij patiënten met COVID-19 (infecties met SARS-CoV-2), https://swab.nl/nl/covid-19, May, 1, 2020
4. Karunajeewa, H. A., et al, Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria, Antimicrob Agents Chemother, 2008, 52(1), 237-43
5. Kofoed, P. E., et al, Treatment of children with Plasmodium falciparum malaria with chloroquine in Guinea-Bissau., Am J Trop Med Hyg, 2002, 67(1), 28-31
6. Siqueira, A. M., Slow clearance of Plasmodium vivax with chloroquine amongst children younger than six months of age in the Brazilian Amazon., Mem Inst Oswaldo Cruz, 2014, 109 (5), 540-5
7. Kofoed, P. E., et al, Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations., Trans R Soc Trop Med Hyg, 2007, 101 (3), 231-8
8. Wallace Manufacturing Chemists Ltd. , SmPC Malarivon syrup (29-11-2018), www.medicines.org.uk., 2018
9. Kofoed, P. E., et al, Paracetamol versus placebo in treatment of non-severe malaria in children in Guinea-Bissau: a randomized controlled trial., Malar J, 2011, 10, 148
10. Nationaal Vergiftigingen Informatie Centrum (NVIC), Choroquine- last update Jan 20, 2020, www.vergiftigingeninfo.nl
11. Verscheijden, L. en Wildt de S., Dose simulations for pediatric population using Simcyp based on Zhao (2014) - manuscript in preparation, March 2020
12. Gao J,. et al, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies., Biosci Trends, 2020, doi: 10.5582
13. Kadam, P. et al, Evaluation of pharmacokinetics of single-dose chloroquine in malnourished children with malaria- a comparative study with normally nourished children., Indian J Pharmacol , 2016, 48 (5), 498-502
14. Ursing, J., et al , Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance., PLoS One, 2014, 9 (1), e86801
15. Anez, A., et al., Evaluation of the paediatric dose of chloroquine in the treatment of Plasmodium vivax malaria, Malar J, 2016, 15(1), 371
16. Ursing, J., et al , High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria, J Infect Dis, 2016, 213 (8), 1315-21
17. Ursing, J., et al. , High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children., Antimicrob Agents Chemother, 2020, 64(3)
18. Ursing, J., et al, Chloroquine is grossly overdosed and overused but well tolerated in Guinea-bissau., Antimicrob Agents Chemother , 2009, 53 (1), 180-5
19. Obua, C. et al , Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen., Br J Clin Pharmacol, 2008, 65 (4), 493-501
20. Chandra, R. et al, Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study, Malar J, 2015, 14, 108
21. Zhao, Q. et al, Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets., Malar J, 2014, Jan (29), 13-36
22. Mahévas M, et al, No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: Results of a study using routinely collected data to emulate a target trial, Preprint, 2020
23. Perinel S, et al, Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients. , Clin Infect Dis, 2020
24. Chen Z, et al, Efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial, Preprint, 2020
25. Magagnoli J, et al, Outcomes of hydroxychloroquine usage in united states veterans hospitalized with covid-19, Preprint, 2020
26. Tang W et al, Hydroxychloroquine in patients with COVID-19: An open-label, randomized, controlled trial., Preprint, 2020

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