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

子宮外孕 Tubal ectopic pregnancy (off-label use)

Anticancer-Folate Antimetabolites

Onset of action: Antirheumatic: 3 to 6 weeks; additional improvement may continue longer than 12 weeks. Absorption: Oral: Highly variable; dose dependent; decreased absorption at higher doses (pediatric patients: >40 mg/m2; adult patients: >80 mg/m2); possibly due to saturation effect. IM injection: Complete. Distribution: 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. Vd: IV: 0.18 L/kg (initial); 0.4 to 0.8 L/kg (steady state). Protein binding: ~50%. Metabolism: Partially metabolized by intestinal flora (after oral administration) to DAMPA by carboxypeptidase; hepatic aldehyde oxidase converts methotrexate to 7-hydroxy methotrexate; polyglutamates are produced intracellularly and are just as potent as methotrexate; their production is dose- and duration-dependent and they are slowly eliminated by the cell once formed. Polyglutamated forms can be converted back to methotrexate. Bioavailability: Oral: Children: Highly variable: 23% to 95%; Adults: Low doses ((30 mg/m2): ~60%; in general, bioavailability is dose dependent and decreases as the dose increases (especially at doses >80 mg/m2 [>40 mg/m2 in pediatric patients]). Half-life elimination: Children: ALL: 0.7 to 5.8 hours (dose range: 6.3 to 30 mg/m2); pJIA: 0.9 to 2.3 hours (dose range: 3.75 to 26.2 mg/m2). Adults: Low dose (oral): 3 to 10 hours; High dose (IV): 8 to 15 hours. Time to peak, serum: Oral: Children: 0.7 to 4 hours (reported for a 15 mg/m2 dose); Adults: 0.75 to 6 hours; IM: Children and Adults: 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%).

History of severe hypersensitivity (including anaphylaxis) to methotrexate or any component of the formulation; breastfeeding (product-specific; refer to manufacturer's labeling).Additional contraindications for patients with psoriasis, rheumatoid arthritis or polyarticular-course juvenile idiopathic arthritis: Pregnancy, alcohol use disorder, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes (overt or laboratory evidence); preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia).

When used for the medical management of ectopic pregnancy, methotrexate has not been shown to adversely affect fertility or ovarian reserve. Future pregnancies should be delayed until resolution of the ectopic pregnancy has been confirmed and at least 3 months after the last methotrexate dose (ACOG 2018).

Available guidelines contraindicate breastfeeding in patients taking methotrexate for the treatment of tubal ectopic pregnancy

>10%:Gastrointestinal: Diarrhea (children, adolescents, adults: ?11%), nausea (children, adolescents, adults: ?11%), vomiting (children, adolescents, adults: ?11%)Hepatic: Increased liver enzymes (children, adolescents, adults: 14% to 15%)1% to 10%:Dermatologic: Alopecia (children, adolescents, adults: ?10%), burning sensation of skin (3% to 10%), dermatitis (?3%), pruritus (?3%), skin photosensitivity (3% to 10%), skin rash (children, adolescents, adults: ?3%)Gastrointestinal: Stomatitis (children, adolescents, adults: 2% to 10%)Hematologic & oncologic: Leukopenia (children, adolescents, adults: 1% to 3%), pancytopenia (1% to 3%), thrombocytopenia (3% to 10%)Nervous system: Dizziness (children, adolescents, adults: ?3%), headache (children, adolescents, adults: ?1%)Respiratory: Interstitial pneumonitis (1%)Frequency not defined:Cardiovascular: Chest painDermatologic: Diaphoresis, exacerbation of psoriasis (plaque erosion)Gastrointestinal: Aphthous stomatitisGenitourinary: DysuriaNervous system: Chemical arachnoiditis (intrathecal; acute), chills, malaiseOphthalmic: Eye discomfortOtic: TinnitusRespiratory: Epistaxis, upper respiratory tract infection

Tubal ectopic pregnancy (off-label use):
1. Single-dose regimen:
IM 50 mg/m2 on day 1. Measure serum hCG levels on days 4 and 7; if hCG decrease is <15%, repeat dose (methotrexate 50 mg/m2) on day 7
2. Two-dose regimen:
IM 50 mg/m2 on day 1. Measure serum hCG levels on day 4 and administer a second dose of methotrexate 50 mg/m2. Measure serum hCG levels on day 7. If hCG decrease is <15%, administer a third dose of methotrexate 50 mg/m2 and measure serum hCG again on day 11; if hCG decrease is <15% on day 11, administer a fourth dose of methotrexate 50 mg/m2 and measure serum hCG levels on day 14.
3. Multidose regimen (in combination with leucovorin):
IM 1 mg/kg on days 1, 3, 5, and 7 alternating with leucovorin calcium on days 2, 4, 6, and 8. Measure serum hCG on each day of methotrexate administration. If serum hCG decreases by >15% from previous measurement, discontinue methotrexate (total treatment may be between 1 and 4 doses). If serum hCG decreases by <15% from previous measurement, administer methotrexate (maximum 4 doses).

N/A

CrCl >50 mL/minute/1.73 m²: No adjustment necessary.

CrCl 10 to 50 mL/minute/1.73 m²: Administer 50% of dose.

CrCl <10 mL/minute/1.73 m²: Administer 30% of dose.

Hemodialysis: Administer 30% of dose.

Peritoneal dialysis (PD): Administer 30% of dose.

Continuous renal replacement therapy (CRRT): Administer 50% of dose.

Bilirubin 3.1 to 5 mg/dL or transaminases >3 times ULN: Administer 75% of dose.

Bilirubin >5 mg/dL: Avoid use.

1. Powder for Solution
(1) Store at a controlled room temperature between 20 and 25 degrees C (68 and 77 degrees F), with excursions permitted between 15 and 30 degrees C (59 and 86 degrees F); protect from light.
(2) Solutions of methotrexate stored in plastic syringes appear to be stable for up to 30 days when refrigerated.
2. Solution
(1) Store at a controlled room temperature of 25 degrees C (77 degrees F), with excursions permitted between 15 and 30 degrees C (59 and 86 degrees F). Protect from light.
(2) After further dilution, solution may be stored up to 24 hours between 21 and 25 degrees C.