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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(meth oh TREKS ate)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oncology-related uses: Treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole), acute lymphocytic leukemia (ALL), meningeal leukemia, breast cancer, head and neck cancer (epidermoid), cutaneous T-Cell lymphoma (advanced mycosis fungoides), lung cancer (squamous cell and small cell), advanced non-Hodgkin's lymphomas (NHL), osteosarcoma
Nononcology uses: Treatment of psoriasis (severe, recalcitrant, disabling) and severe rheumatoid arthritis (RA), including polyarticular-course juvenile idiopathic arthritis (JIA)
Use: Unlabeled/Investigational
Treatment and maintenance of remission in Crohn's disease; ectopic pregnancy; dermatomyositis/polymyositis; bladder cancer, central nervous system tumors (including nonleukemic meningeal cancers), acute promyelocytic leukemia (maintenance treatment), soft tissue sarcoma (desmoid tumors); acute graft-versus-host disease (GVHD) prophylaxis; medical management of abortion; systemic lupus erythematosus; Takayasu arteritis
Pregnancy Risk Factor
X (psoriasis, rheumatoid arthritis)
Pregnancy Considerations
[U.S. Boxed Warning]: Methotrexate may cause fetal death and/or congenital abnormalities. Studies in animals and pregnant women have shown evidence of fetal abnormalities; therefore, the manufacturer classifies methotrexate as pregnancy category X (for psoriasis or RA). A pattern of congenital malformations associated with maternal methotrexate use is referred to as the aminopterin/methotrexate syndrome. Features of the syndrome include CNS, skeletal, and cardiac abnormalities. Low birth weight and developmental delay have also been reported. The use of methotrexate may impair fertility and cause menstrual irregularities or oligospermia during treatment and following therapy. Methotrexate is approved for the treatment of trophoblastic neoplasms (gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole) and has been used for the medical management of ectopic pregnancy and the medical management of abortion. [U.S. Boxed Warning]: Use is contraindicated for the treatment of psoriasis or RA in pregnant women. Pregnancy should be excluded prior to therapy in women of childbearing potential. Use for the treatment of neoplastic diseases only when the potential benefit to the mother outweighs the possible risk to the fetus. Pregnancy should be avoided for ≥3 months following treatment in male patients and ≥1 ovulatory cycle in female patients. A registry is available for pregnant women exposed to autoimmune medications including methotrexate. For additional information contact the Organization of Teratology Information Specialists, OTIS Autoimmune Diseases Study, at 877-311-8972.
Lactation
Enters breast milk/contraindicated
Breast-Feeding Considerations
Low amounts of methotrexate are excreted into breast milk. Due to the potential for serious adverse reactions in a breast-feeding infant, use is contraindicated in nursing mothers.
Contraindications
Hypersensitivity to methotrexate or any component of the formulation; breast-feeding
Additional contraindications for patients with psoriasis or rheumatoid arthritis: Pregnancy, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency syndrome (overt or laboratory evidence); pre-existing blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
Warnings/Precautions
Boxed Warnings:
• Acute renal failure: See “Concerns related to adverse effects” below.
• Ascites/pleural effusion: See “Disease-related concerns” below.
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Dermatologic reactions: See “Concerns related to adverse effects” below.
• Diarrhea/stomatitis: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
• Hepatotoxicity: See “Concerns related to adverse effects” below.
• Lymphomas: See “Concerns related to adverse effects” below.
• NSAID's: See “Concurrent drug therapy issues” below.
• Opportunistic infections: See “Concerns related to adverse effects” below.
• Pneumonitis: See “Concerns related to adverse effects” below.
• Pregnancy: See “Special populations” below.
• Preservative containing formulations/diluents: See “Dosage form specific issues” below.
• Radiotherapy recipients: See “Special populations” below..
• Renal impairment: See “Disease-related concerns” below.
• Tumor lysis syndrome: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Acute renal failure: [U.S. Boxed Warning]: May cause renal damage leading to acute renal failure, especially with high-dose methotrexate; monitor renal function and methotrexate levels closely, maintain adequate hydration and urinary alkalinization. Use caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy (eg, cisplatin).
• Bone marrow suppression: [U.S. Boxed Warning]: Bone marrow suppression may occur, resulting in anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Use caution in patients with pre-existing bone marrow suppression. Discontinue therapy in RA or psoriasis if a significant decrease in hematologic components is noted.
• Dermatologic reactions: [U.S. Boxed Warning]: Any dose level or route of administration may cause severe and potentially fatal dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme. Radiation dermatitis and sunburn may be precipitated by methotrexate administration. Psoriatic lesions may be worsened by concomitant exposure to ultraviolet radiation.
• Diarrhea/stomatitis: [U.S. Boxed Warning]: Diarrhea and ulcerative stomatitis may require interruption of therapy; death from hemorrhagic enteritis or intestinal perforation has been reported. Use with caution in patients with peptic ulcer disease, ulcerative colitis.
• Fertility: May cause impairment of fertility, oligospermia, and menstrual dysfunction.
• Hepatotoxicity: [U.S. Boxed Warning]: Methotrexate has been associated with acute (elevated transaminases) and potentially fatal chronic (fibrosis, cirrhosis) hepatotoxicity. Risk is related to cumulative dose and prolonged exposure. Monitor closely (with liver function tests, including serum albumin) for liver toxicities. Liver enzyme elevations may be noted, but may not be predictive of hepatic disease in long term treatment for psoriasis (but generally is predictive in rheumatoid arthritis [RA] treatment). With long-term use, liver biopsy may show histologic changes, fibrosis, or cirrhosis; periodic liver biopsy is recommended with long-term use for psoriasis patients with risk factors for hepatotoxicity and for persistent abnormal liver function tests in psoriasis patients without risk factors for hepatotoxicity and in RA patients; discontinue methotrexate with moderate-to-severe change in liver biopsy. Risk factors for hepatotoxicity include history of above moderate ethanol consumption, persistent abnormal liver chemistries, history of chronic liver disease (including hepatitis B or C), family history of inheritable liver disease, diabetes, obesity, hyperlipidemia, lack of folate supplementation during methotrexate therapy, and history of significant exposure to hepatotoxic drugs. Use caution with preexisting liver impairment; may require dosage reduction. Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine).
• Lymphomas: [U.S. Boxed Warning]: Use of low dose methotrexate has been associated with the development of malignant lymphomas; may regress upon discontinuation of therapy; treat lymphoma appropriately if regression is not induced by cessation of methotrexate.
• Neurotoxicity: May cause neurotoxicity including seizures (usually in pediatric ALL patients), leukoencephalopathy (usually with concurrent cranial irradiation) and stroke-like encephalopathy (usually with high-dose regimens). Chemical arachnoiditis (headache, back pain, nuchal rigidity, fever), myelopathy and chronic leukoencephalopathy may result from intrathecal administration.
• Opportunistic infections: [U.S. Boxed Warning]: Immune suppression may lead to potentially fatal opportunistic infections.
• Pneumonitis: [U.S. Boxed Warning]: May cause potentially life-threatening pneumonitis (may occur at any time during therapy and at any dosage); monitor closely for pulmonary symptoms, particularly dry, nonproductive cough. Other potential symptoms include fever, dyspnea, hypoxemia, or pulmonary infiltrate.
• Tumor lysis syndrome: [U.S. Boxed Warning]: Tumor lysis syndrome may occur in patients with high tumor burden; use appropriate prevention and treatment.
Disease-related concerns:
• Ascites/pleural effusions: [U.S. Boxed Warning]: Elimination is reduced in patients with ascites and/or pleural fluid; may require dose reduction or discontinuation. Monitor closely for toxicity.
• Hepatic impairment: Use with caution in patients with pre-existing liver impairment.
• Peptic ulcer disease: Use with caution in patients with peptic ulcer disease; diarrhea and stomatitis may occur.
• Renal impairment: [U.S. Boxed Warning]: Methotrexate elimination is reduced in patients with renal impairment; may require dose reduction or discontinuation; monitor closely for toxicity.
• Ulcerative colitis: Use with caution in patients with ulcerative colitis; diarrhea and stomatitis may occur.
Concurrent drug therapy issues:
• Hepatotoxic agents: Use caution when used with other hepatotoxic agents (azathioprine, retinoids, sulfasalazine).
• Nephrotoxic chemotherapy: Use caution in osteosarcoma patients treated with high-dose methotrexate in combination with nephrotoxic chemotherapy (eg, cisplatin).
• NSAID's: [U.S. Boxed Warning]: Concurrent administration with NSAIDs may cause severe bone marrow suppression, aplastic anemia, and GI toxicity. Do not administer NSAIDs prior to or during high dose methotrexate therapy; may increase and prolong serum methotrexate levels. Doses used for psoriasis may still lead to unexpected toxicities; use caution when administering NSAIDs or salicylates with lower doses of methotrexate for RA. Methotrexate may increase the levels and effects of mercaptopurine; may require dosage adjustments. Vitamins containing folate may decrease response to systemic methotrexate; folate deficiency may increase methotrexate toxicity.
Special populations:
• Elderly: Use caution in the elderly; increased risk of toxicity.
• Pregnancy: [U.S. Boxed Warning]: May cause fetal death or congenital abnormalities; do not use for psoriasis or RA treatment in pregnant women.
• Radiotherapy recipients: [U.S. Boxed Warning]: Concomitant methotrexate administration with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Dosage form specific issues:
• Benzyl alcohol: Injection may contain benzyl alcohol which has been associated with "gasping syndrome" in neonates.
• Preservative containing formulations/diluents: [U.S. Boxed Warnings]: Methotrexate formulations and/or diluents containing preservatives should not be used for intrathecal or high-dose therapy.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warnings]: Should be administered under the supervision of a physician experienced in the use of antimetabolite therapy; serious and fatal toxicities have occurred at all dose levels. For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic, traditional therapy is ineffective.
• Intrathecal safety: When used for intrathecal administration, should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications intended for administration into the central nervous system (Jacobson, 2009).
Adverse Reactions
Note: Adverse reactions vary by route and dosage. Hematologic and/or gastrointestinal toxicities may be common at dosages used in chemotherapy; these reactions are much less frequent when used at typical dosages for rheumatic diseases.
>10%:
Central nervous system (with I.T. administration or very high-dose therapy):
Arachnoiditis: Acute reaction manifested as severe headache, nuchal rigidity, vomiting, and fever; may be alleviated by reducing the dose
Subacute toxicity: 10% of patients treated with 12-15 mg/m2 of I.T. methotrexate may develop this in the second or third week of therapy; consists of motor paralysis of extremities, cranial nerve palsy, seizure, or coma. This has also been seen in pediatric cases receiving very high-dose I.V. methotrexate.
Demyelinating encephalopathy: Seen months or years after receiving methotrexate; usually in association with cranial irradiation or other systemic chemotherapy
Dermatologic: Reddening of skin
Endocrine & metabolic: Hyperuricemia, defective oogenesis or spermatogenesis
Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, anorexia, intestinal perforation, mucositis (dose dependent; appears in 3-7 days after therapy, resolving within 2 weeks)
Hematologic: Leukopenia, myelosuppression (nadir: 7-10 days), thrombocytopenia
Renal: Renal failure, azotemia, nephropathy
Respiratory: Pharyngitis
1% to 10%:
Cardiovascular: Vasculitis
Central nervous system: Dizziness, malaise, encephalopathy, seizure, fever, chills
Dermatologic: Alopecia, rash, photosensitivity, depigmentation or hyperpigmentation of skin
Endocrine & metabolic: Diabetes
Genitourinary: Cystitis
Hematologic: Hemorrhage
Hepatic: Cirrhosis and portal fibrosis have been associated with chronic methotrexate therapy; acute elevation of liver enzymes are common after high-dose methotrexate, and usually resolve within 10 days.
Neuromuscular & skeletal: Arthralgia
Ocular: Blurred vision
Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine and BUN and a fall in urine output; more common with high-dose methotrexate, and may be due to precipitation of the drug.
Respiratory: Pneumonitis: Associated with fever, cough, and interstitial pulmonary infiltrates; treatment is to withhold methotrexate during the acute reaction; interstitial pneumonitis has been reported to occur with an incidence of 1% in patients with RA (dose 7.5-15 mg/week)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acute neurologic syndrome (at high dosages; symptoms include confusion, hemiparesis, transient blindness, and coma); acute respiratory distress syndrome, anaphylaxis, alveolitis, arrhythmia, cognitive dysfunction (has been reported at low dosage), decreased resistance to infection, erythema multiforme, hepatic failure, leukoencephalopathy (especially following craniospinal irradiation or repeated high-dose therapy), lymphoproliferative disorders, mesenteric ischemis (acute), MI, myocardial ischemia, nasal septum perforation, osteonecrosis and soft tissue necrosis (with radiotherapy), pericarditis, plaque erosions (psoriasis), reversible posterior leukoencephalopathy syndrome (RPLS), seizure (more frequent in pediatric patients with ALL), Stevens-Johnson syndrome, stroke, thromboembolism, toxic epidermal necrolysis
Metabolism/Transport Effects
Substrate of P-glycoprotein, SLCO1B1
Drug Interactions
Acitretin: May enhance the hepatotoxic effect of Methotrexate. Risk X: Avoid combination
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Bile Acid Sequestrants: May decrease the absorption of Methotrexate. Risk C: Monitor therapy
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
Ciprofloxacin: May increase the serum concentration of Methotrexate. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Methotrexate. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE. This may result in nephrotoxicity. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of CycloSPORINE (Systemic). This may result in nephrotoxicity. Risk D: Consider therapy modification
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Leflunomide: Methotrexate may enhance the adverse/toxic effect of Leflunomide. Particular concerns are an increased risk of pancytopenia and/or hepatotoxicity. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May decrease the excretion of Methotrexate. Risk D: Consider therapy modification
Penicillins: May decrease the excretion of Methotrexate. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Probenecid: May increase the serum concentration of Methotrexate. Management: Avoid concomitant use of probenecid and methotrexate if possible. If used together, consider lower methotrexate doses and monitor for evidence of methotrexate toxicity. Risk D: Consider therapy modification
Proton Pump Inhibitors: May decrease the excretion of Methotrexate. Antirheumatic doses of methotrexate probably hold minimal risk. Risk C: Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Salicylates: May increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modification
Sapropterin: Methotrexate may decrease the serum concentration of Sapropterin. Specifically, methotrexate may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Sulfonamide Derivatives: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (eg, bone marrow suppression). Risk D: Consider therapy modification
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Theophylline Derivatives: Methotrexate may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Trimethoprim: May enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Risk D: Consider therapy modification
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Methotrexate may enhance the adverse/toxic effect of Vaccines (Live). Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may be associated with increased liver injury).
Food: Methotrexate peak serum levels may be decreased if taken with food. Milk-rich foods may decrease methotrexate absorption. Folate may decrease drug response.
Herb/Nutraceutical: Avoid echinacea (has immunostimulant properties).
Storage
Store tablets and intact vials at room temperature (15°C to 25°C). Protect from light.
I.M., I.V., SubQ: Solution diluted in D5W or NS is stable for 24 hours at room temperature (21°C to 25°C). Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature.
Intrathecal: Intrathecal dilutions are preservative free and should be used as soon as possible after preparation . After preparation, store intrathecal medications (until use) in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.
Reconstitution
Use appropriate precautions for handling and disposal. Use preservative-free preparations for intrathecal or high-dose methotrexate administration.
I.M., I.V., SubQ: Dilute powder with D5W or NS to a concentration of ≤25 mg/mL (20 mg and 50 mg vials) and 50 mg/mL (1 g vial). May further dilute in D5W or NS.
Intrathecal: Prepare intrathecal solutions with preservative-free NS, lactated Ringer's, or Elliot's B solution to a final volume of up to 12 mL (volume generally based on institution or practitioner preference). Intrathecal methotrexate concentrations may be institution specific or based on practitioner preference, generally ranging from a final concentration of 1 mg/mL (per prescribing information; Grossman, 1993; Lin, 2008) up to ~2-4 mg/mL (de Lemos, 2009; Glantz, 1999). For triple intrathecal therapy (methotrexate 12 mg/hydrocortisone 24 mg/cytarabine 36 mg), preparation to final volume of 12 mL is reported (Lin, 2008). Intrathecal medications should NOT be prepared during the preparation of any other agents.
Compatibility
Stable in D5NS, D5W, NS.
Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, asparaginase, aztreonam, bleomycin, cefepime, ceftriaxone, cimetidine, cisplatin, cyclophosphamide, cytarabine, daunorubicin HCl, diphenhydramine, doxorubicin HCl, doxorubicin liposome, etoposide, etoposide phosphate, famotidine, filgrastim, fludarabine, fluorouracil, furosemide, gallium nitrate, ganciclovir, granisetron, heparin, hydromorphone, imipenem/cilastatin, leucovorin calcium, linezolid, lorazepam, melphalan, mesna, methylprednisolone sodium succinate, metoclopramide, mitomycin, morphine, ondansetron, oxacillin, oxaliplatin, paclitaxel, piperacillin/tazobactam, prochlorperazine edisylate, ranitidine, sargramostim, teniposide, thiotepa, vinblastine, vincristine, vinorelbine. Incompatible: Chlorpromazine, gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol. Variable (consult detailed reference): Dexamethasone sodium phosphate, droperidol, vancomycin.
Compatibility in syringe: Compatible: Bleomycin, cisplatin, cyclophosphamide, doxapram, doxorubicin HCl, fluorouracil, furosemide, heparin sodium, leucovorin calcium, mitomycin, vinblastine, vincristine. Incompatible: Droperidol. Variable (consult detailed reference): Metoclopramide.
Compatibility when admixed: Compatible: Cyclophosphamide, cyclophosphamide with fluorouracil, cytarabine, fluorouracil, hydroxyzine HCl, ondansetron, sodium bicarbonate, vincristine. Incompatible: Bleomycin.
Mechanism of Action
Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis. Methotrexate is cell cycle specific for the S phase of the cycle.
The MOA in the treatment of rheumatoid arthritis is unknown, but may affect immune function. In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin.
In Crohn's disease, it may have immune modulator and anti-inflammatory activity.
Pharmacodynamics/Kinetics
Onset of action: Antirheumatic: 3-6 weeks; additional improvement may continue longer than 12 weeks
Absorption: Oral: Dose dependent; well absorbed at low doses (<30 mg/m2), incomplete after higher doses; I.M. injection: Complete
Distribution: Penetrates slowly into 3rd space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); sustained concentrations retained in kidney and liver
Vd: 0.18 L/kg (initial); 0.4-0.8 L/kg (steady state)
Protein binding: ~50%
Metabolism: <10%; degraded by intestinal flora to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-OH methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed. Polyglutamated forms can be converted back to methotrexate.
Bioavailability: Dose dependent; ~60% at low doses
Half-life elimination: Low dose: 3-10 hours; High dose: 8-15 hours
Time to peak, serum: Oral: 1-2 hours; I.M.: 30-60 minutes
Excretion: Urine (44% to 100%); feces (small amounts)
Dosage
Details concerning dosing in combination regimens should also be consulted.
Note: Doses between 100-500 mg/m2 may require leucovorin calcium rescue. Doses >500 mg/m2 require leucovorin calcium rescue: Oral, I.M., I.V.: Leucovorin calcium 10-15 mg/m2 every 6 hours for 8 or 10 doses, starting 24 hours after the start of methotrexate infusion. Continue until the methotrexate level is ≤0.1 micromolar (10-7 M). Some clinicians continue leucovorin calcium until the methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8 M).
If the 48-hour methotrexate level is >1 micromolar (10-6 M) or the 72-hour methotrexate level is >0.2 micromolar (2 x 10-7 M): I.V., I.M, Oral: Leucovorin calcium 100 mg/m2 every 6 hours until the methotrexate level is ≤0.1 micromolar (10-7 M). Some clinicians continue leucovorin calcium until the methotrexate level is <0.05 micromolar (5 x 10-8 M) or 0.01 micromolar (10-8 M).
Children:
Dermatomyositis (unlabeled use): Oral: 15-20 mg/m2/week as a single dose once weekly or 0.3-1 mg/kg/dose once weekly
GVHD (acute) prophylaxis (unlabeled use): I.V.: Refer to adult dosing.
Juvenile idiopathic arthritis (JIA): Oral, I.M.: 10 mg/m2 once weekly, then 5-15 mg/m2/week as a single dose or as 3 divided doses given 12 hours apart
Antineoplastic dosage range:
Oral, I.M.: 7.5-30 mg/m2/week or every 2 weeks
I.V.: 10-18,000 mg/m2 bolus dosing or continuous infusion over 6-42 hours
Pediatric solid tumors (high-dose): I.V.:
<12 years: 12-25 g/m2
≥12 years: 8 g/m2
Acute lymphocytic leukemia (intermediate-dose): I.V.: Loading: 100 mg/m2 bolus dose, followed by 900 mg/m2/day infusion over 23-41 hours.
Meningeal leukemia: I.T.: 6-12 mg/dose based on age. Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer, 1983; Kerr, 2001):
<1 year: 6 mg/dose
1 year: 8 mg/dose
2 years: 10 mg/dose
≥3 years: 12 mg/dose
Adults:
Antineoplastic dosage range: I.V.: Range is wide from 30-40 mg/m2/week to 100-12,000 mg/m2 with leucovorin calcium rescue
Breast cancer: I.V.: 30-60 mg/m2 days 1 and 8 every 3-4 weeks
Head and neck cancer: Oral, I.M., I.V.: 25-50 mg/m2 once weekly
Lymphoma, non-Hodgkin's: I.V.:
30 mg/m2 days 3 and 10 every 3 weeks or
120 mg/m2 day 8 and 15 every 3-4 weeks or
200 mg/m2 day 8 and 15 every 3 weeks or
400 mg/m2 every 4 weeks for 3 cycles or
1 g/m2 every 3 weeks or
1.5 g/m2 every 4 weeks
Meningeal leukemia: I.T.: Usual dose: 12 mg/dose. Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer, 1983; Kerr, 2001).
Mycosis fungoides (cutaneous T-cell lymphoma): Oral, I.M.: Initial (early stages):
5-50 mg once weekly or
15-37.5 mg twice weekly
Osteosarcoma: I.V.: 8-12 g/m2 weekly for 2-4 weeks
Psoriasis: Note: Some experts recommend concomitant folic acid 1-5 mg/day (except the day of methotrexate) to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.
Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or
Oral, I.M., SubQ: 10-25 mg/dose given once weekly; titrate to lowest effective dose
Note: An initial test dose of 2.5-5 mg is recommended in patients with risk factors for hematologic toxicity or renal impairment (Kalb, 2009).
Rheumatoid arthritis: Note: Some experts recommend concomitant folic acid at a dose of least 5 mg/week (except the day of methotrexate) to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.
Oral (manufacturer labeling): 7.5 mg once weekly or 2.5 mg every 12 hours for 3 doses/week (dosage exceeding 20 mg/week may cause a higher incidence and severity of adverse events); alternatively, 10-15 mg once weekly, increased by 5 mg every 2-4 weeks to a maximum of 20-30 mg once weekly has been recommended by some experts (Visser, 2009)
I.M., SubQ (unlabeled route): 15 mg once weekly (dosage varies, similar to oral) (Braun, 2008)
Trophoblastic neoplasms:
Oral, I.M.: 15-30 mg/day for 5 days; repeat in 7 days for 3-5 courses
I.V.: 11 mg/m2 days 1 through 5 every 3 weeks
Unlabeled uses:
Active Crohn's disease (unlabeled use): Induction of remission: I.M., SubQ: 15-25 mg once weekly; remission maintenance: 15 mg once weekly
Note: Oral dosing has been reported as effective but oral absorption is highly variable. If patient relapses after a switch to oral, may consider returning to injectable.
Bladder cancer (unlabeled use): I.V.:
30 mg/m2 day 1 and 8 every 3 weeks or
30 mg/m2 day 1, 15, and 22 every 4 weeks
Dermatomyositis/polymyositis (unlabeled uses):
Oral: Initial: 7.5-15 mg/week, often adjunctively with high-dose corticosteroid therapy; may increase in weekly 2.5 mg increments to target dose of 10-25 mg/week (Note: Administration of folate 5-7 mg/week has been used to reduce side effects). (Briemberg, 2003; Newman, 1995; Wiendl, 2008)
I.V., I.M.: Doses of 20-60 mg/week have been employed if failure with oral therapy (doses >50 mg/week may require leucovorin calcium rescue) (Briemberg, 2003)
Ectopic pregnancy (unlabeled use): I.M.:
Single-dose regimen: Methotrexate 50 mg/m2 on day 1; Measure serum hCG levels on days 4 and 7; if needed, repeat dose on day 7 (Barnhart, 2009)
Two-dose regimen: Methotrexate 50 mg/m2 on day 1; Measure serum hCG levels on day 4 and administer a second dose of methotrexate 50 mg/m2; Measure serum hCG levels on day 7 and if needed, administer a third dose of 50 mg/m2 (Barnhart, 2009)
Multidose regimen: Methotrexate 1 mg/kg on day 1; leucovorin calcium 0.1 mg/kg I.M. on day 2; measure serum hCG on day 2; methotrexate 1 mg/kg on day 3; leucovorin calcium 0.1 mg/kg on day 4; measure serum hCG on day 4; continue up to a total of 4 courses based on hCG concentrations (Barnhart, 2009)
GVHD (acute) prophylaxis: I.V.: 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3 and 6 after allogeneic transplant (in combination with cyclosporine and prednisone) (Chao, 1993; Chao, 2000; Ross, 1999) or 15 mg/m2/dose on day 1 and 10 mg/m2/dose on days 3, 6, and 11 after allogeneic transplant (in combination with cyclosporine) (Chao, 2000)
Nonleukemic meningeal cancer (unlabeled uses): I.T.: 10-12 mg/dose twice weekly for 4 weeks, then weekly for 4 weeks, then monthly (NCCN CNS cancer guidelines v.2.2009) or 12 mg/dose twice weekly for 4 weeks, then weekly for 4 doses, then monthly for 4 doses (Glantz, 1998) or 10 mg twice weekly for 4 weeks, then weekly for 1 month, then every 2 weeks for 2 months (Glantz, 1999)
Takayasu arteritis, refractory or relapsing disease (unlabeled use):Oral: Initial dose: 0.3 mg/kg/week (maximum: 15 mg/week), titrated by 2.5 mg increments every 1-2 weeks until reaching a maximum tolerated weekly dose of 25 mg (use in combination with a corticosteroid; Hoffman, 1994)
Elderly:
Meningeal leukemia: I.T.: Consider a dose reduction (CSF volume and turnover may decrease with age)
Rheumatoid arthritis/psoriasis: Oral: Initial: 5-7.5 mg/week, not to exceed 20 mg/week
Dosing adjustment in renal impairment: The FDA-approved labeling does not contain dosage adjustment guidelines. The following guidelines have been used by some clinicians:
Clcr 61-80 mL/minute: Administer 75% of dose
Clcr 51-60 mL/minute: Administer 70% of dose
Clcr 10-50 mL/minute: Administer 30% to 50% of dose
Clcr <10 mL/minute: Avoid use
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary
Peritoneal dialysis effects: Supplemental dose is not necessary
CAVH effects: Unknown
Aronoff, 2007:
Children:
Clcr 10-50 mL/minute: Administer 50% of dose
Clcr <10 mL/minute: Administer 30% of dose
Hemodialysis: Administer 30% of dose
Continuous ambulatory peritoneal dialysis (CAPD): Administer 30% of dose
Continuous renal replacement therapy (CRRT): Administer 50% of dose
Adults:
Clcr 10-50 mL/minute: Administer 50% of dose
Clcr <10 mL/minute: Avoid use
Hemodialysis: Administer 50% of dose
Continuous renal replacement therapy (CRRT): Administer 50% of dose
Kintzel, 1995:
Clcr 46-60 mL/minute: Administer 65% of normal dose
Clcr 31-45 mL/minute: Administer 50% of normal dose
Clcr <30 mL/minute: Avoid use
Dosage adjustment in hepatic impairment: The FDA-approved labeling does not contain dosage adjustment guidelines. The following guidelines have been used by some clinicians (Floyd, 2006):
Bilirubin 3.1-5 mg/dL or transaminases >3 times ULN: Administer 75% of dose
Bilirubin >5 mg/dL: Avoid use
Dosage: Combination Regimens
Bladder cancer:
CMV
M-VAC (Bladder Cancer)
Breast cancer:
CMF
CMF-IV
Dox-CMF (Sequential)
Endometrial cancer: MVAC (Endometrial Cancer)
Gestational trophoblastic tumor:
CHAMOCA (Modified Bagshawe Regimen)
CHAMOMA (Bagshawe Regimen)
EMA/CO
EP/EMA
Leukemia, acute lymphocytic:
Hyper-CVAD + Imatinib
Hyper-CVAD (Leukemia, Acute Lymphocytic)
Larson Regimen (ALL)
Linker Protocol (ALL)
MTX/6-MP/VP (Maintenance)
POMP
PVA (POG 8602)
Leukemia, acute promyelocytic:
Tretinoin-Daunorubicin (APL)
Tretinoin-Daunorubicin-Cytarabine (APL)
Tretinoin-Idarubicin (APL)
Lymphoma, non-Hodgkin's:
CODOX-M
COMLA
Hyper-CVAD (Lymphoma, non-Hodgkin's)
IMVP-16
MACOP-B
m-BACOD
Pro-MACE-CytaBOM
Lymphoma, non-Hodgkin's (Burkitt's): CODOX-M/IVAC
Lymphoma, non-Hodgkin's: (Mantle Cell): Hyper-CVAD + Rituximab
Osteosarcoma:
HDMTX
MTX-CDDPAdr
POG-8651
Soft tissue sarcoma: Methotrexate-Vinblastine (Desmoid Tumor)
Administration: I.M.
May be administered I.M.
Administration: I.V.
May be administered I.V.; I.V. administration may be as slow push, short bolus infusion, or 24- to 42-hour continuous infusion
Specific dosing schemes vary, but high dose should be followed by leucovorin calcium to prevent toxicity; refer to Leucovorin Calcium monograph
Administration: Other
May be administered I.T or SubQ.
Monitoring Parameters
Laboratory tests should be performed on day 5 or day 6 of the weekly methotrexate cycle (eg, psoriasis, RA) to detect the leukopenia nadir and to avoid elevated LFTs 1-2 days after taking dose.
Patients with psoriasis:
CBC with differential and platelets (baseline, 7-14 days after initiating therapy or dosage increase, every 2-4 weeks for first few months, then every 1-3 months); BUN and serum creatinine (baseline and every 2-3 months); consider PPD for latent TB screening (baseline); LFTs (baseline, monthly for first 6 months, then every 1-2 months); chest x-ray (baseline if underlying lung disease)
Liver biopsy for patients with risk factors for hepatotoxicity: Baseline or after 2-6 months of therapy and with each 1-1.5 g cumulative dose interval
Liver biopsy for patients without risk factors for hepatotoxicity: If persistent elevations in 5 of 9 AST levels during a 12-month period, or decline of serum albumin below the normal range with normal nutritional status. Consider biopsy after cumulative dose of 3.5-4 g and after each additional 1.5 g.
Patients with RA:
CBC with differential and platelets, serum creatinine and LFTs (baseline then every 2-4 weeks for initial 3 months of therapy, then every 8-12 weeks for 3-6 months of therapy and then every 12 weeks after 6 months of therapy); chest x-ray (baseline); pulmonary function test (if methotrexate-induced lung disease suspected); hepatitis B or C testing (baseline)
Liver biopsy: Baseline (if persistent abnormal baseline LFTs, history of alcoholism, or chronic hepatitis B or C) or during treatment if persistent LFT elevations (6 of 12 tests abnormal over 1 year or 5 of 9 results when LFTs performed at 6-week intervals)
Patients with cancer: Baseline and frequently during treatment: CBC with differential and platelets, serum creatinine, LFTs; chest x-ray (baseline); methotrexate levels and urine pH (with high-dose therapy); pulmonary function test (if methotrexate-induced lung disease suspected)
Ectopic pregnancy (unlabeled use): Prior to therapy, measure serum hCG, CBC with differential, liver function tests, serum creatinine. Serum hCG concentrations should decrease between treatment days 4 and 7. If hCG decreases by >15%, additional courses are not needed however, continue to measure hCG weekly until no longer detectable. If <15% decrease is observed, repeat dose per regimen (Barnhart, 2009).
Reference Range
Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach.
High-dose regimens produce drug levels that are between 0.1-1 micromole/L 24-72 hours after drug infusion
Toxic: Low-dose therapy: >0.2 micromole/L; high-dose therapy: >1 micromole/L
Dietary Considerations
Some products may contain sodium.
Patient Education
You will be more susceptible to infection. May cause sensitivity to sunlight, nausea, vomiting, drowsiness, dizziness, numbness, blurred vision, loss of hair (may be reversible), color change of skin, permanent sterility, or mouth sores. Report immediately any new skin rash, eruptions, redness, or peeling; respiratory difficulty, fever, or cough; rapid heartbeat or palpitations; black or tarry stools; fever; chills; unusual bleeding or bruising; persistent GI disturbances (abdominal pain, diarrhea, constipation); or pain on urination or change in urinary patterns. Oral: It is very important to maintain adequate nutrition and hydration. Avoid alcohol. Infusion/injection: Report immediately any redness, swelling, pain, or burning at infusion/injection site.
Geriatric Considerations
Toxicity to methotrexate or any immunosuppressive is increased in the elderly. Must monitor carefully. For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic, traditional therapy is ineffective. Recommended doses should be reduced when initiating therapy in the elderly due to possible decreased metabolism, reduced renal function, and presence of interacting diseases and drugs. Adjust dose as needed for renal function (Clcr).
Additional Information
Oncology Comment: Methotrexate overexposure: The investigational rescue agent, glucarpidase, is an enzyme which rapidly hydrolyzes extracellular methotrexate into inactive metabolites, resulting in a rapid reduction of methotrexate concentrations. Glucarpidase is available for intrathecal (IT) use through an Emergency Use IND and for I.V. use under an Open-Label Treatment protocol. Refer to Glucarpidase monograph.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Ulcerative stomatitis, gingivitis, glossitis, and mucositis (dose dependent; appears 3-7 days post-therapy and resolves within 2 weeks). Dental professionals should note before prescribing NSAIDS that concurrent administration with methotrexate may cause severe bone marrow suppression, aplastic anemia, and GI toxicity (see Warnings). Although the risk is lower at the methotrexate dosages used for rheumatoid conditions/psoriasis, the addition of an NSAID or salicylate may still lead to unexpected toxicities; caution is warranted.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness or dizziness
Mental Health: Effects on Psychiatric Treatment
Leukopenia is common; avoid clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Monitor closely if used in presence of preexisting conditions that increase potential for toxicity (eg, renal impairment, peptic ulcer disease, ulcerative colitis, hepatic impairment, bone marrow suppression). Evaluate for additional contraindications with psoriasis or rheumatoid arthritis. Patient should be monitored closely for hyper-/hypothyroidism, pneumonitis (dry, nonproductive cough), gastrointestinal disturbance (ulcerative stomatitis, pain, intestinal perforation), dermatological reactions, and renal failure (decreased urine output).
Oncology: Emetic Potential
≥250 mg/m2: Moderate (30% to 90%)
50-250 mg/m2: Low (10% to 30%)
≤50 mg/m2: Very low (<10%)
Oral: Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 1 g
Injection, solution: 25 mg/mL (2 mL, 10 mL)
Injection, solution [preservative free]: 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL, 40 mL)
Tablet, oral: 2.5 mg
Trexall™: 5 mg, 7.5 mg, 10 mg, 15 mg [scored]
Tablet, oral [dose-pack]:
Rheumatrex®: 2.5 mg [scored]
Pricing: U.S. (www.drugstore.com)
Solution (Methotrexate Sodium)
25 mg/mL (2): $15.99
25 mg/mL (10): $24.99
25mg/ml (2): $14.99
25mg/ml (10): $24.99
Tablets (Methotrexate)
2.5 mg (30): $31.99
Tablets (Trexall)
10 mg (30): $556.92
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International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
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