FOLEX PFS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FOLEX PFS (FOLEX PFS).
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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FOLEX PFS (FOLEX PFS).
| Breastfeeding | Contraindicated in breastfeeding. Methotrexate is excreted in human milk and can accumulate in neonatal tissues. M/P ratio not established but reported to be 0.08:1 in limited data. |
| 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. |
■ 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 |
["Pregnancy and lactation (FDA Pregnancy Category X)","Severe renal impairment (eGFR < 30 mL/min/1.73 m²)","Severe hepatic impairment (cirrhosis, active hepatitis)","Alcoholism or alcoholic liver disease","Pre-existing blood dyscrasias (e.g., bone marrow hypoplasia, severe anemia, leukopenia, thrombocytopenia)","Active immunodeficiency syndromes (e.g., AIDS)","Hypersensitivity to methotrexate or any component of the formulation","Concurrent treatment with live vaccines","Breastfeeding"]
| 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"] |
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| 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. |