Pediatric Formulary

Dosages

Side effects in children

Warnings & precautions in children

Contra-indications in children

Interactions

Renal impairment

References

Methotrexate

Generic name

Methotrexate

Brand name

ATC Code

L04AX03

Pharmacokinetics in children

Data from a randomized trial in juvenile rheumatoid arthritis patients (from 2.8 to 15.1 years of age) suggested greater oral bioavailability of methotrexate in the fasted state. In children with JIA, the dose-normalized area under the plasma concentration versus time curve (AUC) of methotrexate increased with age and was lower than in adults. The dose-normalized AUC of the metabolite 7-hydroxymethotrexate was independent of age (SmPC)

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

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Available formulations

No information is present at this moment.

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Dosages

Juvenile Idiopathic Arthritis (J.I.A.); JIA associated chronic uveitis.
Oral 0 years up to 18 years ^{[7] [10] [11] [13] [15]} 10 - 15 mg/m²/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. Subcutaneous 0 years up to 18 years ^{[7] [10] [11] [13] [15]} 10 - 15 mg/m²/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Juvenile Idiopathic Arthritis (J.I.A.); JIA associated chronic uveitis.

Oral
- 0 years up to 18 years
  ^{[7]
  
  [10]
  
  [11]
  
  [13]
  
  [15]}
  - 10 - 15 mg/m²/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
Subcutaneous
- 0 years up to 18 years
  ^{[7]
  
  [10]
  
  [11]
  
  [13]
  
  [15]}
  - 10 - 15 mg/m²/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Oncological conditions
Oral 0 years up to 18 years ^{[6] [7] [8]} Note: the dose and dosing frequency of cytostatic agents depend on the condition and are very much subject to new insights. Cytostatic drugs are mostly used in oncology and haematology in combinations. For this reason, please refer to the detailed treatment protocols. The dosage from the SmpC is given as an indication: up to 30 mg/m² orally; higher dosages must be given parenterally. Intravenous 0 years up to 18 years Note: the dose and dosing frequency of cytostatic agents depend on the condition and are very much subject to new insights. Cytostatic drugs are mostly used in oncology and haematology in combinations. For this reason, please refer to the detailed treatment protocols. The dosage from the SmPC is given as an indication: up to 40 mg/m².

Oncological conditions

Oral
- 0 years up to 18 years
  ^{[6]
  
  [7]
  
  [8]}
  - Note:
    the dose and dosing frequency of cytostatic agents depend on the condition and are very much subject to new insights. Cytostatic drugs are mostly used in oncology and haematology in combinations. For this reason, please refer to the detailed treatment protocols.
    
    The dosage from the SmpC is given as an indication: up to 30 mg/m² orally; higher dosages must be given parenterally.
Intravenous
- 0 years up to 18 years
  - Note:
    the dose and dosing frequency of cytostatic agents depend on the condition and are very much subject to new insights. Cytostatic drugs are mostly used in oncology and haematology in combinations. For this reason, please refer to the detailed treatment protocols.
    
    The dosage from the SmPC is given as an indication: up to 40 mg/m².

Crohn’s disease
Oral 20 up to 30 kg ^{[2] [3] [4] [5]} 10 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. 30 up to 40 kg ^{[2] [3] [4] [5]} 15 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. 40 up to 50 kg ^{[2] [3] [4] [5]} 20 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. ≥ 50 kg ^{[2] [3] [4] [5]} 25 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. Subcutaneous 20 up to 30 kg ^{[2] [3] [4] [5]} 10 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. 30 up to 40 kg ^{[2] [3] [4] [5]} 15 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. 40 up to 50 kg ^{[2] [3] [4] [5]} 20 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. ≥ 50 kg ^{[2] [3] [4] [5]} 25 mg/dose once a week. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Crohn’s disease

Oral
- 20 up to 30 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 10 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- 30 up to 40 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 15 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- 40 up to 50 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 20 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- ≥ 50 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 25 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
Subcutaneous
- 20 up to 30 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 10 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- 30 up to 40 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 15 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- 40 up to 50 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 20 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
- ≥ 50 kg
  ^{[2]
  
  [3]
  
  [4]
  
  [5]}
  - 25 mg/dose once a week.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Juvenile dermatomyositis
Oral 1 month up to 18 years ^{[9] [23]} 10 - 15 mg/m²/dose once a week. Max: 40 mg/dose. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. Subcutaneous 1 month up to 18 years ^{[9] [23]} 15 - 20 mg/m²/dose once a week. Max: 40 mg/dose. Intravenous administration is preferable for active myositis or vasculopathy of the skin. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Juvenile dermatomyositis

Oral
- 1 month up to 18 years
  ^{[9]
  
  [23]}
  - 10 - 15 mg/m²/dose once a week. Max: 40 mg/dose.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
Subcutaneous
- 1 month up to 18 years
  ^{[9]
  
  [23]}
  - 15 - 20 mg/m²/dose once a week. Max: 40 mg/dose.
  - - Intravenous administration is preferable for active myositis or vasculopathy of the skin.
    - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Moderate to severe plaque psoriasis
Oral 2 years up to 18 years ^{[12] [14]} 0.2 - 0.4 mg/kg/dose once a WEEK. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.

Juvenile idiopathic arthritis (JIA)
Subcutaneous 3 years up to 18 years ^{[10] [11]} 10 - 15 mg/m²/dose Once a week. To prevent toxicity, MTX treatment is always combined with folic acid, 5 mg once a week, one or two days after MTX administration.

Severe constitutional eczema
Oral 2 years up to 18 years ^{[24] [25] [26] [29] [30] [31]} 10 - 15 mg/m²/dose ONCE A WEEK. Max: 25 mg/dose. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. If improvement has not been observed within 3 months using the highest tolerated dose, discontinuation of methotrexate should be considered. Treatment by or after consultation with a pediatric specialist (dermatologist) experienced in the use of methotrexate in this indication. Subcutaneous 2 years up to 18 years ^{[24] [25] [30]} 10 - 15 mg/m²/dose ONCE A WEEK. Max: 25 mg/dose. To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX. If improvement has not been observed within 3 months using the highest tolerated dose, discontinuation of methotrexate should be considered. Treatment by or after consultation with a pediatric specialist (dermatologist) experienced in the use of methotrexate in this indication.

Severe constitutional eczema

Oral
- 2 years up to 18 years
  ^{[24]
  
  [25]
  
  [26]
  
  [29]
  
  [30]
  
  [31]}
  - 10 - 15 mg/m²/dose ONCE A WEEK. Max: 25 mg/dose.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
    - If improvement has not been observed within 3 months using the highest tolerated dose, discontinuation of methotrexate should be considered.
    - Treatment by or after consultation with a pediatric specialist (dermatologist) experienced in the use of methotrexate in this indication.
Subcutaneous
- 2 years up to 18 years
  ^{[24]
  
  [25]
  
  [30]}
  - 10 - 15 mg/m²/dose ONCE A WEEK. Max: 25 mg/dose.
  - To prevent toxicity, treatment with MTX is always combined with folic acid once a week, one or two days after administering MTX.
    - If improvement has not been observed within 3 months using the highest tolerated dose, discontinuation of methotrexate should be considered.
    - Treatment by or after consultation with a pediatric specialist (dermatologist) experienced in the use of methotrexate in this indication.

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

75% of normal single dose, adjustment of dosing interval is not necessary. Monitor the (side) effects of MTX (blood count (leukocytes, platelets), ASAT, ALAT) and monitor renal function.

GFR 30-50 ml/min/1.73 m2

50% of normal single dose, adjustment of dosing interval is not necessary. Monitor the (side) effects of MTX (blood count (leukocytes, platelets), ASAT, ALAT) and monitor renal function.

GFR 10-30 ml/min/1.73 m2

30% of normal single dose, adjustment of dosing interval is not necessary. Monitor the (side) effects of MTX (blood count (leukocytes, platelets), ASAT, ALAT) and monitor renal function.

GFR < 10 ml/min/1.73 m2

Avoid use.

Clinical consequences

Reduced renal function decreases the clearance of methotrexate, thus increasing the risk of toxicity. During the use of methotrexate, renal function may decrease.

The first signs of toxicity are often impairment of the mucosa of the mouth and gastrointestinal tract (bleeding, ulcers, gingivitis, glossitis, stomatitis, vomiting and diarrhoea) and other mucosal inflammations. Dose-dependent side effects of methotrexate include nephrotoxicity (renal insufficiency), pneumonitis (sometimes fatal pulmonary insufficiency), neurological effects (headache, drowsiness, blurred vision, aphasia, hemiparesis, paresis and convulsions), leukoencephalopathy, severe pancytopenia.

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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

Common: gastrointestinal problems, headaches, fatigue, impaired liver function, elevated risk of infection.

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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

Note: The usual dosage for JIA, Crohn’s disease and juvenile dermatomyositis is once a week!

Extravasation: Severe reactions are not to be expected.

Antidote/rescue treatment: folinic acid. In conjunctivitis, 0.03% folinic acid eye drops can be used if necessary, or 1% in cases of contamination in the eye.
When administered in high doses, the urine is made alkaline in order to reduce nephrotoxicity.
Supplementation of folic acid at 5 mg/week (not within 24 hours after taking methotrexate) reduces the side effects in adults. On the other hand, in cases of toxicity, the effect can be antagonized by taking 5 mg folic acid 24 hours after taking methotrexate.

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.

After 9 months of clinically inactive disease, consideration should be given to tapering and discontinuation of the MTX treatment dose. (JIA and Constitutional Eczema).

Monitoring

At the start of treatment check of creatinine, ALAT and complete blood count (NVK 2018).
Recheck 4 weeks after start and after each dose increase (Yee and Orchard 2018, Irvine et al. 2018).
Subsequently, at a stable dose, follow-up every 3-4 months (if previous findings were not abnormal).
The following recommendations apply for deviating lab values:
- Liver enzymes> 2x normal value: reduce dose and monitor every 4-6 weeks. If> 3x normal value: stop temporarily and evaluate the lowest possible safe dose upon restart (NVK 2018).
Ask whether you have had varicella in the past or test if in doubt (Irvine et al. 2018, NVK 2018, Purvis et al. 2019).
Pay attention to vaccination advice during MTX use.
MTX is contraindicated throughout pregnancy due to the risk of birth defects. Both men and women of childbearing age must take adequate contraceptive precautions during use and for at least six months after discontinuation (Zorginstituut Nederland).

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Interactions

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

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Other immunosuppressants
	Azathioprine Related Medicines Menu">	L04AX01

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

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References

Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
Uhlen S, et al, Efficacy of methotrexate in pediatric Crohns disease: a French multicenter study, Inflamm Bowel Dis, 2006, 12, 10537
Ravikumara M, et al, Role of methotrexate in the management of Crohn disease, J Pediatr Gastroenterol Nutr, 2007, 44, 42730
Akobeng AK, Crohn\'s disease: current treatment options., Arch Dis Child, 2008, Sep;93(9), 787-92
Turner D, et al, Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn\'s disease., Am J Gastroenterol., 2007, Dec;102(12), 2804-12
Medac, SPC Metoject (RVG 29427), www.cbg-meb.nl, Geraadpleegd 10 juni 2010, http://db.cbg-meb.nl/IB-teksten/h29427.pdf
Pharmachemie BV, SPC Methotrexate 2,5 mg/ml (RVG 08343), www.cbg-meb.nl, Geraadpleegd 10 juni 2010, http://db.cbg-meb.nl/IB-teksten/h08434.pdf
EBEWE Pharma Ges.m.b.H. Nfg. KG, SPC Ebetrexat (RVG 105616), www.cbg-meb.nl, Geraadpleegd 10 juni 2010, http://db.cbg-meb.nl/IB-teksten/h105616.pdf
CBO, Richtlijn Dermatomyositis, polymyositis en sporadische \'inclusion body\' myositis, www.cbo.nl, 2004, 99-111
CBO, Richtlijn Diagnostiek en behandeling van Reumatoide Artritis, www.cbo.nl, 2009, 77
Armbrust W. et al, Werkboek Kinderreumatologie. Derde druk, www.nvk.nl (voor leden), 2014
NVDV, Multidisciplinaire evidence-based richtlijn psoriasis, 2017
Nederlands Oogheelkundig Gezelschap, Richtlijn Uveitis, 2015
NVDV, Multidisciplinary evidence-based guideline psoriasis, 2017
Nederlandse Vereniging voor Kindergeneeskunde, Richtlijn Juveniele idiopathische artritis, medicamenteuze behandeling van kinderen met, www.nvk.nl, 11 aporil 2018
MMI, Gelbe Liste Online, Accessed July 10, 2018
medac, SmPC metex Injektionslösung 7,5 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml (28905.01.01), 07/2015
Pfizer, SmPC Methotrexat “Lederle“ Tabletten 2,5 mg, 10 mg (1974.00.01), 03/2018
Pfizer, SmPC Lantarel FS 7,5 mg, 10 mg, 15 mg, 20 mg, 25 mg Injektionslösung (28900.01.01), 03/2018
medac, SmPC metex PEN 7,5 mg, 10 mg, 12,5 mg, 15 mg, 17,5 mg, 20 mg, 22,5 mg, 25 mg, 27,5 mg, 30 mg Fertigpen (86737.00.00), 03/2018
Hexal, SmPC MTX HEXAL 2,5 mg, 5 mg, 7,5 mg, 10 mg, 15 mg Tabletten (12887.00.02), 03/2018
Pfizer, SmPC Lantarel 2,5 mg, 7,5 mg, 10 mg Tabletten (9709.00.00), 03/2018
Bellutti Enders, F et al, Consensus-based recommendations for the management of juvenile dermatomyositis, Ann Rheum Dis, 2016, 1-12
Anderson, K., et al , Treatment of severe pediatric atopic dermatitis with methotrexate: A retrospective review., Pediatr Dermatol, 2019, 36(3), 298-302
Dvorakova, V., et al, Methotrexate for Severe Childhood Atopic Dermatitis: Clinical Experience in a Tertiary Center., Pediatr Dermatol, 2017, 34(5), 528-534
El-Khalawany, M. A., et al, Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt., Eur J Pediatr, 2013, 172(3), 351-6
Irvine, A. D.et al , A randomized controlled trial protocol assessing the effectiveness, safety and cost-effectiveness of methotrexate vs. ciclosporin in the treatment of severe atopic eczema in children: the TREatment of severe Atopic eczema Trial (TREAT)., Br J Dermatol, 2018, 179(6), 1297-1306
Nederlandse Vereniging voor Kindergeneeskunde, Richtlijn "Juveniele idiopathische artritis, medicamenteuze behandeling van kinderen met", www.nvk.nl, 2018
Purvis, D., et al , Long-term effect of methotrexate for childhood atopic dermatitis., J Paediatr Child Health, 2019, 55(12), 1487-1491
Rahman, S. I., et al, The methotrexate polyglutamate assay supports the efficacy of methotrexate for severe inflammatory skin disease in children., J Am Acad Dermatol, 2014, 70(2), 252-6
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
NKFK Working group on dosing in renal impairment, Extrapolation of KNMP risk analysis renal function to children, 20 Dec 2021

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Methotrexate

Methotrexate

Pharmacokinetics in children

dose recommendation of formulary compared to licensed use (on-label versus off-label)

Available formulations

Dosages

Renal impaiment in children > 3 months

GFR 50-80 ml/min/1.73 m2

GFR 30-50 ml/min/1.73 m2

GFR 10-30 ml/min/1.73 m2

GFR < 10 ml/min/1.73 m2

Clinical consequences

Side effects in children

Contra-indications

Warnings & precautions in children

Interactions

References

Changes

Changes