• 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).

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
• 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, (INCLUDING ANAPHYLAXIS)HYPERSENSITIVITY REACTIONS , 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.

(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;

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

• IT (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).
• IT (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).
• IT (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).
• IT (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).
• IT (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.

Jylamvo, Otrexup, Rasuvo, Rheumatrex, Trexall, Xatmep

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

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

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

Pharmacologic Classification: antimetabolites

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).

Metoject

(effects on blood counts)

• 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.
• 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.

meth-o-TREX-ate