Methotrexate

Reviewed on 9/1/2021

Brand Name: Trexall, Otrexup, Rasuvo

Generic Name: methotrexate

Drug Class: Immunosuppressants; Antineoplastics, Antimetabolite; DMARDs, Immunomodulators

What Is Methotrexate and How Does It Work?

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole.

  • In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also indicated in the treatment of meningeal leukemia.
  • Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin's lymphomas.
  • Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor.
  • Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation.
  • It is important to ensure that a psoriasis "flare" is not due to an undiagnosed concomitant disease affecting immune responses.
  • Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose nonsteroidal anti-inflammatory agents (NSAIDs).
  • Aspirin, (NSAIDs), and/or low-dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored.
  • Steroids may be reduced gradually in patients who respond to methotrexate.
  • Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects.
  • Rest and physiotherapy as indicated should be continued.
  • Methotrexate is available under the following different brand names: Trexall, Otrexup, and Rasuvo.

What Are Dosages of Methotrexate?

Dosages of Methotrexate:

Adult and Pediatric Dosage Forms and Strengths

Injectable solution

  • 25 mg/mL

Powder for injection

  • 1g/vial (25 mg/mL when reconstituted)

SC autoinjector (Otrexup)

  • 7.5 mg/0.4mL
  • 10 mg/0.4mL
  • 12.5 mg/0.4mL
  • 15 mg/0.4mL
  • 17.5 mg/0.4mL
  • 20 mg/0.4mL
  • 22.5 mg/0.4mL
  • 25 mg/0.4mL

SC autoinjector (Rasuvo)

  • 2.5 mg/0.05mL (delivers doses between 7.5 mg and 30 mg in 2.5 mg increments)

Tablet

  • 2.5 mg
  • 5 mg
  • 7.5 mg
  • 10 mg
  • 15 mg

Dosage Considerations – Should be Given as Follows:

Neoplasms

  • Antineoplastic dosage range: 30-40 mg/m²/week to 100-12,000 mg/m² with leucovorin rescue
  • Trophoblastic neoplasms: 15-30 mg/day orally/intramuscularly (IM) for 5 days; maybe repeated
  • Burkitt lymphoma, stage I/II: 10-25 mg/day orally for 4-8 days
  • Dosing considerations
    • Various dosing regimens exist; consult an oncologist

Meningeal Leukemia

  • Adult: 12 mg intrathecally (IT); not to exceed 15 mg/dose every 2-7 days; administer 1 additional dose after cell count on CSF returns to normal;
  • Adult dosing considerations
    • Administration at intervals less than 1 week may result in increased subacute toxicity
    • Use preservative-free methotrexate only; dilute to 1 mg/mL in preservative-free NS
  • Children under 1 year: 6 mg intrathecally (IT) every 2-5 days
  • Children 1-2 years: 8 mg IT every 2-5 days
  • Children 2-3 years: 10 mg IT every 2-5 days
  • Children 3 years and older: 12 mg IT every 2-5 days
  • Pediatric dosing considerations
    • Use preservative-free methotrexate for injection only
    • Dilute to 1 mg/mL in preservative-free 0.9% NaCl

Osteosarcoma

  • 12 g/m² intravenously (IV) over 4 hours on weeks 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44, and 45 after surgery in combination with other chemotherapy; leucovorin rescue
  • If peak serum methotrexate is less than 454 mcg/mL at end of initial infusion, the dose may be increased to 15 g/m² in subsequent treatments

Dosing considerations

  • High-dose therapy requires adequate hydration and urine alkalinization
  • Delay methotrexate if severe myelosuppression, hepatotoxicity, mucositis, or pleural effusion present

Rheumatoid Arthritis

  • Indicated for management of severe, active rheumatoid arthritis (RA) in adults who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs
  • Initial: 7.5 mg orally as a single weekly dose, OR
  • 2.5 mg orally every 12 hours for 3 sequential doses per week
  • Increase orally dose to optimum response; single dose not to exceed 20 mg/week orally (increased risk of bone marrow suppression); reduce to lowest possible effective dose
  • Otrexup (SC): If used as initial therapy, start at the lowest available dose (i.e., 10 mg subcutaneously [SC] once/week)
  • Rasuvo (SC), initial dose: 7.5 mg as a single SC dose once weekly; adjust auto-injector dose by 2.5 mg increments as clinically required

Polyarticular Juvenile Idiopathic Arthritis

  • Management of active polyarticular juvenile idiopathic arthritis (pJIA) in children who have had an insufficient response or intolerance to an adequate trial of first-line therapy including full dose NSAIDs
  • Initial: 10 mg/m² orally/IM/SC once/week
  • If switching from orally to subcutaneously (Otrexup, Rasuvo), consider higher bioavailability with SC compared with orally (see Pharmacology Absorption section)
  • Dosing Considerations (PJIA)
    • Data with doses up to 30 mg/m²/week in children exist, although there are too few published studies to assess how doses greater than 20 mg/m²/week might affect the risk of serious toxicity in children
    • Experience does suggest, however, that children receiving 20 to 30 mg/m²/week (0.65-1 mg/kg/week) may have better absorption and fewer GI side effects if methotrexate is administered either intramuscularly (IM) or subcutaneously

Psoriasis

  • For symptomatic control of severe, recalcitrant, disabling psoriasis in adults not adequately responsive to other forms of therapy; use only with established diagnosis (by biopsy and/or after dermatologic consultation)
  • Initial: 10-25 mg weekly in single orally/SC/IM/IV dose; not to exceed 30 mg/week
  • Gradually adjust the dose to achieve optimal clinical response; use the lowest dose and longest rest period possible with a return to conventional topical therapy encouraged
  • Trexall: May give weekly dose divided as 2.5 mg orally every 12 hours for 3 sequential doses
  • Otrexup (SC): If used as initial therapy, start the lowest available dose (i.e., 10 mg SC once/week)
  • Rasuvo (SC): 10-25 mg SC once weekly

Breast Cancer

Head and Neck Cancer

  • 40 mg/m2 IV; once weekly until disease progression or unacceptable toxicity

Mycosis Fungoides (Cutaneous T-cell Lymphoma)

  • 5-50 mg orally/intramuscularly (IM) once weekly or 15-37.5 mg twice weekly for those who have responded poorly to a weekly therapy

Dosing Modifications

Renal impairment, adult

  • CrCl 10-50 mL/min: 50% of dose at normal dosing interval
  • CrCl less than 10 mL/min: Avoid use
  • Intermittent hemodialysis: 50% of the dose at a normal dosing interval
  • Continuous renal replacement therapy: 50% of the dose at a normal dosing interval

Renal impairment, pediatric

  • CrCl 10-50 mL/min/1.73mm²: 50% dose
  • CrCl less than 10 mL/min/1.73 mm²: 30% dose

Hepatic impairment

  • Bilirubin 3.1-5.0 mg/dL or AST greater than 3 times ULN: Give 75% of the dose
  • Bilirubin greater than 5.0 mg/dL: Avoid use

Dosing Considerations

  • Otrexup and Rasuvo (SC injections) are not indicated for neoplastic disease
  • If switching from orally to SC (Otrexup, Rasuvo), consider higher bioavailability with SC compared with orally (see Pharmacology Absorption section)

Ectopic Pregnancy (Off-label)

  • 50 mg/m² IM; measure serum hCG levels on days 4 and 7; may repeat the dose on day 7 if necessary
  • If hCG levels decrease less than 15% between days 4 and 7, administer methotrexate 50 mg/m² IM; if hCG is 15% or more between days 4 and 7, discontinue treatment and measure hCG weekly until reaching non-pregnant levels

Acute Lymphoblastic Leukemia (Orphan)

  • Orphan indication sponsor
    • Only for Children Pharmaceuticals; 35 bis rue Gay; Lucic, France
  • Oral solution
  • Orphan designation for the treatment of acute lymphoblastic leukemia in pediatric patients (0 through 16 years of age)
  • Sponsor
    • Silvergate Pharmaceuticals, Inc; 6251 Greenwood Plaza Blvd, Suite 101; Greenwood Village, CO 80111

QUESTION

The term arthritis refers to stiffness in the joints. See Answer

What Are Side Effects Associated with Using Methotrexate?

Side effects associated with the use of Methotrexate, include the following:

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

What Other Drugs Interact with Methotrexate?

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns, or for more information about this medicine.

SLIDESHOW

What Is Rheumatoid Arthritis (RA)? Symptoms, Treatment, Diagnosis See Slideshow

What Are Warnings and Precautions for Methotrexate?

Warnings

  • For use in life-threatening neoplastic disease or patients with psoriasis or rheumatoid arthritis with the severe recalcitrant disabling disease, not adequately responsive to other forms of therapy
  • Deaths reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis
  • Monitor patients closely for bone marrow, liver, lung, and kidney toxicities
  • Inform patients of risks involved; the patient should be under a physician's care throughout therapy
  • High dose regimens recommended for osteosarcoma requires meticulous care; high dose regimens are investigational; a therapeutic advantage not established
  • Not recommended for women of childbearing potential, due to teratogenic activity, unless the benefit-risk ratio is acceptable
  • May cause fetal death or congenital abnormalities; use is contraindicated in pregnant women
  • Methotrexate formulations or diluents containing preservatives should not be used for intrathecal or high-dose therapy
  • May cause renal damage leading to acute renal failure, especially in high doses
  • Elimination is reduced in impaired renal function, ascites, or pleural effusions; reduce the dose and monitor carefully for toxicity
  • Bone marrow suppression, aplastic anemia, and GI toxicity were reported with high doses and concurrent administration of NSAIDs
  • Any dose level or route of administration may cause severe and potentially fatal dermatologic reactions
  • Tumor lysis syndrome may occur in patients with high tumor burden
  • Administer therapy under the supervision of a physician experienced in the use of antimetabolite therapy
  • Diarrhea and ulcerative stomatitis may necessitate interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur
  • Methotrexate has been associated with acute and potentially fatal chronic hepatotoxicity; acutely, liver enzyme elevations are common but are usually transient and asymptomatic and not predictive of subsequent hepatic disease; periodic liver biopsies are recommended for psoriatic patients receiving long-term therapy
  • Low-dose methotrexate has been associated with the development of malignant lymphomas
  • Immune suppression may lead to potentially fatal opportunistic infections
  • May cause potentially fatal pneumonitis at any time during therapy even at low doses and is not fully reversible; pulmonary symptoms (especially a dry, non-productive cough) may require interruption of therapy and careful investigation
  • Concomitant use with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis
  • This medication contains methotrexate
  • Do not take Trexall, Otrexup, or Rasuvo if you are allergic to methotrexate or any ingredients contained in this drug
  • Keep out of reach of children
  • In case of overdose, get medical help or contact a Poison Control Center immediately

Contraindications

  • Pregnancy: Do not use due to potential for fetal death and teratogenic effects
  • Nursing: Do not use due to potential for serious adverse effects in infants
  • Alcoholism, alcoholic liver disease, or another chronic liver disease
  • Immunodeficiency syndromes
  • Preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant
  • Hypersensitivity: Do not use with known hypersensitivity; severe reactions have been observed with the use

Effects of Drug Abuse

  • No information provided

Short-Term Effects

  • Caution should be used while driving or operating machinery due to the risk of dizziness and fatigue
  • See "What Are Side Effects Associated with Using Methotrexate?"

Long-Term Effects

  • See "What Are Side Effects Associated with Using Methotrexate?”

Cautions

  • Only for use by physicians experienced in antimetabolite therapy
  • For intrathecal and high-dose methotrexate therapy, use preservative-free formulation; preserved formulation of methotrexate is not for intrathecal or high dose therapy; contains benzyl alcohol
  • Elderly patients: monitor closely for early signs of hepatic, bone marrow, and renal toxicity
  • Response in 3-6 weeks; the patient may continue to improve for another 12 weeks or more
  • Elimination reduced with renal impairment, ascites, or pleural effusions; monitor closely for renal, bone marrow, lung, or liver toxicity
  • Taking folic acid 1 mg/day orally may significantly reduce liver toxicity
  • Dermatologic toxicity: severe, potentially fatal skin reactions have been reported; psoriatic lesions may also be aggravated by UV radiation and sunburns may be recalled or worsened
  • Good oral care recommended (risk of mucositis)
  • Use extreme caution with active infection, peptic ulceration, and ulcerative colitis
  • Immunizations: Maybe ineffective during therapy and live virus vaccines is not recommended due to the risk of infection
  • Ectopic pregnancy: Ideally, human chorionic gonadotropin should be less than 5000 International Units/L, and sonogram normally
  • Acute and chronic hepatotoxicity: Acutely, liver enzyme elevations are common but are usually transient and asymptomatic and not predictive of subsequent hepatic disease; periodic liver biopsies are recommended for psoriatic patients receiving long-term therapy; should not be used in patients with alcoholism, alcoholic liver disease, or another chronic liver disease
  • Pulmonary toxicity: Pulmonary fibrosis, pulmonary interstitial infiltrates, and lung disease may occur acutely at any time during therapy (weekly doses greater than 7.5 mg) but are fully reversible; symptoms (especially dry cough) may necessitate interruption of treatment and investigation
  • Methotrexate clearance rates vary widely and are generally decreased at higher doses
  • Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information); if glucarpidase used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase; there are published case reports of intravenous and intrathecal glucarpidase treatment to hasten
  • clearance of methotrexate in cases of overdose
  • GI toxicity: Diarrhea or ulcerative stomatitis warrants discontinuance of therapy (risk of hemorrhagic enteritis or intestinal perforation)
  • Bone marrow suppression: May cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia; use caution in patients with preexisting hematopoietic impairment and with concomitant use of NSAIDs; a significant drop in blood counts warrants discontinuation of therapy
  • May impair fertility, cause oligospermia, and menstrual dysfunction; exclude pregnancy before initiating treatment
  • Neurotoxicity: May cause neurotoxicity, including stroke-like encephalopathy, seizures, leukoencephalopathy, and myelopathy
  • Nephrotoxicity: Risk of acute renal failure especially at high doses
  • Caution should be used while driving or operating machinery due to the risk of dizziness and fatigue

Pregnancy and Lactation

  • Do not use methotrexate in pregnancy. The risks involved outweigh the potential benefits. Safer alternatives exist
  • Methotrexate is excreted in breast milk; do not nurse while using methotrexate
References
SOURCE:
Medscape. Methotrexate.
https://reference.medscape.com/drug/trexall-methotrexate-343201
References:
DailyMed. Methotrexate.
https://dailymed.nlm.nih.gov/dailymed/
drugInfo.cfm?setid=6cf2e15a-6286-41f7-aa7d-3968d735c864

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