Methotrexate

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 22.04.2021

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Synonym(s)

Amethopterin; MTX

Definition
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Immunosuppressive cytostatic drug (antimetabolite; folic acid antagonist) of importance for rheumatology and dermatology. According to the German and European S3 guidelines, it is suitable as a conventional standard therapy, especially for the long-term treatment of severe and moderate symptoms. After fumaric acid esters, it is the conventional systemic therapy form most frequently used by dermatologists in Germany.

Half-life
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Oral availability is stated as 60-90%. Max. The half-life in serum is about 6-7 hours at low doses. Intracellular enzymatic conversion produces long-acting, biologically active MTX polyglutamates.

Pharmacodynamics (Effect)
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Inhibition of the dihydrofolate reductase-dependent formation of dihydrofolate. As a result, a large number of intracellular folic acid-dependent reactions are blocked. Inhibition of the methylation of various phospholipids, proteins, nucleic acids. Inhibition of the activity of antigen-presenting Langerhans cells. Inhibitory effect on TNF-alpha-induced expression of ICAM-1 and VCAM-1 of vascular endothelia (downregulation of ICAM-1 gene expression).

Indication
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Limited indication
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  • Severe alcoholism with hepatopathy, hepatitis (viral), non-alcohol steatosis hepatis, limited renal insufficiency especially when taking other nephrotoxic drugs (e.g. NSAID, here: lowering the MTX dose), poor compliance, polymorbidity.
  • MTX should be temporarily interrupted in case of: vomiting, diarrhea, acute infections, stomatitis, gastrointestinal ulcers.
  • Vaccination therapy against dead vaccines may be limited.
  • MTX should be discontinued 3 months before a live vaccination.

Dosage and method of use
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Methotrexate systemic:

  • "Low-dose"! MTX therapy (e.g. for psoriasis): 7.5-10 -25 mg/week as shock therapy (once a week orally, i.v., i.m. s.c.) or as interval therapy 3 or 4 times 2.5 mg p.o. in 12-hour intervals, e.g. on Mondays and Tuesdays (so-called tartaric frost scheme).
  • MTX: subcutaneous dose vs. oral dose. Due to its better efficacy and better bioavailability, the s.c. therapy using an auto-injector (e.g. metex Pen) is increasingly preferred to oral therapy.
  • For children, a dosage adapted to body weight or body surface (10-15mg/sqm KOF/week) is recommended.
  • In combination with TNF-alpha antagonists, a lower dose of 7.5-10.0mg/week is recommended).

Methotrexate topical (n. Wohlrab J et al)

  • Methotrexate remains galenically stable in a concentration of up to 0.5% in DAC base cream and can be easily incorporated. When applied on a limited skin area no relevant systemic bioavailability is observed. Indications are localized foci of mycosis fungoides as well as lymphomatoid papulosis.
  • Rp. Methotrexate (acid form) 0.25/0.5
  • Base cream DAC ad 100,0
  • S.: Apply a thin layer to the affected areas 1 x daily. Use Fingerling.

Undesirable effects
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  • Pneumological ADRs:
    • Pneumonia (acute onset with dyspnea, fever<38°C, tachypnea, signs of interstitial or alveolar infiltration, leukocytosis < 15,000, neg. blood and sputum culture, restriction disorder).
    • Pulmonary fibrosis,
  • Haematological ADR:
    • blood count disorders
  • Gatrointestinal ADR:
    • gastrointestinal disorders
    • gastrointestinal ulcers
  • Hepatologic and nephrologic ADRs:
  • Dermatologic ADR:
  • Other ADRs:
    • Hyperuricemia
    • disturbance of ovulation and spermatogenesis
    • Osteoporosis
  • Note: For the treatment of overdoses and acute toxicities, the immediate administration of the antidote leucovorin (5-formyl tetrahydrofolate) is recommended. Dose: 10 mg/m2 KO i.v. or orally.
  • Reminder. Serious adverse effects (e.g. leukopenia) may occur with low endogenous folic acid depot (often in elderly patients) already with a dosage of 15-25 mg/week after 1-2 weeks of therapy; in this case, continuous monitoring of serum MTX levels is recommended! Simultaneous administration of folic acid (analogous dose to MTX).

Interactions
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Increase of toxicity by:
  • Reduced renal excretion with simultaneous administration of aminoglycosides, sulfonamides, cephalosporins, ciclosporin A, cisplatin, penicillin, amoxicillin, mezlocillin, anti-inflammatory drugs, omeprazole, probenecid, colchicine.
  • Additives synergistic toxicity with simultaneous administration of trimethoprim/sulfmethoxazole, pyrimethamine.
  • Displacement of MTX from the plasma bond with simultaneous administration of ASS, ethanol, barbiturates, phenytoin, retinoids, sulfonamides, tetracyclines, sulfonylureas.
  • Increased hepatotoxicity with simultaneous administration of ethanol, retinoids.

Contraindication
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Absolute contraindications: Pregnancy, lactation, hypersensitivity to MTX, severe uncontrolled infections, severe bone marrow depression (leukopenia<3000/ul, thrombocytopenia <100.000/ul, anemia) Liver dysfunction with transaminase values >2xONW, gastrointestinal ulcers, severe renal failure (creatinine clearance <20ml/min).

Preparations
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Methotrexate Lederle; MTX Hexal; Metex; Lantarel

Note(s)
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  • Before starting therapy (routine laboratory, hepatitis serology, pregnancy test, HIV serology) and in intervals of 4 weeks control of blood, liver and kidney parameters (in polymorbid patients possibly more closely; after longer monitoring without complications 8-week control appointments are sufficient).
  • Before any systemic therapy (of psoriasis) it is recommended to perform an "Interferon-gamma Release Assay -IGRA - e.g. Quantiferon -TB-Gold-Test).
  • Medical history regarding the amount of usual alcohol consumption, previous liver diseases, previous or current use of hepatotoxic drugs, drug abuse, membership in an HIV risk group. Family history of liver disease, diabetes, overweight! Men and women must use effective contraception during therapy and up to 3 months after discontinuing the preparation!
  • Based on the data of a meta-analysis, the task force of the US-American "National Psoriasis Foundation" continues to recommend the performance of a liver biopsy in case of clinical suspicion of liver structural damage or additional risk factors. Even with high cumulative total doses, a liver biopsy may be justified under certain circumstances according to the above recommendations. This does not appear necessary to us. Instead, we recommend regular monitoring of liver function by laboratory and imaging procedures (sonography).
  • Combination therapies
    • The combination therapy "MTX with other immunomdoulators (e.g. fumaric acid esters) or immunosuppressive drugs" is considered by some authors to be contra-induced. Our experience with the combination MTX/fumaric acid ester can be described as good, especially in the case of psoriasis arthropathica (regular laboratory checks!).
    • The combination therapy "MTX with biologicals (e.g. Enbrel)" is standard.
  • Use of MTX for fertility:
    • Women: Safe contraceptive measures must be continued for 3 months after stopping the therapy!
    • Men: Fertility restrictions are documented. The changes are reversible. It is recommended to wait 3 months before a planned conception. Attention should be drawn to the possibility of cryopreservation of sperm!
  • In psoriatic patients who have received both PUVA and a high-dose methotrexate therapy, the risk of lymphoma should increase 4-fold!
  • For patients suffering from gastrointestinal complaints, the (very well tolerated) subcutaneous injection method (pre-filled syringes) is recommended.
  • Folic acid administration during MTX therapy: The additional administration of folic acid is handled differently in Europe and America. In Europe, MTX therapy is often carried out without folic acid administration. An additional folic acid dose is only given in case of MTX intolerance or serologically proven folic acid deficiency (macrocytosis, hyperchromasia in the blood count). Other signs of folic acid deficiency are inflammation of the mucous membranes (oral mucosa). In these cases, MTX therapy can be interrupted for a short time and folic acid can be administered in high doses until it subsides (e.g. 3 times/day 1 tbl. of folican). Subsequently, continuation of the MTX therapy (but simultaneously with folic acid). In the USA, folic acid is mainly given after each MTX intake or MTX injection (usually 24 hours after the first dose). However, there are different dosage recommendations:
    • Usually 5 mg folic acid (e.g. 1 tablet of Folsan) 24 hours after MTX (independent of the MTX dose) is the usual dose.
    • Alternatively, adjust the folic acid dose to the MTX dose (e.g. 15 mg MTX and 15 mg folic acid equivalent).
  • There are also differences with regard to the time of substitution: in America 24 hours after MTX administration or daily intake (1 mg/day) (in Germany 5 mg tablets are used). In Europe (especially in Germany), many rheumatology centres do not give folic acid until 48 hours after the treatment. Background: the action of MTX is essentially based on a blockade of the folic acid metabolism, MTX and its metabolite remain in the body for 48 hours until elimination. MTX itself remains in the body for about 24 hours, the metabolite also for another 24 hours. Folic acid applications that are too early should cancel the effect or lead to a weakening of MTX.

Literature
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  1. Barland C et al (2003) Addition of low-dose methotrexate to infliximab in the treatment of a patient with severe, recalcitrant pustular psoriasis. Arch Dermatol 139: 949-950
  2. Feldman SR et al (2003) Strategy to manage the treatment of severe psoriasis: considerations of efficacy, safety and cost. Expert Opinion Pharmacother 4: 1525-1533
  3. Grunewald S et al (2007) Systemic dermatological treatment with relevance for male fertility. J Dtsch Dermatol Ges 5: 15-21
  4. Harley CR et al (2003) Treatment compliance and dosage administration among rheumatoid arthritis patients receiving infliximab, etanercept, or methotrexate. At J Manag Care 9: 136-143
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  7. Moreno JC et al (2003) Psoriasis, vasculitis and methotrexate. J Eur Acad Dermatol Venereol 17: 466-468
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  9. Panthirana O et al (2009) European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol 23 Suppl 2:1-70
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  16. Wohlrab J et al (2015) Methotrexate for topical application in a magistral formulation. JDDG 13: 891-902
  17. Zackheim HS et al (2003) Low-dose methotrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad 49: 873-878

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Last updated on: 22.04.2021