藥劑部參考美國 Johns Hopkins 大學研究團隊所建立的 NxP (Nephrotoxic Potential) 專家共識分級清單，本品具「顯著以上腎毒性風險」，被認定具中度至高度腎損傷潛勢，特別是同時合併其他腎毒性藥物、脫水、高齡或既有腎功能異常的患者族群，應更加注意。

#高警訊藥品

Oncology uses:
1. Acute lymphoblastic leukemia (ALL): as part of a combination chemotherapy regimen
2. Breast cancer: as part of a combination chemotherapy regimen
3. Head and neck cancer: as a single agent
4. Cutaneous T-Cell lymphoma: Treatment of advanced mycosis fungoides
5. Meningeal leukemia
6. Gestational trophoblastic neoplasia: as part of a combination chemotherapy regimen
7. Advanced non-Hodgkin lymphomas (NHL)
8. Osteosarcoma: as part of a combination chemotherapy regimen
Nononcology uses:
1. Polyarticular juvenile idiopathic arthritis: For patients whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose nonsteroidal anti-inflammatory drugs (NSAIDs)
2. Psoriasis: Severe, recalcitrant, disabling psoriasis (in adults) that is not adequately responsive to other therapies
3. Rheumatoid arthritis: Severe, active RA in adults whose disease is unresponsive to or who are intolerant of first-line therapy, including full-dose NSAIDs.

Antineoplastic Agent, Antimetabolite (Antifolate); Antirheumatic, Disease Modifying; Immunosuppressant Agent
Methotrexate binds to and inhibits dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis, thus interfering with DNA synthesis, repair, and cellular replication. Methotrexate is cell cycle specific for the S phase of the cycle.

Onset of action:
Antirheumati: 3 to 6 weeks; additional improvement may continue longer than 12 weeks.
Absorption:
IM: Complete
Distribution:
1. Penetrates slowly into third space fluids (eg, pleural effusions, ascites), exits slowly from these compartments (slower than from plasma); sustained concentrations retained in kidney and liver.
2. Vd: 0.18 L/kg (initial); 0.4 to 0.8 L/kg (steady state)
3. Protein binding: ~50%
Half-life elimination:
1. Children: (ALL) 0.7 to 5.8 hours; (pJIA) 0.9 to 2.3 hours
2. Adults: 8 to 15 hours
Time to peak, serum:
30 to 60 minutes
Excretion:
Dose and route dependent; IV: Urine (80% to 90% as unchanged drug; 5% to 7% as 7-hydroxy methotrexate); feces ((10%).

1. Known hypersensitivity to methotrexate or any component of the formulation
2. Breast-feeding
3. Additional contraindications for patients with psoriasis, rheumatoid arthritis or polyarticular-course juvenile idiopathic arthritis: Pregnancy, alcoholism, chronic liver disease, immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia), severe kidney impairment (CrCl<10mL/min).<20230928>

1. Methotrexate can cause embryo-fetal toxicity, including fetal death; Consider the benefits and risks of methotrexate.
2. The use of methotrexate for the treatment of rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis, and psoriasis is contraindicated in pregnancy.

Breastfeeding is contraindicated by some manufacturers during treatment. Other manufacturers recommend discontinuing breastfeeding during treatment and for 1 week after the final methotrexate dose.

Common:
Dermatologic: Photosensitivity, Rash
Gastrointestinal: Diarrhea, Nausea and vomiting
Hematologic: Leukopenia, Thrombocytopenia
Neurologic: Dizziness
Serious:
Cardiovascular: Pericardial effusion, Thromboembolic disorder
Dermatologic: Toxic epidermal necrolysis
Gastrointestinal: Gastrointestinal hemorrhage, Stomatitis
Hematologic: Aplastic anemia, Malignant lymphoma, Myelosuppression, Pancytopenia
Hepatic: Cirrhosis of liver, Hepatic fibrosis, Hepatitis, Hepatotoxicity, Liver failure
Neurologic: Encephalopathy, Neurotoxicity, Seizure
Renal: Nephrotoxicity
Respiratory: Interstitial pneumonia
Other: Infectious disease, Tumor lysis syndrome

Acute lymphoid leukemia:
CALGB 8811 regimen (as a component of combination chemotherapy): Intrathecal: 15 mg on day 1 of early intensification phase, repeat in 4 weeks
Breast cancer:
IV: 40 mg/m2 days 1 and 8 every 4 weeks (in combination with cyclophosphamide and fluorouracil) for 6 to 12 cycles
Head and neck cancer, advanced:
IV: 40 mg/m2 once weekly until disease progression or unacceptable toxicity
Meningeal leukemia:
Intrathecal: 12 to 15 mg (MAX 15 mg/dose) every 2 to 7 days; continue for 1 dose beyond CSF cell count normalization
Non-Hodgkin lymphoma:
1. Burkitt lymphoma (with leucovorin rescue): (Adults ≤65 y/o) 300 mg/m2 over 1 hour on day 10 followed by 2,700 mg/m2 over 23 hours; (Adults >65 y/o) 100 mg/m2 over 1 hour on day 10 followed by 900 mg/m2 over 23 hours
2. Mantle cell lymphoma (with leucovorin rescue): 200 mg/m2 bolus on day 1 or day 2 followed by 800 mg/m2 over 24 hours during even courses (2, 4, 6, and 8) of 21-day treatment cycles
Osteosarcoma: For Adults ≤30 years
IV: 12 g/m2 (maximum: 20 g/dose) over 4 hours (followed by leucovorin rescue) for 4 doses during induction (before surgery) at weeks 4, 5, 9, and 10, and for 8 doses during maintenance (after surgery) at weeks 15, 16, 20, 21, 24, 25, 28, and 29 (in combination with doxorubicin and cisplatin)

Acute lymphoid leukemia, Interim maintenance:
1. High-dose methotrexate: (IV) 500 mg/m2 over 30 minutes followed by 4,500 mg/m2 over 23.5 hours to complete a total dose of 5,000 mg/m2 over 24 hours on days 1, 15, 29, and 43 (with leucovorin rescue)
2. Escalating-dose methotrexate: (IV) Initial 100 mg/m2 then escalate dose by 50 mg/m2 every 10 days for 5 doses total
Acute lymphoid leukemia, CNS prophylaxis intrathecal therapy:
<1 year: 6 mg; 1 to <2 years: 8 mg; 2 to <3 years: 10 mg; 3 to 8 years: 12 mg; >8 years: 15 mg

CrCl (30-59 mL/min): Administer 50% of normal dose.
CrCl (10-29 mL/min): Avoid use. If necessary, administer 50% of normal dose.
CrCl (<10 mL/min): Avoid use. <20230928>

1. Bilirubin <3 mg/dL and AST <180 IU: 100% of the dose
2. Bilirubin 3.1 to 5 mg/dL, or AST >180 IU: 75% of the dose
3. Bilirubin >5 mg/dL: avoided