FOLEX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FOLEX (FOLEX).
Methotrexate, the active ingredient in FOLEX, is a folate analog that inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate, thereby interfering with thymidylate and purine synthesis, leading to inhibition of DNA replication and cell proliferation.
| Metabolism | Methotrexate undergoes hepatic metabolism to polyglutamate metabolites which are retained in cells. It is partially metabolized by aldehyde oxidase and xanthine oxidase. Excretion is primarily renal via glomerular filtration and active tubular secretion. |
| Excretion | Primarily renal excretion of unchanged drug: ~80-90% within 24 hours. Biliary/fecal excretion accounts for <10%. |
| Half-life | Terminal half-life: 3-10 hours (mean ~5 hours) for low-dose regimens; higher doses or renal impairment may prolong half-life up to 24 hours. |
| Protein binding | Approximately 50% bound to serum proteins, primarily albumin. |
| Volume of Distribution | Vd: 0.4-0.8 L/kg (total body water), indicating extensive tissue distribution; higher in pleural effusions or ascites. |
| Bioavailability | Oral bioavailability: dose-dependent, variable (20-80%, higher with low doses); IM: complete but slower absorption; IV: 100%. |
| Onset of Action | Oral: 30-60 minutes; IV: 5-10 minutes; IM: 15-30 minutes. |
| Duration of Action | Duration of antineoplastic effect: 1-4 weeks depending on dose and tissue sensitivity; toxicity (e.g., myelosuppression) may persist longer. Clinical effect often sustained for 2-3 weeks after high-dose therapy. |
30 mg/m2 intravenously once weekly for 2 weeks followed by a 1-week rest period, or 5-10 mg/m2 intramuscularly or intravenously every 3-4 weeks. For rheumatoid arthritis, 7.5-15 mg orally once weekly.
| Dosage form | INJECTABLE |
| Renal impairment | GFR >50 mL/min: no adjustment; GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: avoid use or reduce dose by 75%. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use. |
| Pediatric use | For acute lymphoblastic leukemia: 12.5 mg/m2 orally once weekly; for juvenile idiopathic arthritis: 10-15 mg/m2 orally or subcutaneously once weekly. Maximum single dose: 20 mg. |
| Geriatric use | Start at lowest end of dosing range (e.g., 5-7.5 mg orally weekly for rheumatoid arthritis) due to increased risk of toxicity from reduced renal function and folate stores. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FOLEX (FOLEX).
| Breastfeeding | Contraindicated during breastfeeding. Methotrexate (active component) is excreted in breast milk with an M/P ratio of approximately 0.08; risk of infant accumulation due to long half-life. Do not breastfeed during therapy or for at least 1 week after last dose. |
| Teratogenic Risk | FDA Pregnancy Category X. First trimester: High risk of miscarriage, neural tube defects, craniofacial anomalies, and limb defects. Second and third trimesters: Fetal growth restriction, skeletal abnormalities, functional deficits. Avoid use during pregnancy. |
■ FDA Black Box Warning
FOLEX (methotrexate) may cause severe toxicity including death, especially with high doses. Severe reactions include myelosuppression, hepatotoxicity, pulmonary fibrosis, renal failure, and gastrointestinal ulceration. Must be used only by physicians experienced in antimetabolite therapy. Patients should be closely monitored for bone marrow, liver, and renal toxicity.
| Serious Effects |
["Hypersensitivity to methotrexate or any component","Breastfeeding","Severe renal impairment (creatinine clearance <10 mL/min)","Severe hepatic impairment (e.g., cirrhosis, active hepatitis)","Pre-existing severe bone marrow depression (e.g., pancytopenia)","Pregnancy (teratogenic and embryotoxic)"]
| Precautions | ["Hepatotoxicity: Risk of acute and chronic liver injury, fibrosis, and cirrhosis, especially with prolonged use or pre-existing liver disease","Myelosuppression: Risk of severe pancytopenia, especially in renal impairment or with concurrent NSAIDs","Pulmonary toxicity: Acute or chronic interstitial pneumonitis, fibrosis","Renal toxicity: Acute renal failure due to precipitation of methotrexate in renal tubules, especially with high doses","Gastrointestinal toxicity: Ulceration, perforation, hemorrhage","Dermatologic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis","Concurrent NSAIDs increase methotrexate toxicity"] |
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| Fetal Monitoring |
| Monitor CBC, liver function tests (AST, ALT, bilirubin), renal function (serum creatinine, BUN), and methotrexate trough levels. In pregnant patients (if unavoidable), serial fetal ultrasound and echocardiography. Maternal monitoring for pulmonary toxicity, myelosuppression, and hepatotoxicity. |
| Fertility Effects | Folex can cause reversible oligospermia and menstrual dysfunction. Preclinical studies show impaired fertility with reduced implantation rates. May reduce sperm count and motility in males. In females, may cause ovarian failure and premature menopause. Effects typically reverse upon drug discontinuation. |