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methotrexate (Rheumatrex, MTX)

Indications: - treatment of malignancies - breast cancer - head & neck cancer - bladder cancer bladder - acute lymphoblastic leukemia - including intrathecal methotrexate for meningeal leukemia - lymphomas (Hodgkin's disease & non-Hodgkin's lymphoma) - osteogenic sarcoma - gestational trophoblastic carcinoma - treatment of autoimmune disease - rheumatoid arthritis {improves long-term survival} [10,11] - psoriasis & psoriatic arthritis - Reiter's syndrome - polymyositis, dermatomyositis [18] - systemic lupus erythematosus - Wegener's granulomatosis - vasculitis [18] - treatment of tubal ectopic pregnancy [5,6] Contraindications: 1) severe renal insufficiency 2) severe hepatic impairment 3) severe bone marrow suppression 4) preganacy or lactation - discontinue 3 months prior to conception [3] 6) regular alcohol consumption * abortifacient * discontinue >= 3 months prior to pregnancy [3] Dosage: 1) solid tumors: 20-40 mg/m2 IV/PO every 1-3 weeks 2) leukemias: 200-500 mg/m2 IV every 2-4 weeks 3) intrathecal 10-15 mg liquid preserve free, 2-4 mL volume 4) rheumatoid arthritis: a) start 7.5 mg PO/IM/SC weekly b) max 50 mg weekly c) ideal dose is as high as 25 mg/week, assuming normal renal function [22] d) adjunctive therapy with folic acid 1 mg QD [20] e) subcutaneous methotrexate is more effective than once-weekly oral dosing [22] & should be tried before resorting to a biologic agent 5) psoriasis: 12.5-50 mg IM/PO weekly-monthly 6) tubal ectopic pregnancy: 50 mg/m2 IM single dose [5,6] Injection: 25 & 50 mg/mL (2 mL, 10 mL). Powder for injection: 20 mg, 1000 mg. SC syringe 2.5-3 mL, needle 25 g, 5/8 inch (VA) IM syringe 2.5-3 mL, needle 22 g, 1.5 inch (VA) Tabs: 2.5 mg. Pharmacokinetics: 1) dose-dependent oral absorption - impaired absorption with oral doses > 15 mg [21] 2) well distributed to body water 3) undergoes polyglutamation in cell, a) product inhibits AICAR transformylase of purine synthesis b) results in increased release of adenosine 4) 10% metabolized to a potentially nephrotoxic metabolite 5) 90% eliminated in the urine 6) elimination 1/2life is 3 hours 7) onset of action is 3-6 weeks {RA} [9] Monitor: 1) CBC, serum creatinine, LFT's a) baseline & monthly for 1st 3 months after initating or increasing dose b) then every 3 months [14] c) use with leflunomide requires monthly serum AST, serum ALT, serum albumin [14] d) hold for serum ALT, serum AST 2x upper limit of normal 2) baseline chest x-ray [3] 3) liver biopsy after 1.5-2 or 3-4 grams (cumulative); not done much at VAMC 4) SLCO1B1 genotyping - allelic SNP variants associated with SLCO1B1 are associated with GI toxicity Adverse effects: 1) stomatitis (2%) 2) elevated serum transaminases (24%) 3) hepatic cirrhosis (liver biopsy recommended at cumulative doses > 1.5-2 grams, 3-4 grams on another account) 4) myelosuppression, leukopenia (7%), macrocytic anemia [3] 5) opportunistic infection (10%) 6) pneumonitis (3-7%, < 5% [3]) a) most serious complication [19] - increased risk of death due to lung disease (RR 1.53) b) may follow upper respiratory tract infection c) no clear dose-response relationship d) chest X-ray: diffuse reticular & ground-glass opacities e) prognosis generally good after stopping methotrexate f) glucocorticoids may be of benefit [3] 7) gastrointestinal intolerance a) nausea, mild (< 100 mg) b) diarrhea 8) teratogenic & may cause permanent sterility - discontinue 3 months prior to conception [3] 9) acute renal failure a) precipitates in renal tubules (hyperuricemia) b) alkaline diuresis may be helpful 10) skin disorders - pruritus, skin desquamation, erythema, vasculitis, alopecia, depigmentation or hyperpigmentation, photosensitivity - methotrexate increases frequency of rheumatoid nodules & may lead to occurrence of nodules at unusual places such as fingertip pads - hand & foot syndrome [3] - skin cancer [25] 11) conjunctivitis 12) cystitis 13) arthralgia 14) CNS toxicity: a) encephalopathy b) seizures c) fever/chills d) dizziness 15) CNS toxicity with intrathecal administration: a) arachnoiditis b) subacute toxicity c) demyelinating encephalopathy (months to years later) 16) has been associated with rapid progression of HIV1 infection [3] 17) low dose (up to 20 mg weekly) 2.2% vs 1.1% for placebo [25] - gastrointestinal distress, pulmonary complications, infections - hematologic adverse events - skin cancer [25] - osteoporotic fractures of the distal tibia [26] 18) more adverse effects in patients with psoriatic arthritis than rheumatoid arthritis [27] 19) folic acid deficiency: ensure compliance *Toxicity: glucarpidase (Voraxaze) FDA-approved for treatment of methotrexate toxicity due to renal failure * adverse effects including alopecia, myelosuppression, liver-function test abnormalities, & gastrointestinal symptoms may be responsive to folic acid [20] Drug interactions: 1) leucovorin a) antagonizes early effects of methotrexate b) used as rescue 2) Septra/Bactrim & other trimethoprim-containing agents increase risk of myelosuppression 3) NSAIDs & probenecid increase methotrexate serum levels & toxicity 4) alcohol in combination may increase risk of hepatic injury - 1 drink (14 g of ethanol)/day does not appear to increase serum transaminases [23] - > 1 drink/day increases risk of alcholic hepatitis [23] 5) cholesterol binding resins & fiber decrease absorption of methotrexate 6) live virus vaccines 7) pyrimethamine 8) phenytoin 9) 5-fluorouracil 10) caffeine may reduce effectiveness of methotrexate [12] Test interactions: increases serum K+ Laboratory: 1) specimen: a) serum, plasma (heparin, EDTA) b) cerebrospinal fluid (CSF) c) centrifuge & remove cells as soon as possible d) stable at 4 degrees for 24 hours e) stable at -20 degrees for 1 month f) collect specimen at 30 minutes after low dose IV g) collect specimen at 2 hours after low dose oral h) collect specimen at 24, 48 & 72 after high dose IV i) protect from light 2) methods: HPLC, RIA, REA, enzyme inhibition, EIA, FPIA 3) interferences: -> RIA: hyperbilirubinemia, lipemia, methemoglobinemia, & methotrexate metabolites may interfere 4) labs with Loincs - methotrexate in erythrocytes - methotrexate in body fluid - methotrexate in serum/plasma - methotrexate free in serum/plasma - methotrexate in CSF - methotrexate in urine Mechanism of action: 1) folic acid analog 2) binds to dihydrofolate reductase inhibiting thymidine formation 3) diminishes inflammation by increasing adenosine levels [12] - increases release of adenosine from cells [17] 4) may also diminish inflammation by inhibition of polyamines [17] 5) high activity during S phase 6 Mechanism of drug resistance: a) defective transport via folate transporter b) decreased activity of folyl-polyglutamate synthetase c) increased activity of target enzyme dihydrofolate reductase

Interactions

drug interactions

Related

dihydrofolate reductase (DHFR, tetrahydrofolate dehydrogenase) folate transporter folylpolyglutamate synthase, mitochondrial; folylpoly-gamma-glutamate synthetase; FPGS; tetrahydrofolylpolyglutamate synthase; tetrahydrofolate synthase (FPGS) methotrexate in serum/plasma

General

aminopterin disease-modifying antirheumatic agent (DMARD) folate antagonist; folic acid analog; folic acid antagonist

Properties

MISC-INFO: elimination route KIDNEY LIVER 1/2life 8-15 HOURS toxic-range >0.02 UMOL/L <1-2 wk after low dose> >5 UMOL/L <24 hr after high dose> >0.5 UMOL/L <48 hr after high dose> >0.05 UMOL/L <72 hr after high dose> protein-binding 65% elimination by hemodialysis + hemoperfusion + peritoneal dialysis - pregnancy-category X safety in lactation -

References

  1. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 598
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022.
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Journal Watch 20(3):25, 2000
  6. Lipscomb et al NEJM 341:1974, 1999
  7. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  8. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 529, 533
  9. UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  10. Prescriber's Letter 9(5):26 2002
  11. Journal Watch 22(10):76, 2002 Choid HK et al, Lancet 359:1173, 2002
  12. Prescriber's Letter 10(4):23 2003
  13. Turesson C & Matteson EL, Genetics of rheumatoid arthritis Mayo Clin Proc 2006; 81:94
  14. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  15. Neeman N, Aronson MD, Schulze JE, Shmerling RH. Improving pregnancy counseling for women with rheumatoid arthritis taking methotrexate. Am J Med. 2009 Nov;122(11):998-1000 PMID: 19854323
  16. Thompson AE, Bashook PG. Rheumatologists' recommended patient information when prescribing methotrexate for rheumatoid arthritis. Clin Exp Rheumatol. 2010 Jul-Aug;28(4):539-45. PMID: 20663404
  17. Chan ES, Cronstein BN. Methotrexate--how does it really work? Nat Rev Rheumatol. 2010 Mar;6(3):175-8 PMID: 20197777
  18. Deprecated Reference
  19. Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheumatol. 2014 Apr;66(4):803-12. PMID: 24757133
  20. Shea B et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2013 Jun 4; 5:CD000951 PMID: 23728635
  21. Callen JP Methotrexate for Alopecia Areata NEJM Journal Watch. Feb 11, 2015 Massachusetts Medical Society (subscription needed) http://www.jwatch.org
  22. Rohr MK, Mikuls TR, Cohen SB, Thorne JC, O'Dell JR. Underuse of methotrexate in the treatment of rheumatoid arthritis: A national analysis of prescribing practices in the US. Arthritis Care Res (Hoboken) 2017 Jun; 69:794. PMID: 27863180
  23. Humphreys JH, Warner A, Costello R et al. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis 2017 Sep; 76:1509 PMID: 28341765 Free PMC Article
  24. Shea B, Swinden MV, Ghogomu ET et al Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. J Rheumatol. 2014 Jun;41(6):1049-60. Review. PMID: 24737913
  25. Solomon Dh, Glynn RJ, Karlson EW et al Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020. Feb 18 PMID: 32066146 https://annals.org/aim/article-abstract/2761423/adverse-effects-low-dose-methotrexate-randomized-trial - Bykerk VP A Call to Systematically Monitor for Adverse Events in Users of Low-Dose Methotrexate Therapy. Ann Intern Med. 2020. Feb 18 PMID: 32066142 https://annals.org/aim/article-abstract/2761577/call-systematically-monitor-adverse-events-users-low-dose-methotrexate-therapy
  26. Argawal PG et al Triads in Dermatology Indian J Dermatol. 2013 Sep-Oct; 58(5): 346-351 PMID: 24082177 PMCID: PMC3778772 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778772/
  27. Harris S Methotrexate: Side Effects Worse for Patients With Psoriatic Arthritis. PsA linked with more side effects than RA overall; smaller differences with TNFi. MedPage Today December 2, 2022 https://www.medpagetoday.com/reading-room/acrr/psoriaticarthritis/102014 - Patel S Clinical Implications of Methotrexate Side Effects in Psoriatic Arthritis and Rheumatoid Arthritis. Study looks at treatment burden from the patient's point of view. MedPage Today December 2, 2022 https://www.medpagetoday.com/reading-room/acrr/psoriaticarthritis/102013 - Ogdie A, Maksabedian Hernandez EJ, Shaw Y et al Side Effects of Methotrexate and Tumor Necrosis Factor Inhibitors: Differences in Tolerability Among Patients With Psoriatic Arthritis and Rheumatoid Arthritis. ACR. Open Rheumatology. 2022. Aug 15 PMID: 35971643 Free PMC article https://onlinelibrary.wiley.com/doi/full/10.1002/acr2.11467

Component-of

cyclophosphamide/methotrexate/5-fluorouracil (CMF)

Databases & Figures

PUBCHEM correlations Therapeutic Inducers of Apoptosis