FOLEX
Clinical safety rating
cautionComprehensive clinical and safety monograph for FOLEX (FOLEX).
Comprehensive clinical and safety monograph for FOLEX (FOLEX).
FDA-approved: Treatment of neoplastic diseases (e.g., acute lymphoblastic leukemia, breast cancer, head and neck cancer, non-Hodgkin lymphoma, osteosarcoma)FDA-approved: Treatment of severe psoriasis (adult, recalcitrant, disabling)FDA-approved: Treatment of active rheumatoid arthritis (adult, severe, active) and polyarticular juvenile idiopathic arthritisOff-label: Management of ectopic pregnancyOff-label: Treatment of Crohn's diseaseOff-label: Management of uveitis
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. |
| Molecular Weight | 454.44 |
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 | Category D - Known human teratogen. Contraindicated in pregnancy, especially during organogenesis (weeks 3-8). Risk of miscarriage, neural tube defects, and craniofacial anomalies. |
| 2nd trimester | Category D - Continued risk; avoid use. Potential for fetal growth restriction and developmental abnormalities. |
| 3rd trimester | Category D - Avoid use, especially near term, due to risk of neonatal myelosuppression and immunosuppression. |
Clinical note
Comprehensive clinical and safety monograph for FOLEX (FOLEX).
| Placental transfer | Active placental transfer via folate receptors; concentration in fetal circulation comparable to maternal levels. |
| Breastfeeding | Excreted into breast milk in small amounts; potential for infant toxicity and immunosuppression. Contraindicated during breastfeeding. |
| Lactation Rating | L5 - Contraindicated |
| 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. |
| 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. |
■ 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 |
PregnancyBreastfeedingSevere renal impairment (CrCl <10 mL/min)Pre-existing severe bone marrow suppressionHypersensitivity to methotrexate
| 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 |
| Food/Dietary | Avoid alcohol completely; may increase hepatotoxicity. No specific food restrictions, but maintain adequate hydration. Avoid folic acid-rich foods (e.g., fortified cereals, legumes) if combining with leucovorin rescue in high-dose therapy due to potential interference. Take folic acid supplements at a different time than methotrexate if prescribed. |
| Clinical Pearls | Folex (methotrexate) is a folate analog antimetabolite used in oncology and autoimmune diseases. Administer leucovorin rescue 24 hours after high-dose methotrexate to prevent severe toxicity. Monitor renal function and methotrexate levels closely. Avoid NSAIDs as they reduce renal clearance and increase toxicity. Hepatotoxicity and pulmonary fibrosis are serious adverse effects. Intrathecal administration requires preservative-free formulation. |
| Patient Advice | Take folic acid supplements as prescribed to reduce side effects unless on high-dose therapy with leucovorin rescue. · Avoid alcohol completely during treatment due to increased risk of liver damage. · Report any signs of infection, unusual bleeding, or shortness of breath immediately. · Drink plenty of fluids to help flush the drug from your kidneys unless otherwise instructed. · Do not take any over-the-counter medications, especially NSAIDs (like ibuprofen), without consulting your doctor. · Use effective contraception during and for at least 3 months after treatment for both men and women. · Follow your dosing schedule exactly; missed doses can reduce effectiveness or increase toxicity. |
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