CONTINUING PROFESSIONAL DEVELOPMENT ANF iFOLIO CLINICAL UPDATE:
Methotrexate for the treatment of rheumatoid arthritis: a medication update update Methotrexate - a medication Read this article and complete the quiz the to earn 0.5to iFolio hour Read this article and complete quiz earn 0.5 iFolio hour Brand name: Methoblastin, Methotrexate, Trexject1 Drug class: antimetabolites, disease-modifying antirheumatic drugs (DMARDs)1,2,3
MECHANISM OF ACTION
Methotrexate ameliorates symptoms of inflammation and suppresses immune responses.1 However, the mechanism of its immunomodulatory effects is unclear.1
ADMINISTRATION
Methotrexate is administered orally, or by subcutaneous or intramuscular injection.1
INDICATIONS
Methotrexate in indicated for severe, recalcitrant, active rheumatoid arthritis in adults unresponsive to, or intolerant of, other treatment options.2,3,4 Note: methotrexate is indicated in a number of other conditions, such as psoriasis, Crohn’s disease, juvenile idiopathic arthritis, and as a cancer treatment.2,3,4
CONTRAINDICATIONS
Methotrexate is contraindicated in patients with:1,2,3 • • • • • •
Hypersensitivity to methotrexate Severe hepatic impairment Severe renal impairment Severe acute or chronic infections Evidence of immunodeficiency syndromes Psoriasis or rheumatoid arthritis with peptic ulcer disease or ulcerative colitis • Alcoholism or alcoholic liver disease • Bone marrow depression or pre-existing blood dyscrasias.
Methotrexate is also contraindicated for women who are pregnant or planning a pregnancy, or who are breastfeeding.1
INTERACTIONS
Methotrexate has a number meaningful drug interactions.
of
clinically
Colestyramine interferes with enterohepatic recycling of methotrexate and may decrease its concentration and efficacy.5 Concurrent use of colystyramine and methotrexate should be avoided.5 Ciclosporin may increase the efficacy of methotrexate and lead to increased renal or hepatic toxicity.5 If they are used concurrently, the patient should be carefully monitored and the dose of either or both drugs adjusted if necessary.5
avoided if possible.5 If they are used concurrently, the patient should be closely monitored for adverse effects and the methotrexate dose reduced if necessary.5 Trimethoprim and sulfamethoxazole may increase methotrexate toxicity (bone marrow suppression).5 Concurrent use of trimethoprim and/or sulfamethoxazole and methotrexate should be avoided if possible.5 If they are used concurrently, the patient should be monitored for haematological toxicity and other adverse effects.5 Live vaccines should not be administered to patients taking methotrexate.2,5 As methotrexate is an immunosuppressant it may reduce the immunological response to the vaccination, and severe antigenic reactions may occur.2,5 The significance of some interactions varies according to the methotrexate dose.2,5 Some drugs such as ciprofloxacin and levetiracetam increase methotrexate concentration and the risk of toxicity but only when high doses of methotrexate are given, such as for cancer treatments.2,5 Potential interactions at the low doses administered for the treatment of rheumatoid arthritis are not clinically meaningful.2,5 Other drugs such as penicillin, proton pump inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDS) are unlikely to have clinically meaningful interactions with methotrexate at the lower doses associated with rheumatoid arthritis, however the evidence is not clear.2,5 Until the situation is clearer, caution should be exercised when using these medications concurrently with methotraxte.2,5
hypoplasia of skull bones, wide fontanels, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, short limbs, talipes, hypodactyly, and syndactyly.7 Women using methotrexate should use effective contraception and discontinue treatment at least three months before a planned pregnancy.7 Methotrexate should not be used while breastfeeding.7,8 It is excreted in breastmilk and may accumulate in the infant’s tissues.7
ADVERSE EFFECTS
The most common adverse effects associated with methotrexate include nausea, vomiting, diarrhoea, mucosal ulcers, malaise, alopecia, leucopenia, thrombocytopenia, photosensitivity, infection, and increased aminotransferases.1 Other adverse effects include anaemia and oligospermia.1 Rarely, methotrexate is associated with severe skin reactions, pneumonitis, pulmonary fibrosis, hepatotoxicity, and anaphylactoid reactions.1 Concomitant treatment with folic acid may decrease the incidence or severity of adverse effects (folic acid should not be taken on the same day as methotrexate).2,3,4
REFERENCES 1.
Methotrexate. 2020 [cited 2021 Jan 6]. In: Australian Medicines Handbook [Internet]. Adelaide (Australia): Australian Medicines Handbook. Available from: https://amhonlineamh-net-au/ chapters/rheumatological-drugs/immunomodulating-drugs/immunosuppressants-rheumatology/methotrexate-immunomodulator
2.
Methoblastin. 2020 [cited 2021 Feb 14]. In: MIMS Online database [Internet]. North Sydney (Australia): MIMS Australia. Available from: https://www.mimsonline.com.au/ Search/ AbbrPI.aspx?ModuleName= Product%20Info&searchKeyword=methotrexate&PreviousPage=~/Search/QuickSearch. aspx&SearchType=&ID=10420001_2
3.
Trexject. 2020 [cited 2021 Feb 14]. In: MIMS Online database [Internet]. North Sydney (Australia): MIMS Australia. Available from: https://www.mimsonline.com.au/Search/ AbbrPI.aspx?ModuleName= Product%20Info&searchKeyword=methotrexate&PreviousPage=~/Search/QuickSearch. aspx&SearchType=&ID=28860001_2
4.
DBL Methotrexate Injection. 2020 [cited 2021 Feb 14]. In: MIMS Online database [Internet]. North Sydney (Australia): MIMS Australia. Available from: https://www.mimsonline. com.au/ Search/AbbrPI.aspx?ModuleName=Product%20Info&searchKeyword=methotrexate&PreviousPage=~/Search/ QuickSearch.aspx&SearchType=&ID=10430001_2
5.
Drug interactions: Methotrexate. 2020 [cited 2021 Feb 20]. In: Australian Medicines Handbook [Internet]. Adelaide (Australia): Australian Medicines Handbook. Available from: https://amhonline.amh.net.au/interactions/methotrexate
6.
Principles of immunomodulatory drug use for rheumatological diseases in adults. 2020 [cited 2021 Feb 10]. In: eTG Complete [Internet]. Melbourne (Australia): Therapeutic Guidelines Limited. Available from: https:// tgldcdp-tg-org-au/viewTopic?topicfile=principles-immunomodulatory-drug-use-rheumatological-diseases-in-adults&sectionId=rhg3-c04-s4#toc_d1e47
DOSAGE
The dose of methotrexate is initially 10-15mg once a week, with the dose adjusted according to the response.1 The usual maintenance dose is 10-25mg once a week (maximum 25mg if administered by injection, 30mg if administered orally).1 Methotrexate should be taken on the same day each week.1 Regular monitoring of disease activity should be undertaken, and the methotrexate dose adjusted if necessary to remain in the therapeutic range.6 Oral and parenteral methotrexate are not bioequivalent.1 As bioavailability is higher with parenteral administration, if changing from oral to parenteral administration the patient should be carefully monitored and consideration should be given to reducing the dose.1
PRECAUTIONS Renal impairment
Nitrous oxide may increase the incidence of methotrexate’s adverse effects.5 Concurrent use of nitrous oxide and methotrexate should be avoided if possible.5 If they are used concurrently, the patient should be closely monitored and calcium folinate rescue considered.5
If creatinine clearance (CrCl) is 10-50mL/ minute, the adult dosage should be reduced.1 Methotrexate is contraindicated if the patient’s CrCl is less than 10mL/minute.1
7.
Methotrexate. 2020 [cited 2021 Jan 6]. In: Pregnancy and Breastfeeding Medicines Guide [Internet]. Melbourne (Australia): The Royal Women’s Hospital. Available from: https:// thewomenspbmg.org.au/ medicines/methotrexate
Pregnancy and breastfeeding
8.
Probenecid reduces methotrexate’s renal excretion and increases its toxicity.5 Concurrent use of probenecid and methotrexate should be
Methotrexate should not be used during pregnancy.7,8 It has been associated with fetal malformations including microcephaly,
Drug use in pregnancy and breastfeeding. 2020 [cited 2021 Feb 10]. In: eTG Complete [Internet]. Melbourne (Australia): Therapeutic Guidelines Limited. Available from: https:// tgldcdp-tg-org-au/quicklinks?type=Pregnancy%20and%20 breastfeeding&bf=breastfeeding_m.htm
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