Methotrexate


Generic Medicine Info
Indications and Dosage
Intramuscular, Intravenous
Acute lymphoblastic leukaemia
Adult: As maintenance: 20-30 mg/m2 via IM inj twice weekly or 2.5 mg/kg via IV inj every 14 days. If relapse occur, may repeat the initial induction regimen.
Elderly: Dose reduction may be necessary.

Intramuscular
Choriocarcinoma, Trophoblastic neoplasm
Adult: 15-30 mg daily for a 5-day course, may repeat course for 3-5 times as necessary with at least 1 week rest periods between courses until toxicity subsides.
Elderly: Dose reduction may be necessary.

Intramuscular
Mycosis fungoides
Adult: 50 mg once weekly or 25 mg twice weekly, Alternatively, 5-50 mg once weekly or 15-37.5 mg twice weekly. Dose reduction or discontinuation is based on patient response and haematologic monitoring. Treatment regimen, protocols, and guidelines may vary among countries (refer to detailed product guideline).
Elderly: Dose reduction may be necessary.

Intramuscular, Intravenous
Psoriasis
Adult: In patient with severe, uncontrolled case, unresponsive to conventional therapy: Test dose: 5-10 mg 1 week prior to therapy. Then, 10-25 mg weekly via IM or IV inj, adjusted according to patient response.
Elderly: Dose reduction may be necessary.

Intrathecal
Meningeal leukaemia
Adult: 12 mg once weekly, repeated usually until CSF cell count returns to normal, at this point, 1 additional dose is recommended. For prophylactic use, refer to local protocols or guidelines.
Child: ≥3 years Same as adult dose.
Elderly: Dose reduction may be necessary.

Intravenous
Breast cancer
Adult: In combination with cyclophosphamide and fluorouracil: 40 mg/m2 on days 1 and 8 every 4 weeks.
Elderly: Dose reduction may be necessary.

Intravenous
Osteosarcoma
Adult: In combination with other chemotherapeutic agents and with leucovorin rescue: Initially, 8-12 g/m2 infused over 4 hours. Treatment regimen may vary among countries (refer to detailed product guideline).

Oral
Choriocarcinoma, Trophoblastic neoplasm
Adult: 15-30 mg daily for a 5-day course, may repeat course for 3-5 times as necessary with at least 1 week rest periods between courses until toxicity subsides.
Elderly: Dose reduction may be necessary.

Oral
Rheumatoid arthritis
Adult: In patient with severe case, unresponsive or intolerant to other therapy: Initially, 7.5-15 mg once weekly, may increase to 20-25 mg once weekly, according to patient response. Alternatively, 2.5 mg 12 hourly for 3 doses once weekly.
Elderly: Dose reduction may be necessary.

Oral
Burkitt's lymphoma
Adult: Stages 1-2: Recommended dose: 10-25 mg daily for 4-8 days. Stage 3: In combination with other antitumour agents: 0.625-2.5 mg/kg daily. In all stages, therapy usually consists of several courses interposed with 7-10 days rest periods.
Elderly: Dose reduction may be necessary.

Oral
Juvenile idiopathic arthritis
Child: In patient with inadequate response to NSAIDs: ≥3 years Initially, 10-15 mg/m2 once weekly, adjusted gradually to achieve optimal response. In therapy-refractory cases, dose may be increased to 20 mg/m2 once weekly.

Oral
Mycosis fungoides
Adult: Recommended dose: 2.5-10 mg daily. Alternatively, 5-50 mg once weekly or 15-37.5 mg twice weekly, or 25 mg once weekly increased to 50 mg once weekly. Dose reduction or discontinuation is based on patient response and haematologic monitoring. Treatment regimen, protocols, and guidelines may vary among countries (refer to detailed product guideline).
Elderly: Dose reduction may be necessary.

Oral
Psoriasis
Adult: In patient with severe, uncontrolled case, unresponsive to other therapy: Test dose: 2.5-5 mg 1 week prior to therapy. Then, 7.5-15 mg once weekly, may increase to 20-25 mg weekly as necessary. Alternatively, 10-25 mg once weekly with test dose of 5-10 mg 1 week prior to therapy. Doses may be adjusted according to patient response and haematological toxicity.
Elderly: Dose reduction may be necessary.

Oral
Acute lymphoblastic leukaemia
Adult: In combination with prednisolone for induction of remission: Initially, 3.3 mg/m2 daily for 4-6 weeks. Maintenance dose: 20-30 mg/m2 twice weekly.
Child: ≥3 years Same as adult dose.

Subcutaneous
Psoriasis
Adult: In patient with severe, uncontrolled case, unresponsive to conventional therapy: Initially, 10-25 mg once weekly, gradually adjust dose according to patient response.
Elderly: Dose reduction may be necessary.

Subcutaneous
Polyarticular juvenile idiopathic arthritis
Child: 2-16 years Initially, 10 mg/m2 once weekly, gradually adjust up to 20-30 mg/m2 once weekly. Max: 25 mg.

Subcutaneous
Rheumatoid arthritis
Adult: Initially, 7.5 mg once weekly, adjust dose gradually according to individual response and tolerability.
Elderly: Dose reduction may be necessary.
Renal Impairment
PO Juvenile idiopathic arthritis; Acute lymphoblastic leukaemia Burkitt's lymphoma
PO, IM Trophoblastic neoplasm; Choriocarcinoma; Mycosis fungoides
IV Breast cancer
Intrathecal Meningeal leukaemia
IV, IM Acute lymphoblastic leukaemia; Psoriasis
Dose adjustments for methotrexate dose <100 mg/m2:
CrCl (mL/min) Dosage
<30
Contraindicated.
30-59
Use 50% of the dose.
Dose adjustments for methotrexate dose >100 mg/m2:
CrCl (mL/min) Dosage 
<60
Contraindicated.
Approx 60
Use 63% of the dose.
Approx 80
Use 75% of the dose.

PO Rheumatoid arthritis; Psoriasis
CrCl (mL/min) Dosage
<30
Contraindicated.
30-59 Use 50% of the dose.

SC Rheumatoid arthritis; Polyarticular juvenile idiopathic arthritis; Psoriasis
CrCl (mL/min) Dosage
<10
Contraindicated.
10-50
Use 50% of the dose.
Administration
Should be taken on an empty stomach. Best taken on an empty stomach. May be taken w/ meals to reduce GI discomfort. Avoid taking w/ milk-rich products.
Reconstitution
IV: Dilute vial with 5% dextrose or 0.9% NaCl solution to a concentration of ≤25 mg/mL or 50 mg/mL, may dilute further in 5% dextrose or 0.9% NaCl solution. Intrathecal: Dilute with preservative-free 0.9% NaCl, lactated Ringer’s or Elliot’s B solution to a final volume of up to 12 mL or according to local protocol. Usual final concentration: 1 mg/mL up to approx 2-4 mg/mL.
Contraindications
Pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anaemia), active infection, immunodeficiency syndrome (with overt or laboratory evidence), known active gastrointestinal ulcer disease, alcoholism. Severe renal impairment. Significant hepatic impairment (>5 mg/dL bilirubin levels), alcoholic liver disease. Immunisation with live vaccines. Pregnancy and lactation.
Special Precautions
Patient with pleural effusion, ascites, folic acid deficiency; inactive and chronic infection (e.g. herpes zoster, TB, hepatitis B or C); risk factors for hepatotoxicity (e.g. persistent abnormal liver chemistries, history of above moderate alcohol consumption, family history of liver disease, diabetes, obesity, hyperlipidaemia), ulcerative colitis. Dehydrated and debilitated patient. Patient undergoing radiotherapy and orthopaedic surgery. Mild to moderate renal impairment. Children and elderly.
Adverse Reactions
Significant: Acute renal failure, bone marrow suppression (e.g. anaemia, pancytopenia, neutropenia, leucopenia, thrombocytopenia); gastrointestinal toxicity including ulcerative stomatitis and diarrhea; malignant lymphomas (low dose), impairment of fertility, oligospermia, menstrual dysfunction, pulmonary alveolar haemorrhage; encephalopathy/leucoencephalopathy; radiation recall dermatitis and sunburn; anaphylactic reaction, nonproductive cough, tumour lysis syndrome (in patients with high tumour burden), convulsions (intrathecal).
Blood and lymphatic system disorders: Megaloblastic anaemia, haematopoietic disorders, lymphoproliferative disorder, lymphadenopathy.
Cardiac disorders: Pericardial effusion.
Ear and labyrinth disorders: Tinnitus.
Endocrine disorders: Diabetes mellitus.
Eye disorders: Conjunctivitis, blurred vision, retinopathy.
Gastrointestinal disorders: Dyspepsia, abdominal pain, nausea, vomiting, mucositis, gingivitis, haematemesis, melena, pancreatitis, enteritis, gastrointestinal ulceration and bleeding.
General disorders and administration site conditions: Fatigue, lethargy, fever, chills, wound healing impairment, asthenia.
Infections and infestations: Respiratory or cutaneous bacterial infections, reactivation of inactive chronic infection.
Investigations: Abnormal LFT (e.g. increased AST, ALT, bilirubin, alkaline phosphatase).
Metabolism and nutrition disorders: Loss of appetite.
Musculoskeletal and connective tissue disorders: Osteoporosis, stress fractures, arthralgia/myalgia, increased rheumatic nodules.
Nervous system disorders: Headache, drowsiness, vertigo, paresis, hemiparesis.
Psychiatric disorders: Depression, confusion, mood alterations, insomnia, psychoses.
Renal and urinary disorders: Ulceration of the bladder, disturbed micturition, oliguria, haematuria, dysuria, anuria, proteinuria, electrolyte disturbance, nephropathy.
Reproductive system and breast disorders: Gynaecomastia, decreased libido, vaginal bleeding or ulceration, inflammation of the vagina, vaginal discharge.
Respiratory, thoracic and mediastinal disorders: Epistaxis.
Skin and subcutaneous tissue disorders: Alopecia, photosensitivity, pruritus, acne, ulceration, ecchymosis, erythema, exanthema, herpetiform eruptions of the skin, pigmentary changes, onycholysis, petechiae, hidradenitis, telangiectasia, furunculosis, painful damage to psoriatic lesions, nail hyperpigmentation, acute paronychia.
Vascular disorders: Thromboembolic events (e.g. arterial thrombosis, cerebral thrombosis, DVT, retinal thrombosis, thrombophlebitis, pulmonary embolus), vasculitis, hypotension.
Potentially Fatal: Hepatotoxicity (fibrosis, cirrhosis), acute or chronic interstitial pneumonitis often associated with eosinophilia, Pneumocystis jirovecii pneumonia, severe dermatologic reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, skin necrosis, erythema multiforme).
IM/Intra-arterial/IV/Parenteral/PO/SC: X
Patient Counseling Information
This drug may cause fatigue and dizziness, if affected, do not drive or operate machinery.
Monitoring Parameters
Assess pregnancy status prior to therapy in women of childbearing potential. Oncology: Monitor CBC with differential and platelets, serum creatinine, BUN, LFT at baseline and during therapy; methotrexate levels and urine pH (in high-dose methotrexate); fluid and electrolyte status (in patients with impaired elimination); chest x-ray at baseline; pulmonary function test; signs of toxicities in patients with impaired elimination (e.g. patients with ascites, pleural effusion). Evaluate urinary chorionic gonadotropin (hCG) during initial therapy (in patient with choriocarcinoma). Psoriasis: Monitor CBC with differential and platelets at baseline, 7-14 days after initial therapy or dose increase, every 2-4 weeks for the first few months then every 1-3 months depending on patient condition; BUN and serum creatinine at baseline and every 2-3 months; LFTs at baseline, monthly for 6 months then every 1-2 months; chest x-ray at baseline (patient with underlying disease); pulmonary function test. May consider purified protein derivative skin test for latent TB screening at baseline. Obtain liver biopsy at baseline or after 2-6 months, and with a total cumulative dose of 1.5 g and after each additional 1-5 g in patients with risk factors for hepatotoxicity, or in those without risk factors (with persistent elevations in 5 of 9 AST levels during 12-month period or decreased serum albumin below normal range with normal nutritional status) receiving high doses. Rheumatoid arthritis: CBC with differential and platelets, serum creatinine, LFT at baseline and every 2-4 weeks for 3 months after initial therapy or dose increases, then every 8-12 weeks during 3-6 months of therapy, every 12 weeks beyond 6 months of therapy, thereafter; chest x-ray within 1 year prior to therapy; hepatitis B and C serology (in high-risk patients). Perform TB testing annually for those who live, travel or work in areas with TB exposure. Obtain liver biopsy (in patients with risk factors for hepatotoxicity) at baseline or during treatment if with persistent increase in LFT. Juvenile idiopathic arthritis: Monitor CBC monthly; renal and liver function every 1-2 months; pulmonary function tests (if drug-induced lung disease is suspected).
Overdosage
Symptoms: Haematological (e.g. leucopenia, thrombocytopenia, anaemia, pancytopenia, bone marrow suppression) and gastrointestinal (e.g. mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulcer and bleeding) reactions; Chronic overdose: Sepsis or septic shock, renal failure, aplastic anaemia; Intrathecal: Headache, nausea, vomiting, seizure or convulsion, acute toxic encephalopathy; cerebellar herniation associated with increased intracranial pressure, death. Management: Initiate parenteral Ca folinate therapy within 1 hour after methotrexate administration, at a dose equal to the methotrexate dose received by the patient. Administer leucovorin as antidote within 1 hour at a dose equal to or greater than the methotrexate dose. Renal dialysis, blood transfusions and reverse barrier nursing may also be necessary. Hydration and urinary alkalisation may be necessary in case of large overdose. Acute intermittent haemodialysis using a high flux dialysator may be considered for effective clearance of methotrexate. Administer glucarpidase in patients with delayed methotrexate clearance due to impaired kidney function. Avoid concomitant administration of leucovorin within 2 hours or after a dose of glucarpidase.
Drug Interactions
Increased serum concentration with ciprofloxacin, ciclosporin, penicillin, levetiracetam, probenecid, salicylates, sulfonamides, and PPI (e.g. omeprazole, pantoprazole), phenylbutazone, phenytoin. May enhance adverse effect (particularly pancytopenia) of leflunomide. Concomitant high-dose methotrexate and cisplatin may enhance nephrotoxicity. Reduced intestinal absorption with tetracyclines, non-absorbable broad-spectrum antibiotics, colestyramine. Decreased efficacy with vitamin preparations or other products containing folic acid or its derivatives. Increased risk of marked haematopoietic disorders with trimethoprim-sulfamethoxazole, chloramphenicol, pyrimethamine. Enhanced hepatotoxicity with azathioprine, retinoids and sulfasalazine. May increase plasma levels of mercaptopurine and theophylline. Potentiated effect with nitrous oxide.
Potentially Fatal: May reduce efficacy of live vaccines. Increased risk of severe haematologic (e.g. bone marrow suppression and aplastic anaemia) and gastrointestinal toxicity with certain NSAIDs.
Food Interaction
Decreased absorption with milk-rich foods.
Action
Description: Methotrexate is a folate antimetabolite that competitively inhibits the dihydrofolate reductase and prevents formation of tetrahydrofolate, which is necessary for thymidylate and purine formation, thus preventing DNA synthesis, repair and cellular replication. It is most active in the S-phase of the cell cycle. Its mechanism of action in the management of rheumatoid arthritis and juvenile idiopathic arthritis is still unknown but may be due to its immunosuppressive effect. In psoriasis, it is thought to target rapidly proliferating epithelial cells in the skin.
Onset: Antirheumatic: 3-6 weeks, may continue longer than 12 weeks.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Rapidly and completely absorbed after IM doses. Bioavailability: Approx 60% (low dose). Time to peak plasma concentrations: 0.75-6 hours (oral); 30-60 minutes (IM).
Distribution: Distributes to tissues and extracellular fluids; penetrates ascitic fluid and effusions. Crosses placenta; enters breast milk. Volume of distribution: IV: 0.18 L/kg (initial); 0.4-0.8 L/kg (steady state). Plasma protein binding: Approx 50%.
Metabolism: Partly metabolised in the intestinal flora by carboxypeptidase to DAMPA; undergoes hepatic metabolism by aldehyde oxidase to form 7-hydroxy methotrexate; and intracellular metabolism into polyglutamates, which may also be converted by hydrolase enzymes back to methotrexate.
Excretion: Mainly via urine (80-90% as unchanged drug; 5-7% as 7-hydroxy methotrexate); faeces (<10%). Elimination half-life: Approx 3-10 hours (low-dose treatment); 8-15 hours (high-dose treatment).
Chemical Structure

Chemical Structure Image
Methotrexate

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 126941, Methotrexate. https://pubchem.ncbi.nlm.nih.gov/compound/Methotrexate. Accessed July 27, 2021.

Storage
Tab: Store between 20-25°C. Protect from light. Oral solution: Store between 2-8°C; 15-30°C for up to 60 days. Do not freeze. Avoid excessive heat. IV/SC inj: Store between 15-30°C. Protect from light. IM inj: Store below 25°C. Intrathecal inj: Use immediately after preparation. This is a cytotoxic drug. Any unused portions should be disposed of in accordance with local requirements.
MIMS Class
Cytotoxic Chemotherapy / Immunosuppressants
ATC Classification
L04AX03 - methotrexate ; Belongs to the class of other immunosuppressants.
L01BA01 - methotrexate ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.
References
Anon. Methotrexate. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/04/2020.

Buckingham R (ed). Methotrexate. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/04/2020.

Joint Formulary Committee. Methotrexate. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/04/2020.

Maxtrex Tablets 10 mg (Pfizer Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Maxtrex Tablets 2.5 mg (Pfizer Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Methofill 15 mg Solution for Inj in Pre-filled Injector (Accord Healthcare Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Methotrexate 100 mg/mL Injection (Hospira UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Methotrexate 2.5 mg/mL Injection (Hospira UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Methotrexate 25 mg/mL Injection (Hospira UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 08/04/2020.

Methotrexate Injection, Powder, Lyophilized, For Solution (Fresenius Kabi USA, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/04/2020.

Methotrexate Tablet (Aurobindo Pharma Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/04/2020.

Otrexup Injection, Solution (Antares Pharma, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 12/05/2020.

Disclaimer: This information is independently developed by MIMS based on Methotrexate from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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