because of risk of serious neurotoxicity Infections Increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections (eg, Pneumocystis jiroveci pneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, disseminated Herpes zoster and cytomegalovirus infections) Closely monitor patients for development of signs and symptoms of infection during and after treatment; withhold or discontinue in patients who develop serious infections Renal Toxicity Can cause renal toxicity including irreversible acute renal failure Monitor renal function and withhold or discontinue as needed for severe renal toxicity For high-dose regimens, follow recommendations to decrease renal injury and mitigate renal toxicity (eg, hydration, alkalinize urine, leucovorin rescue) Patients with impaired renal function have increased risk for toxicity Consider administration of glucarpidase in patients with toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed clearance due to impaired renal function Hepatotoxicity Can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and fatal liver Avoid use in patients with chronic liver disease, unless benefits clearly outweigh risks; risk increased with heavy alcohol consumption In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver function tests; risk of hepatotoxicity appears to increase with total cumulative dose ≥1.5 g Assess liver function before initiating and monitor liver function tests during treatment; withhold or discontinue methotrexate Injection as appropriate Dermatologic reactions Severe, including fatal, dermatologic reactions reported (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme) Psoriasis may be aggravated by concomitant exposure to UV radiation Can cause radiation recall dermatitis and photodermatitis (sunburn) reactivation Monitor for signs of dermatologic toxicity and withhold or permanently discontinue for severe dermatologic adverse reactions Counsel patients to avoid excessive sun exposure and use sun protection measures Folic acid supplementation Neoplastic diseases: Products containing folic acid or its derivatives may decrease the clinical effectiveness of methotrexate; avoid products containing folic acid or folinic acid unless clinically indicated Non-neoplastic diseases: Folate deficiency may increase methotrexate adverse reactions; administer folic acid or folinic acid to patients with rheumatoid arthritis, pJIA, and psoriasis Drug interaction overview Drugs that increase methotrexate systemic exposure or adverse effects If unable to avoid coadministration, monitor closely for methotrexate adverse effects Penicillin or sulfonamide antibiotics Highly protein-bound drugs (eg, oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (eg, dapsone, pemetrexed, pyrimethamine, sulfonamides) Aspirin and other NSAIDs; unexpectedly severe and fatal GI toxicity can occur with concomitant administration of methotrexate (primarily at high dose) Mercaptopurine Hepatotoxic products Weak acids (eg, salicylates) Nephrotoxic products Nitrous oxide Avoid nitrous oxide anesthesia; consider alternative therapies in patients who have received prior nitrous oxide anesthesia Coadministration with nitrous oxide anesthesia potentiates methotrexate’s effect on folate-dependent metabolic pathways, which may increase risk of severe methotrexate adverse reactions Folic acid H5Avoid coadministration of folic/folinic acid supplements unless specifically prescribed (eg, for use with rheumatoid arthritis, psoriasis, or pJIA) Coadministration with folic acid or its derivatives decreases clinical effectiveness of methotrexate in patients with neoplastic diseases Methotrexate competes with reduced folates for active transport across cell membranes Theophylline Monitor theophylline levels and adjust theophylline dosage accordingly Methotrexate may increase theophylline plasma concentrations Immunizations Update immunization per guidelines before initiating methotrexate if possible May be ineffective during therapy and live virus vaccines are not recommended due to risk of infection Disseminated infections following administration of live vaccines reported Pregnancy Based on published reports and mechanism of action, can cause embryo-fetal toxicity and fetal death when administered to pregnant women Advise pregnant women with neoplastic diseases of potential risk to fetus; preservative benzyl alcohol can cross placenta; when possible, use preservative-free formulation when methotrexate Injection needed during pregnancy to treat a neoplastic disease Verify pregnancy status of females of reproductive potential before initiating Contraindicated in pregnant women with nonmalignant disease Contraception Females Can cause fetal harm when administered to pregnant women; Use effective contraception during and for 6 months after final dose Males Can cause chromosomal damage to sperm cells Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after final dose Infertility Females: Can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy; unknown if infertility may be reversed in all affected females Males: Can cause oligospermia or infertility during and after cessation of therapy; unknown if infertility may be reversed in all affected males Lactation Limited published literature report the presence of methotrexate in human milk in low amounts; no information is available on the effects on breastfed infants or milk production Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during therapy and for 1 week after final dosePregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair, and cellular replication; cell cycle specific for S phase of cycle May inhibit rapid proliferation of epithelial cells in skin Absorption Bioavailability (PO): 60% at PO doses <30 mg/m², bioavailability is significantly less at doses >80 mg/m² Bioavailability (SC, Otrexup): 17, 13, 31, and 36% greater than PO methotrexate at doses of 10, 15, 20, and 25 mg respectively AUC (SC, Rasuvo): 35%, 49%, 51%, and 68% greater than PO methotrexate at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg respectively Peak plasma time: PO, 1-2 hr; IM, 30-60 min Distribution Protein bound: 50% Vd: Initial, 0.18 L/kg; steady-state, 0.4-0.8 L/kg Metabolism Metabolized by liver and intracellularly Metabolites: Polyglutamated forms Elimination Half-life: Psoriasis, rheumatoid arthritis, and low-dose cancer treatment, 3-10 hr; high-dose treatment, 8-15 hr Excretion: Urine (80-100% within 24 hr), feces (small amounts) IV Incompatibilities Additive: Bleomycin Syringe: Droperidol, metoclopramide (may be compatible at low concentrations of metoclopramide) Y-site: Chlorpromazine, dexamethasone sodium phosphate(?), droperidol(?), gemcitabine, idarubicin, ifosfamide, midazolam, nalbuphine, promethazine, propofol IV/IM Preparation Reconstitute with D5W or NS: 20-mg vial, up to 25 mg/mL; 1-g vial, up to 50 mg/mL May dilute further for IV infusion IV/IM Administration Administer by IM, IV push, or IV infusion Regular IV given with no more than 25 mg/mL IV push: Administered at 10 mg/min IV infusion (usually >100 mg): Administered over 30 minutes to 4 hours, or according to institutional protocol High-dose therapy (uses 1-g vial): Administered over 4 hours Specific dosing schemes vary, but high doses should be followed by leucovorin 24 hours after initiation of therapy to prevent toxicity IT Administration Use only preservative-free product May dilute further with preservative-free 0.9% NaCl Before administration, equal volume of CSF is usually withdrawn; administer drug only if easy flow of blood-free CSF is noted SC Administration Otrexup is a single-dose auto-injector available in doses between 10 to 25 mg (in 5-mg increments) for once-weekly SC use only Rasuvo is a single-dose auto-injector available in doses between 7.5 and 30 mg (in 2.5-mg increments) for once-weekly SC use only RediTrex is a single-dose prefilled syringe available in doses between 7.5 and 25 mg (in 2.5-mg increments) for once-weekly SC use only Use another formulation in patients who require PO, IM, IV, intra-arterial, or IT dosing Visually inspect for particulate matter and discoloration prior to administration; do not use if seal is broken Administer SC in abdomen or thigh May self-inject if determined appropriate by a physician and have received proper training on preparation and administration; a trainer device is available Handling and disposal consistent with recommendation for cytotoxic drugs Oral Administration Oral solution (Xatmep) Intended for oral use only Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity Measure dose with an accurate measuring device to provide the correct dose, such as an oral syringe provided by the pharmacist (do NOT use a household teaspoon) May take with or without food; food does not affect AUC, but decreased maximum concentration levels by 50% and delayed the absorption Storage Store intact vials at room temperature Protect from light BRAND FORM. UNIT PRICE PILL IMAGE Xatmep oral- 2.5 mg/mL solutionXatmep oral- 2.5 mg/mL solutionCopyright © 2010 First DataBank, Inc.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs. 2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs. 3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs. 4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. NC NOT COVERED – Drugs that are not covered by the plan. Code Definition PA Prior Authorization Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription. QL Quantity Limits Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered. ST Step Therapy Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription. OR Other Restrictions Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription. 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