Methotrexate

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LogoWarningBox4.pngIt is given only once a week in its commonest indication, as an immunosuppressant. The obvious mistake is for this to be given daily, which produces cytotoxic doses and has resulted in fatalities
Info bulb.pngThere is strong evidence that you should not withhold methotrexate being used as an immunosuppressive before or during surgery[1]

Contents

Introduction

Clinical Use

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Use should be according to guidelines and patients need a monitoring diary (NPSA template)

Indications

Administration

Oral Care about dose, usually less than 15mg weekly for immunosuppression.

S/C

IM

Clinical Issues

Contra-indications

Cautions and Interactions

There are a number of interactions users should be aware of and where guidance can vary. It is often recommended to stop methotrexate at times of intercurrent infection needing short courses of antibiotics. The associations do seem to have real world consequences where attribution in individuals of possible toxicity is difficult[4]. High dose chemotherapy (>1 g/m2) or parental immunotherapy is where these interactions are most important.

  • High dose aspirin is unsafe while other NSAIDs seem fine (despite the SPC warning of occasional severe toxicity and the definite increase in drug levels - probably the differential dosing used in different indications reflects to some degree likelihood of patient being on a NSAID)[5]
  • The rare but under recognized toxic interaction with penicillins is because they are weak acids and inhibit methotrexate excretion[6]
  • Folate antagonists such as trimethoprim or sulphamethoxazole can cause acute megaloblastic pancytopenia
  • Salicylates and sulphonamides (including oral hypoglycaemics) interact with methotrexate protein binding so are not recommened to be co-administered.
  • Other immunosuppressive agents can be expected to increase the risk of cytotoxic side effects.
  • Cola drinks that contain phosphoric acid can cause toxicity[7]
  • Proton pump inhibitors[8]

Side effects

Special advice

Rheumatoid patients had a lower complication rate, including infections for the year following elective orthopedic surgery if the drug was not withheld. [9]

Pharmacology

Cleared by the kidney, through tubular secretions and glomerular filtration. Weak acids compete with methotrexate excretion within the kidney tubules.

References

  1. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Annals of the rheumatic diseases. 2001;60:214-7.
  2. Anandakumar C, Choolani MA, Adaikan PG, Wong YC, Gopal M, Marshall B, et al. Combined chemotherapy in the medical management of tubal pregnancy. The Australian & New Zealand journal of obstetrics & gynaecology 1995;35:437-40.
  3. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy. Fertil Steril. 2006 Nov
  4. Saurat JH, Guérin A, Yu AP, Latremouille-Viau D, Wu EQ, Gupta SR, Bao Y, Mulani PM. High prevalence of potential drug-drug interactions for psoriasis patients prescribed methotrexate or cyclosporine for psoriasis: associated clinical and economic outcomes in real-world practice. Dermatology (Basel, Switzerland). 2010; 220(2):128-37.(Link to article – subscription may be required.)
  5. Uwai Y, Suzuki R, Iwamoto K. Effect of nonsteroidal anti-inflammatory drugs on pharmacokinetics of methotrexate: a meta-analysis.. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2011; 131(5):853-61.
  6. Sathi N, Ackah J, Dawson J. Methotrexate induced neutropenia associated with coprescription of penicillins: serious and under-reported? Rheumatology (Oxford, England). 2006 Mar; 45(3):361-2; author reply 363-4.(Link to article – subscription may be required.)
  7. Santucci R, Levêque D, Herbrecht R. Cola beverage and delayed elimination of methotrexate. British journal of clinical pharmacology. 2010 Nov; 70(5):762-4.(Link to article – subscription may be required.)
  8. Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. British journal of clinical pharmacology. 2009 Jan; 67(1):44-9.(Link to article – subscription may be required.)
  9. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Annals of the rheumatic diseases. 2001;60:214-7.
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