FOLEX PFS
Clinical safety rating
cautionComprehensive clinical and safety monograph for FOLEX PFS (FOLEX PFS).
Comprehensive clinical and safety monograph for FOLEX PFS (FOLEX PFS).
Neoplastic diseases: gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphocytic leukemia, meningeal leukemia, breast cancer, head and neck cancer, advanced mycosis fungoides, lung cancer (especially squamous cell and small cell types), advanced non-Hodgkin's lymphomas.Psoriasis (severe, recalcitrant, disabling, not adequately responsive to other therapy)Rheumatoid arthritis (active, severe, refractory to first-line therapy)Off-label uses: ectopic pregnancy, sarcoidosis, inflammatory bowel disease (Crohn's disease), vasculitis, systemic lupus erythematosus, dermatomyositis, juvenile idiopathic arthritis, graft-versus-host disease, multiple sclerosis, polymyositis, acute graft rejection prophylaxis
Methotrexate is a folate analog that inhibits dihydrofolate reductase (DHFR), blocking the synthesis of tetrahydrofolate and thereby interfering with DNA synthesis, repair, and cellular replication. It also exhibits immunosuppressive and anti-inflammatory effects through inhibition of purine and pyrimidine synthesis and reduction of cytokine production.
| Metabolism | Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which are retained for prolonged periods. The primary metabolic pathway involves conversion to 7-hydroxymethotrexate by aldehyde oxidase. Renal excretion is the major route of elimination, with approximately 80-90% of the dose excreted unchanged in the urine within 24 hours. Enterohepatic recirculation occurs. Biliary excretion accounts for a minor fraction. |
| Excretion | Primarily renal excretion as unchanged drug; approximately 80-90% excreted unchanged in urine within 24 hours. Biliary/fecal excretion is minimal (<10%). |
| Half-life | Terminal elimination half-life: 6-12 hours in patients with normal renal function. With impaired renal function, half-life is prolonged (up to 24-48 hours). Low-dose methotrexate (e.g., for rheumatoid arthritis) has half-life 3-10 hours. High-dose methotrexate has a triphasic elimination: alpha phase (0.75 hours), beta phase (3.5 hours), and terminal gamma phase (10-20 hours). |
| Protein binding | Approximately 50% bound to serum albumin, primarily to albumin. Binding is saturable at high doses. |
| Volume of Distribution | Volume of distribution: 0.4-0.8 L/kg (40-80 L/70 kg). Higher doses may increase Vd due to tissue binding. Distributes into third-space fluids, including pleural effusions and ascites. |
| Bioavailability | Oral: 60-70% (dose-dependent, saturable absorption). IM: 76-100% relative to IV. IV: 100%. |
| Onset of Action | Oral: Onset of action for rheumatoid arthritis is 6-8 weeks for clinical effect. IV/IM: For antineoplastic effect, onset is within hours to days, dependent on tumor type and dose. |
| Duration of Action | Duration of action after a single dose: Antineoplastic effect lasts up to weeks; immunosuppressive effect for rheumatoid arthritis lasts 4-8 weeks after single dose. Weekly dosing maintains effect. |
| Molecular Weight | 454.44 |
Methotrexate 30-40 mg/m2 IV once weekly or 7.5-15 mg PO once weekly as single dose or divided into 3 doses over 24 hours.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl 30-60 mL/min: reduce dose by 30-50%; CrCl <30 mL/min: avoid use or use extreme caution with dose reduction >50%. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: avoid use. |
| Pediatric use | Juvenile idiopathic arthritis: 10-15 mg/m2 IV/IM once weekly; leukemia maintenance: 15-30 mg/m2 PO/IM once weekly. |
| Geriatric use | Start at lower end of dosing range (e.g., 7.5-10 mg once weekly) due to reduced renal and hepatic function; monitor for myelosuppression and mucositis. |
| 1st trimester | Contraindicated due to teratogenicity; causes fetal death and congenital anomalies. |
| 2nd trimester | Contraindicated; risks of fetal growth restriction and adverse effects. |
| 3rd trimester | Contraindicated; associated with fetal and neonatal toxicity. |
Clinical note
Comprehensive clinical and safety monograph for FOLEX PFS (FOLEX PFS).
| Placental transfer | Active placental transfer occurs; fetal drug levels reach 25-33% of maternal levels. |
| Breastfeeding | Excreted in human milk; potential for serious adverse reactions in nursing infants; discontinue breastfeeding or drug. |
| Lactation Rating | L5 |
| Teratogenic Risk | FDA Pregnancy Category X. First trimester: severe teratogenic effects including neural tube defects, craniofacial anomalies, and limb defects. Second trimester: increased risk of fetal growth restriction, oligohydramnios, and fetal loss. Third trimester: neonatal myelosuppression, immunosuppression, and acute renal failure. |
| Fetal Monitoring | Complete blood count with differential, liver function tests (AST, ALT, bilirubin), serum creatinine, and urinalysis weekly during pregnancy. Ultrasound for fetal growth and anomalies every 4 weeks. Amniocentesis for methotrexate levels if exposure occurs. |
| Fertility Effects | Reversible oligospermia and menstrual dysfunction in both sexes. May cause ovarian failure and premature menopause. Risk of transient infertility during treatment. |
■ FDA Black Box Warning
WARNING: METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS EXPERIENCED IN ANTIMETABOLITE THERAPY. DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS. PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW SUPPRESSION, HEPATOTOXICITY, PULMONARY TOXICITY, AND RENAL TOXICITY. METHOTREXATE IS CONTRAINDICATED IN PREGNANCY AND LACTATION. DOSING FOR NON-NEOPLASTIC DISEASES (PSORIASIS AND RHEUMATOID ARTHRITIS) IS ONCE WEEKLY; DAILY DOSING HAS LED TO FATAL TOXICITY. ACCIDENTAL OVERDOSAGE HAS RESULTED IN FATALITIES.
| Serious Effects |
BreastfeedingPregnancySevere renal impairment (CrCl < 10 mL/min)Severe hepatic impairmentPre-existing bone marrow aplasiaHypersensitivity to methotrexate
| Precautions | Bone marrow suppression: leukopenia, thrombocytopenia, anemia, pancytopenia, Hepatotoxicity: acute hepatitis, hepatic fibrosis, cirrhosis (especially with chronic use), Pulmonary toxicity: pneumonitis, interstitial alveolitis, pulmonary fibrosis, Renal toxicity: nephropathy, renal failure (due to precipitation of methotrexate and its metabolites in the renal tubules), Gastrointestinal toxicity: ulcerative stomatitis, diarrhea, hemorrhagic enteritis, Infections: increased risk of opportunistic infections (e.g., Pneumocystis jirovecii pneumonia), Dermatologic reactions: photosensitivity, Stevens-Johnson syndrome, Neurologic effects: encephalopathy, seizures, headache, Monitoring: baseline and periodic complete blood counts, liver function tests, renal function tests, chest X-ray, Methotrexate elimination is impaired in patients with renal impairment, ascites, or pleural effusions, leading to increased toxicity, Concurrent use of NSAIDs may increase methotrexate toxicity |
| Food/Dietary | Foods high in folate (e.g., dark leafy greens, beans, liver) may theoretically reduce methotrexate efficacy; however, patients are often given folic acid supplements to mitigate toxicity. Caffeine may interfere with methotrexate clearance; avoid excessive caffeine intake (e.g., >4 cups coffee/day). Grapefruit and grapefruit juice may increase methotrexate levels via CYP inhibition; avoid concurrent consumption. Alcohol consumption during methotrexate therapy significantly increases risk of hepatocellular injury and is contraindicated. Avoid folic acid-fortified foods (e.g., enriched cereals, breads) in large amounts unless supplementing under medical direction. |
| Clinical Pearls | Methotrexate (FOLEX PFS) is a folate analog antimetabolite; always confirm dose and route as intrathecal use has high risk of neurotoxicity. Leucovorin rescue is mandatory after high-dose methotrexate (typically >500 mg/m²) to prevent severe myelosuppression and mucositis. Monitor renal function closely as methotrexate is primarily renally excreted; accumulation can cause acute kidney injury. Hydration and urine alkalinization (target urine pH >7) enhance excretion and reduce nephrotoxicity. Avoid concurrent use of NSAIDs and weak acids (e.g., aspirin, penicillin) as they decrease renal clearance. Intrathecal administration carries risk of chemical arachnoiditis, seizures, and leukoencephalopathy; assess for neurotoxicity symptoms after dosing. Methotrexate can cause pneumonitis; rule out infection if new respiratory symptoms develop. |
| Patient Advice | Take methotrexate exactly as prescribed; do not change dose or frequency without consulting your doctor. · Avoid alcohol completely during treatment to reduce risk of hepatotoxicity. · Drink plenty of fluids (aim for 2-3 liters daily) to prevent kidney damage. · Notify your healthcare provider immediately if you develop mouth sores, fever, chills, sore throat, easy bruising/bleeding, shortness of breath, or yellowing of skin/eyes. · Women of childbearing potential must use effective contraception during treatment and for at least 3 months after last dose; methotrexate is teratogenic. · Do not take any over-the-counter pain relievers (especially NSAIDs like ibuprofen, naproxen) without clearance, as they increase toxicity risk. · Folic acid supplementation may be prescribed to reduce side effects; take it exactly as directed. · Avoid live vaccines while on treatment and for 3 months after discontinuation. · Limit sun exposure and use sunscreen as methotrexate may increase photosensitivity. |
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