methotrexate

meth-o-TREX-ate

Therapeutic Classification: antineoplastics, antirheumatics (DMARDs), Immunosuppressant agents

Pharmacologic Classification: antimetabolites

High Alert

Acute lymphoblastic leukemia (in combination with other chemotherapy drugs).
Treatment and prophylaxis of meningeal leukemia.
Non-Hodgkin's lymphoma (in combination with other chemotherapy drugs).
Osteosarcoma (in combination with other chemotherapy drugs).
Breast cancer (in combination with other chemotherapy drugs).
Squamous cell carcinoma of the head and neck.
Gestational trophoblastic neoplasia (in combination with other chemotherapy drugs).
Severe, active rheumatoid arthritis and polyarticular juvenile idiopathic arthritis in patients with intolerance or an inadequate response to first-line therapy.
Severe, recalcitrant, disabling psoriasis in patients with an inadequate response to other therapies.
Mycosis fungoides (cutaneous T-cell lymphoma) (as monotherapy or in combination with other chemotherapy drugs).

Interferes with folic acid metabolism. Result is inhibition of DNA synthesis and cell reproduction (cell-cycle S-phase–specific).
Also has immunosuppressive activity.

Therapeutic effects:

Death of rapidly replicating cells, particularly malignant ones, and immunosuppression.

Absorption: Small doses are well absorbed from the GI tract. Larger doses incompletely absorbed.

Distribution: Actively transported across cell membranes, widely distributed. Does not reach therapeutic concentrations in the CSF. Absorption in children is variable (23–95%) and dose-dependent.

Metabolism/Excretion: Excreted mostly unchanged by the kidneys.

Half-Life: Low dose: 3–10 hr; high dose: 8–15 hr (↑ in renal impairment).

(effects on blood counts)

ROUTE	ONSET	PEAK	DURATION
PO, IM, IV	4–7 days	7–14 days	21 days
SUBQ	unknown	unknown	unknown

Contraindicated in:

Hypersensitivity;
Alcoholism or hepatic impairment;
Immunosuppression;
↓bone marrow reserve;
OB: Pregnancy;
Lactation: Lactation;
Pedi: Products containing benzyl alcohol should not be used in neonates.

Use Cautiously in:

Cranial radiation (↑ risk of leukoencephalopathy);
Peptic ulcer disease or ulcerative colitis;
Renal impairment (CCr must be ≥60 mL/min prior to therapy);
Active infections;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Geri: Older adults may be more sensitive to toxicity and adverse events.

Derm: alopecia, ERYTHEMA MULTIFORME, painful plaque erosions (during psoriasis treatment), photosensitivity, pruritus, rash, skin ulceration, soft tissue necrosis, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, urticaria

EENT: blurred vision, transient blindness

GI: anorexia, diarrhea, nausea, stomatitis, vomiting, GI PERFORATION, HEPATOTOXICITY

GU: nephropathy, ↓fertility, acute renal failure, menstrual abnormalities, oligospermia

Hemat: anemia, leukopenia, thrombocytopenia, APLASTIC ANEMIA

Metab: hyperuricemia

MS: hemiparesis, osteonecrosis, stress fracture

Neuro: arachnoiditis (IT use only), confusion, dizziness, drowsiness, dysarthria, headache, leukoencephalopathy, malaise, SEIZURES

Resp: INTERSTITIAL PNEUMONITIS

Misc: chills, fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), INFECTION, SECONDARY MALIGNANCY, tumor lysis syndrome

Drug-drug:

The following drugs may ↑ hematologic toxicity of methotrexate: high-dose salicylates, dapsone, pemetrexed, mercaptopurine, NSAIDs, phenytoin, tetracyclines, probenecid, trimethoprim/sulfamethoxazole, penicillins, pyrimethamine, sulfonylureas, and warfarin.
↑risk of hepatotoxicity with other hepatotoxic drugs including azathioprine, sulfasalazine, and retinoids.
↑risk of nephrotoxicity with other nephrotoxic drugs.
↑risk of bone marrow depression with other antineoplastics or radiation therapy.
Radiation therapy↑ risk of soft tissue necrosis and osteonecrosis.
May ↓ antibody response to live-virus vaccines and ↑ risk of adverse reactions.
↑risk of neurologic reactions with acyclovir (IT methotrexate only).
Nitrous oxide may ↑ risk of toxicity; avoid concurrent use.
Folic acid may ↓ antineoplastic effects; avoid concurrent use.
May ↑ levels and risk of toxicity of theophylline.

Drug-Natural Products:

Concomitant use with echinacea and melatonin may interfere with immunosuppression.
Caffeine may ↓ efficacy of methotrexate, similar effect may occur with guarana.

Acute Lymphoblastic Leukemia

IV (Adults and Children ): 10–5,000 mg/m² followed by leucovorin rescue (for doses >500 mg/m²). Lower doses (20–30 mg/m²/wk may be used IM.
PO (Adults ): 20 mg/m² once weekly

Meningeal Leukemia

(Adults and Children ≥9 yr): 12–15 mg given at intervals of 2 or more days up to twice weekly (for treatment) and no more than once weekly (for prophylaxis).
(Children 3–<9 yr): 12 mg given at intervals of 2 or more days up to twice weekly (for treatment) and no more than once weekly (for prophylaxis).
(Children 2–<3 yr): 10 mg given at intervals of 2 or more days up to twice weekly (for treatment) and no more than once weekly (for prophylaxis).
(Children 1–<2 yr): 8 mg given at intervals of 2 or more days up to twice weekly (for treatment) and no more than once weekly (for prophylaxis).
(Children <1 yr): 6 mg given at intervals of 2 or more days up to twice weekly (for treatment) and no more than once weekly (for prophylaxis).

Non-Hodgkin's Lymphoma

IV (Adults and Children ): In combination with other chemotherapy agents: 1000 mg/m² or 3000 mg/m² over 24 hours followed by leucovorin rescue. CNS-directed therapy: 8000 mg/m² over 4 hr followed by leucovorin rescue (as monotherapy) or 3000–8000 mg/m² followed by leucovorin rescue (in combination with immunochemotherapy).
PO (Adults ): 2.5 mg 2–4 times weekly.

Osteosarcoma

IV (Adults and Children ): 12 g/m² (max = 20 g/dose) over 4 hr followed by leucovorin rescue, usually as part of a combination chemotherapeutic regimen (or ↑ dose until peak serum methotrexate level is 1 × 10^-3 M/L but not to exceed 15 g/m²); 12 courses are given starting 4 wk after surgery and repeated at scheduled intervals.

Breast Cancer

IV (Adults ): 40 mg/m² on days 1 and 8 (with other agents; many regimens are used).

Squamous Cell Carcinoma of Head and Neck

IV (Adults ): 40–60 mg/m² once weekly.

Gestational Trophoblastic Neoplasia

IV IM (Adults ): Low-risk gestational trophoblastic neoplasia: 30–200 mg/m².
IV (Adults ): High-risk gestational trophoblastic neoplasia: 300 mg/m² over 12 hr (with other agents).

Mycosis Fungoides

PO (Adults ): Monotherapy: 25–75 mg once weekly; As part of combination regimen: 10 mg/m² twice weekly.
IM (Adults ): Early stage: 5–50 mg once weekly; If poor response to weekly therapy: 15–37.5 mg twice weekly.

Rheumatoid Arthritis

PO IM SC (Adults ): 7.5 mg once weekly (not to exceed 20 mg/wk); when optimal clinical response is obtained, dose should be ↓. Otrexup may be used when dose is 10–20 mg/wk.

Polyarticular Juvenile Idiopathic Arthritis

PO IM SC (Children ): 10 mg/m² once weekly initially, may be ↑ up to 20–30 mg/m²; however, response may be better if doses >20 mg/m² are given IM or SUBQ; Otrexup may be used when dose is 10–25 mg/wk.

Psoriasis

Therapy may be preceded by a 5–10-mg test dose
PO IM SC IV (Adults ): 10–25 mg once weekly (not to exceed 25 mg/wk); when optimal clinical response is obtained, dose should be ↓. Otrexup may be used when dose is 10–25 mg/wk.

(Generic available)

Tablets: 2.5 mg; 5 mg; 7.5 mg; 10 mg; 15 mg
Oral solution (Jylamvo) orange flavor: 2 mg/mL
Oral solution (Xatmep) orange flavor: 2.5 mg/mL
Solution for SUBQ injection (Otrexup): 10 mg/0.4 mL; 12.5 mg/0.4 mL; 15 mg/0.4 mL; 17.5 mg/0.4 mL; 20 mg/0.4 mL; 22.5 mg/0.4 mL; 25 mg/0.4 mL
Solution for SUBQ injection (Rasuvo): 7.5 mg/0.15 mL; 10 mg/0.2 mL; 12.5 mg/0.25 mL; 15 mg/0.3 mL; 17.5 mg/0.35 mL; 20 mg/0.4 mL; 22.5 mg/0.45 mL; 25 mg/0.5 mL; 30 mg/0.6 mL
Powder for injection: 1 g/vial
Solution for injection: 25 mg/mL
Solution for injection (preservative free): 25 mg/mL

Monitor vital signs periodically during administration. Report significant changes.
- Monitor for abdominal pain, diarrhea, or stomatitis; therapy may need to be discontinued.
- Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
- Monitor intake and output ratios and daily weights. Report significant changes in totals.
- Monitor for symptoms of interstitial pneumonitis, which may manifest early as a dry, nonproductive cough.
- Monitor for symptoms of gout (increased uric acid, joint pain, edema). Encourage patient to drink at least 2 L of fluid each day. Allopurinol and alkalinization of urine may be used to decrease uric acid levels.
- Assess nutritional status. Administering an antiemetic prior to and periodically during therapy and adjusting diet as tolerated may help maintain fluid and electrolyte balance and nutritional status.
Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
Assess for development of nuchal rigidity, headache, fever, confusion, drowsiness, dizziness, weakness, or seizures.
Rheumatoid Arthritis: Assess patient for pain and range of motion prior to and periodically during therapy.
Psoriasis: Assess skin lesions prior to and periodically during therapy.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy.Monitor CBC and differential prior to and at least monthly during therapy and at least daily for high-dose regimens. The nadir of leukopenia and thrombocytopenia occurs in 7–14 days. Leukocyte and thrombocyte counts usually recover 7 days after the nadirs. Discontinue methotrexate immediately for any sudden drop in values.
- Monitor renal (BUN and serum creatinine) and hepatic function (AST, ALT, bilirubin, and LDH) prior to and every 1–2 mo during therapy. Urine pH should be monitored prior to high-dose methotrexate therapy and every 6 hr during leucovorin rescue. Urine pH should be kept above 7.0 from before 1st dose through therapy to prevent renal damage.
- May cause ↑ serum uric acid concentrations, especially during initial treatment of leukemia and lymphoma.

Toxicity and Overdose:

Monitor serum methotrexate levels at least daily during high-dose therapy and adjust hydration and leucovorin dosing as needed. This monitoring is essential to plan correct leucovorin dose and determine duration of rescue therapy.
- With high-dose therapy (doses of ≥500 mg/m²), patient must receive leucovorin rescue within 24–48 hr to prevent fatal toxicity. May be considered for intermediate doses of 100 mg/m² to <500 mg/m². Administer IV fluids starting before 1st dose and continuing through therapy to maintain adequate hydration and urine output. Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Glucarpidase may be used for patients with impaired renal function. If glucarpidase is used, do not administer leucovorin within 2 hrs before or after glucarpidase because leucovorin is a substrate for glucarpidase. In cases of massive overdose, hydration and urinary alkalinization with sodium bicarbonate are required to prevent renal tubule damage. Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdoses of methotrexate. Monitor fluid and electrolyte status; patients must be well hydrated. Intermittent hemodialysis using a high-flux dialyzer may be used for clearance until levels are <0.05 micromolar. Methotrexate should be delayed until recovery if WBC <1500/mcL, neutrophil count <200/mcL, platelet count <75,000/mcL, serum bilirubin level >1.2 mg/dL, AST level >450 IU/L, mucositis is present, until evidence of healing, persistent pleural effusion is present, should be drained dry prior to infusion. Adequate renal function is required. Serum creatinine must be normal, CCr must be >60 mL/min, before initiation of therapy. Serum creatinine must be measured before each course of therapy. If ↑ by ≥50% of a prior value, CCr must be >60 mL/min, even if serum creatinine is within normal range.

Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations, and infusion pump settings. Methotrexate for nononcologic use is given at a much lower dose and frequency—often just once a wk. Do not confuse nononcologic dosing regimens with dosing regimens for cancer patients. Do not confuse methotrexate with metolazone or MTX Patch (lidocaine/menthol). Do not confuse Trexall with Paxil.
Administer IV fluids starting before 1st dose and continuing through therapy to maintain adequate hydration and urine output.
Solutions for injection should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard equipment in specially designated containers.
PO: Use only the copackaged syringe to measure Jylamvo; a teaspoon is not an accurate measuring device. Solution is clear yellow; do not administer solutions that are discolored, cloudy, or contain particulate matter.
Otrexup and Rasuvo are not indicated for treatment of neoplastic diseases. Not for patients requiring oral, IM, IV, intra-arterial, or IT dosing, doses <10 mg/wk, doses >25 mg/wk, high-dose regimens, or dose adjustments of less than 5 mg increments.
SC: Otrexup and Rasuvo are single-dose auto-injectors. Inject once weekly in abdomen or upper thigh. Avoid areas where skin is tender, bruised, red, scaly, hard, or has scars or stretch marks. Solution is clear and yellow; do not inject solutions that are discolored or contain particulate matter.
Reconstitute preservative-free methotrexate with preservative-free 0.9% NaCl, Elliot’s B solution, or patient’s CSF to a concentration not greater than 2 mg/mL. May be administered via lumbar puncture or Ommaya reservoir. To prevent bacterial contamination, use immediately.

IV Administration:

Reconstitution: Reconstitute each vial with 25 mL of 0.9% NaCl. Use sterile preservative-free diluents for high-dose regimens, neonates, low-birth weight infants, and intrathecal use to prevent complications from large amounts of benzyl alcohol. Solution is clear yellow; do not use preparations that are cloudy, discolored or that contain a precipitate. Reconstitute immediately before use. Discard unused portion.Concentration: 25 mg/mL for IV push and intermittent/continuous infusions.
Rate: Administer at a rate of 10 mg/min into Y-site of a free-flowing IV.
Intermittent/Continuous Infusion: Diluent: Doses >100–300 mg/m2 may also be diluted in D5W, D5/0.9% NaCl, or 0.9% NaCl and infused as intermittent or continuous infusion.
Rate: Administration rates of 4–20 mg/hr have been used.

Instruct patient to take medication as directed. If a dose is missed, it should be omitted. Consult health care professional if vomiting occurs shortly after a dose is taken. Advise patients taking PO or SUBQ therapy to read Patient Information before starting therapy and with each Rx refill in case of changes.
Instruct patient to notify health care professional promptly if rash, fever; chills; cough; hoarseness; sore throat; signs of infection; lower back or side pain; painful or difficult urination; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or other NSAIDs; may precipitate gastric bleeding.
Instruct patient to inspect oral mucosa for erythema and ulceration. If ulceration occurs, advise patient to use sponge brush and to rinse mouth with water after eating and drinking. Topical therapy may be used if mouth pain interferes with eating. Stomatitis pain may require treatment with opioid analgesics.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Discuss the possibility of hair loss with patient. Explore methods of coping.
Instruct patient not to receive any vaccinations without advice of health care professional.
Caution patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 6 mo after last dose and avoid breastfeeding during and for 1 wk after last dose of therapy. Advise males with female partners of reproductive potential to use effective contraception during and for 3 mo after therapy. Advise patient to notify health care professional if pregnancy is planned or suspected. May impair fertility in both men and women.
Emphasize the need for periodic lab tests to monitor for side effects.
SC: Instruct patient on correct technique for injection and care and disposal of equipment.

Improvement of hematopoietic values in leukemia.
- Decrease in symptoms of meningeal involvement in leukemia.
Decrease in size and spread of non-Hodgkin’s lymphomas and other solid cancers.
Resolution of skin lesions in severe psoriasis.
Decreased joint pain and swelling.
- Improved mobility in patients with rheumatoid arthritis.
Regression of lesions in mycosis fungoides.

Jylamvo, Otrexup, Rasuvo, ~~Rheumatrex,~~ Trexall, Xatmep

Metoject

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