April 26, 2017
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Methotrexate

Medical and Pharmacy Editor:

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.

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/m/week to 100-12,000 mg/m with leucovorin rescue
  • Trophoblastic neoplasms: 15-30 mg/day orally/intramuscularly (IM) for 5 days; may be repeated
  • Burkitt lymphoma, stage I/II: 10-25 mg/day orally for 4-8 days
  • Dosing considerations
    • Various dosing regimens exist; consult 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/m 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 less than 454 mcg/mL at end of initial infusion, dose may be increased to 15 g/m 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 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/m 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/m/week in children exist, although there are too few published studies to assess how doses greater than 20 mg/m/week might affect the risk of serious toxicity in children
    • Experience does suggest, however, that children receiving 20 to 30 mg/m/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 dose to achieve to optimal clinical response; use lowest dose and longest rest period possible with 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 a lowest available dose (i.e., 10 mg SC once/week)
  • Rasuvo (SC): 10-25 mg SC once weekly

Breast Cancer

  • 40 mg/m2 IV; days 1 and 8 every 4 weeks in combination with cyclophosphamide and fluoracil for 6-12 cycles

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 who have responded poorly to 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 dose at normal dosing interval
  • Continuous renal replacement therapy: 50% of dose at normal dosing interval

Renal impairment, pediatric

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

Hepatic impairment

  • Bilirubin 3.1-5.0 mg/dL or AST greater than 3 times ULN: Give 75% of 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/m IM; measure serum hCG levels on days 4 and 7; may repeat dose on day 7 if necessary
  • If hCG levels decrease less than 15% between days 4 and 7, administer methotrexate 50 mg/m IM; ifhCG 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; Lusac, France
  • Oral solution
  • Orphan designation for 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
Medically Reviewed by a Doctor on 4/14/2017



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