methotrexate (Rx)

>10%

Arachnoiditis with intrathecal administration

Subacute toxicity with intrathecal administration (paralysis of extremities, cranial nerve palsy, seizure or coma)

Demyelinating encephalopathy with cranial irradiation or other systemic chemotherapy

Reddening of skin

Hyperuricemia

Ulcerative stomatitis

Glossitis

Gingivitis

Nausea and vomiting

Diarrhea

Anorexia

Intestinal perforation

Mucositis (dose-dependent)

Leukopenia

Thrombocytopenia

Renal failure

Azotemia

Nephropathy

Pharyngitis

1-10%

Alopecia

Photosensitivity

Rash

Abdominal distress

Malaise

Fatigue

Chills, fever

Decreased resistance to infection

Gastrointestinal hemorrhage

Myelosuppression

Disorders of lung, interstitial pneumonia (acute, chronic)

Atrophy of liver, cirrhosis, hepatic fibrosis or necrosis, elevated liver function tests, hepatic failure

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 other chronic liver disease

Immunodeficiency syndromes

Preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia

Hypersensitivity: Do not use with known hypersensitivity; severe reactions have been observed with use

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; 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 with folic acid 1 mg/day PO 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: May be ineffective during therapy and live virus vaccines are not recommended due to risk of infection

Ectopic pregnancy: Ideally, human chorionic gonadotropin should be <5000 International Units/L and sonogram normal

Acute and chronic hepatoxicity: 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 patient with alcoholism, alcoholic liver disease, or other chronic liver disease

Pulmonary toxicity: Pulmonary fibrosis, pulmonary interstitial infiltrates, and lung disease may occur acutely at any time during therapy (weekly doses >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 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 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 strokelike 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 risk of dizziness and fatigue

Use of nitrous oxide anesthesia potentiates effect on folate-dependent metabolic pathways, resulting in potential for increased toxicity such as stomatitis, myelosuppression, and neurotoxicity; avoid concomitant nitrous oxide anesthesia in patients receiving methotrexate; use caution when administering methotrexate after a recent history of nitrous oxide administration

Pregnancy category: X

Lactation: Drug excreted in breast milk; do not nurse

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair, and cellular replication; cell cycle specific for S phase of cycle

May inhibit rapid proliferation of epithelial cells in skin

Absorption

Bioavailability (PO): 60% at PO doses <30 mg/m², bioavailability is significantly less at doses >80 mg/m²

Bioavailability (SC, Otrexup): 17, 13, 31, and 36% greater than PO methotrexate at doses of 10, 15, 20, and 25 mg respectively

AUC (SC, Rasuvo): 35%, 49%, 51%, and 68% greater than PO methotrexate at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg respectively

Peak plasma time: PO, 1-2 hr; IM, 30-60 min

Distribution

Protein bound: 50%

Vd: Initial, 0.18 L/kg; steady-state, 0.4-0.8 L/kg

Metabolism

Metabolized by liver and intracellularly

Metabolites: Polyglutamated forms

Elimination

Half-life: Psoriasis, rheumatoid arthritis, and low-dose cancer treatment, 3-10 hr; high-dose treatment, 8-15 hr

Excretion: Urine (80-100% within 24 hr), feces (small amounts)

IV Incompatibilities

Additive: Bleomycin

Syringe: Droperidol, metoclopramide (may be compatible at low concentrations of metoclopramide)

Y-site: Chlorpromazine, dexamethasone sodium phosphate(?), droperidol(?), gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol

IV/IM Preparation

Reconstitute with D5W or NS: 20-mg vial, up to 25 mg/mL; 1-g vial, up to 50 mg/mL

May dilute further for IV infusion

IV/IM Administration

Administer by IM, IV push, or IV infusion

Regular IV given with no more than 25 mg/mL

IV push: Administered at 10 mg/min

IV infusion (usually >100 mg): Administered over 30 minutes to 4 hours, or according to institutional protocol

High-dose therapy (uses 1-g vial): Administered over 4 hours

Specific dosing schemes vary, but high doses should be followed by leucovorin 24 hours after initiation of therapy to prevent toxicity

IT Administration

Do not use preservative-containing drug

For meningeal leukemia, intrathecal administration is mandatory because CSF penetration is poor

Before administration, equal volume of CSF is usually withdrawn; administer drug only if easy flow of blood-free CSF is noted

SC Administration

Otrexup is a single-dose auto-injector available in doses between 10 to 25 mg (in 5-mg increments) for once-weekly SC use only

Rasuvo is a single-dose auto-injector available in doses between 7.5 and 30 mg (in 2.5-mg increments) for once-weekly SC use only

Use another formulation in patients who require PO, IM, IV, intra-arterial, or IT dosing

Visually inspect for particulate matter and discoloration prior to administration; do not use if seal is broken

Administer SC in abdomen or thigh

May self-inject if determined appropriate by a physician and have received proper training on preparation and administration; a trainer device is available

Handling and disposal consistent with recommendation for cytotoxic drugs

Oral Administration

Oral solution (Xatmep)

• Intended for oral use only
• Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity
• Measure dose with an accurate measuring device to provide the correct dose, such as an oral syringe provided by the pharmacist (do NOT use a household teaspoon)
• May take with or without food; food does not affect AUC, but decreased maximum concentration levels by 50% and delayed the absorption

Storage

Store intact vials at room temperature

Protect from light