Pharmacokinetics in children

Is rapidly broken down into 6-mercaptopurine in vivo.6-MP is then converted by a variety of enzymes (including thiopurine methyl transferase (TPMT)) into active and inactive metabolites. Hereditary abnormalities of the TPMT occur in which there is little or no TPMT activity.

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

Autoimmune diseases

Oral 1 month up to 18 years [1] [2] [11] 1 - 3 mg/kg/day in 1 dose Duration of treatment: In inflammatory intestinal diseases: a treatment duration of at least 12 months should be considered because no clinical effect can be expected within 3-4 months. Other conditions: if there is no improvement within 3 months, consider stopping azathioprine In obese children, dosages on the high end of the dose range may be needed for a adequate response, careful monitoring is recommended.

Prophylaxis for transplant rejection

Oral 1 month up to 18 years [2] Initial dose: 5 mg/kg/day in 1 dose (or in several doses). Maintenance dose: 1 - 4 mg/kg/day in 1 dose (or in several doses). Adapt the dose to the haematological tolerance and clinical picture. In obese children, dosages on the high end of the dose range may be needed for a adequate response, careful monitoring is recommended. Intravenous 1 month up to 18 years [2] Initial dose: 5 mg/kg/day in 1 dose (or in several doses). Maintenance dose: 1 - 4 mg/kg/day in 1 dose (or in several doses). Adapt the dose to the haematological tolerance and clinical picture. In obese children, dosages on the high end of the dose range may be needed for a adequate response, careful monitoring is recommended.

Atopic dermatitis

Oral 2 years up to 18 years [12] [13] [14] [16] [18] [19] 1 - 3 mg/kg/day in 1 dose Consider genotyping at the start of therapy. See warnings and precautions for additonal information If no improvement occurs within 3 months using the highest tolerated dose, discontinuation of azathioprine should be considered. In overweight, doses at the higher end of the dose range may be required for a good response, close monitoring is recommended. See warnings and precautions.

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

No information is present at this moment.

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

Monitoring:

• Check  creatinine, ALT and complete blood count at start of treatment
• Determine the TPMT and NUDT15 genotype. For poor metabolizers or intermediate metabolizers,  dose adjustment is indicated. Click here for recommendations
• Repeat bloodmonitoring 1 month after start, 2 months after start and after each dose increase (Yee and Orchard 2018).
• If genotyping is not performed, additional monitoring is advised 1 week after initiation and 1 week after each dose increase.
• Subsequently, at a stable dose, check every 3 months (if earlier labvelues were normal).
• The following recommendations apply for deviating lab values:
  • Liver enzymes> 2x normal: reduce dose and monitor every 4-6 weeks. If> 3x normal value: temporarily stop and evaluate the lowest possible safe dose upon restart.
  • For lymphocytes <1.0x109 / L and / or neutrophils <1.5x109 / L: reduce dose and consult with pediatric rheumatologist / immunologist if necessary. Monitor weekly.
• Pay attention to vaccination advice during azathioprine use.
• A woman or man of childbearing potential should use adequate contraceptive precautions during therapy and for at least 3 months afterwards. Azathioprine can be used during pregnancy if necessary, but extra monitoring of the newborn is needed.

General cytostatic: a range of cytostatics can trigger hypersensitivity reactions. An emergency set (containing epinephrine, clemastine and hydrocortisone) should be present in the treatment room. The emergency set also contains specific antidotes.

In an American clinical study, 18 children (ages 3 to 14 years) were divided equally into two groups based on their weight and height ratio: one group was below and the other group was above the 75th percentile. Each child received maintenance treatment with 6-mercaptopurine and the dosage was calculated based on their body surface area. The mean AUC (0-∞) value of 6-mercaptopurine in the group above the 75th percentile was 2.4 times lower than that in the group below the 75th percentile. Therefore, obese children may require dosages at the high end of the dose range and careful monitoring of response to treatment is recommended (SmPC).

If serious side effects occur or if the effect does not occur, there may be an abnormal drug metabolism. Thiopurine methyl transferase (TPMT) and nudixhydrolase 15 (NUDT15) can determine 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

Other immunosuppressants
	Methotrexate Related Medicines Menu">	L04AX03

Tumor necrosis factor alpha (TNF-alpha) inhibitors
	Adalimumab Related Medicines Menu">	L04AB04
	Etanercept Related Medicines Menu">	L04AB01
	Infliximab Related Medicines Menu">	L04AB02

Calcineurin inhibitors
	Ciclosporin Related Medicines Menu">	L04AD01
	Tacrolimus Related Medicines Menu">	L04AD02

Mammalian target of rapamycin (mTOR) kinase inhibitors
	Everolimus Related Medicines Menu">	L04AH02

References

1. Turner D, et al. , Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN Evidence-Based Consensus Guidelines. , JPGN, 2012, 55(3), 340-61
2. Aspen Pharma Trading Limited,, SmPC Imuran (RVG 05565) 04-12-2018, www.geneesmiddeleninformatiebank.nl
3. MMI, Online GL. Azathioprin Heumann 50 mg Filmtabletten, Accessed June 27, 2018.
4. Pfaff A. Pharmatrix, Informationen zu Zytrim, http://www.pharmatrix.de/cms/front_content.php?idart=3&id=657&sort=arzneimittel&search=zytrim, Accessed June 27, 2018
5. Pharmatrix, Informationen zu Imurek 25mg.
6. Pharmatrix, Informationen zu Imurek 50mg, http://www.pharmatrix.de/cms/front_content.php?idart=3&id=656&sort=arzneimittel&search=imurek.
7. Recordati Pharma, SmPC Zytrim 50mg Filmtabletten, 47313.01.00, 04/2018
8. Heumann Pharma, SmPC Azathioprin 50mg Filmtabletten, 63079.00.00, 08/2016
9. Heumann Pharma, SmPC Azathioprin 25mg/75mg/100mg Filmtabletten, 93348.00.00/93349.00.00/93350.00.00, 08/2016
10. Aspen, SmPC Imurek 25mg/50mg Filmtablette + 50mg Pulver zur Herstellung einer Infusionslösung (6101735.01.00/6101735.00.00/6101758.00.00), 12/2017
11. Nederlands Oogheelkundig Genootschap, Richtlijn uveitis, 2015
12. Caufield, M., et al, Oral azathioprine for recalcitrant pediatric atopic dermatitis: clinical response and thiopurine monitoring, J Am Acad Dermatol , 2013, 68(1), 29-35
13. Murphy, L. A., et al, Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency., Pediatr Dermatol, 2003, 20(6), 531-4
14. Hon, K. L., et al, Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults, J Dermatolog Treat , 2009, 20(3), 141-5
15. Yee, J., et al, Monitoring recommendations for oral azathioprine, methotrexate and cyclosporin in a paediatric dermatology clinic and literature review, Australas J Dermatol, 2018, 59(1), 31-40
16. Murphy, L. A., et al, A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression, Br J Dermatol, 2002, 147(2), 308-15
17. Nederlandse Vereniging voor Dermatologie en Venerelogie, Richtlijn constitutioneel eczeem., https://nvdv.nl/professionals/richtlijnen-en-onderzoek/richtlijnen/richtlijn-constitutioneel-eczeem, 2019
18. Noguera-Morel, L., et al, A Retrospective Study of Systemic Treatment of Severe Atopic Dermatitis With Azathioprine: Effectiveness and Tolerance in 11 Pediatric Patients, Actas Dermosifiliogr, 2019, 110(3), 227-231
19. Waxweiler, W. T., et al, Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil., Pediatr Dermatol , 2011, 28(6), 689-94
20. Breitkreutz J and Boos J., Paediatric and geriatric drug delivery, PubMed - NCBI., Accessed June 27, 2018.
21. DAZ.online, Individuell für Kinder., https://www.deutsche-apotheker-zeitung.de/daz-az/2014/daz-20-2014/individuell-fuer-kinder. , Accessed June 27, 2018.

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