Methotrexate is a folate antimetabolite. It is an analog of aminopterin, which is also derived from folic acid. The molecular structure of methotrexate differs from folic acid in that it has a hydroxyl group in place of the 4-amino group on the pteridine ring and there is no methyl group at the N10 position. Methotrexate was first used in the treatment of childhood acute lymphocytic leukemia (ALL) in 1948 and has since been approved for the treatment of various malignancies including adult and pediatric ALL, meningeal leukemia, non-Hodgkin lymphoma, osteosarcoma, breast cancer, squamous cell cancer of the head and neck, and gestational trophoblastic neoplasia; the drug is also used for several off-label neoplastic indications. Methotrexate is usually given on a once-weekly basis for certain non-malignant inflammatory conditions, including, but not limited to, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis. Methotrexate has been used as monotherapy, as well as combined with selected disease-modifying antirheumatic drugs (DMARDs) and some biologic DMARD therapies when the response to methotrexate alone is inadequate for these conditions. The ideal combination of therapy for individual patients with inflammatory arthritis conditions is determined by treat to target strategies, severity of disease, and drug tolerance and response. Care must be taken in the chronic use of methotrexate in the treatment of patients with inflammatory conditions to avoid medication dose errors and myelosuppression or other toxicities.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Discuss with the patient the importance of carefully following all dosage instructions including taking the recommended dose as directed. Serious reactions reported with medication errors, including death; these errors most often occurred in patients who were taking methotrexate daily when a weekly dosing regimen was prescribed.
-When switching the dosing regimen from oral administration to IV, IM, or subcutaneous administration, consider potential differences in bioavailability; an alternative dosing regimen may be necessary.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Pediatrics:
-IV Doses of 12 grams/m2 and higher: High
-IV Doses of 5 grams/m2: Moderate
-IV Doses of 38 to 83 mg/m2: Low
-Intrathecal Doses: Moderate
-Oral Doses of 10 mg/m2 and lower: Minimal
-Subcutaneous Doses of 10 mg/m2 and lower: Minimal
Adults:
-IV Doses: Low
-Oral Doses: Minimal/Low
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
-Nonvesicant
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Do not administer to patients who are unable to swallow a tablet.
Oral Liquid Formulations
-NOTE: Be sure to prescribe, dispense and administer the proper product and dosage since products do not provide the same concentration per mL.
Xatmep oral solution (ONLY):
-Contains 2.5 mg of methotrexate per each mL of solution.
-Measure using an accurate calibrated oral (mL) measuring device; a household teaspoon is not an accurate measuring device and could lead to overdosage.
-Provide patients with an appropriate measuring device and instructions for measuring the correct dose. The product contains 2.5 mg of methotrexate in each mL of solution.
Jylamvo oral solution (ONLY):
-Contains 2 mg of methotrexate per each mL of solution.
-Measure using only the copackaged oral dosing syringe; a household teaspoon is not an accurate measuring device and could lead to overdosage.
-The provided dosing syringe utilized mL as the unit of measure (major graduations at every 1 mL and minor graduations at every 0.25 mL). When prescribing, ensure the correct dose is expressed in volume (mL).
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Methotrexate injection that is preservative-free may be administered by IV, IM, subcutaneous, or intrathecal injection.
-Methotrexate injection containing benzyl alcohol may be administered by IV, IM, or subcutaneous injection.
-Only use preservative-free methotrexate injection, which does not contain benzyl alcohol, for the treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available.
-Verify the product concentration prior to preparation and administration to avoid overdosage.
Intravenous Administration
Reconstitution (lyophilized powder vials):
-Reconstitute each 1 g vial with 19.4 mL of an appropriate sterile, preservative-free solution such as 5% Dextrose Injection or 0.9% Sodium Chloride Injection, to a concentration of 50 mg/mL.
-Prepare immediately before use. Discard any unused portions.
Dilution:
-Methotrexate injection may be further diluted in 0.9% Sodium Chloride Injection. High doses of methotrexate administered by IV infusion may be diluted in 5% Dextrose Injection.
-Storage of methotrexate containing benzyl alcohol: After dilution, methotrexate should be used within 4 hours at room temperature (20 to 25 degrees C) or within 24 hours under refrigeration (2 to 8 degrees C).
Intravenous (IV) Infusion
-Administer the diluted admixture as an IV infusion; infusion times may differ based on dosage regimen.
-High-dose methotrexate is typically administered as an IV infusion over 3 to 24 hours. Refer to protocol when applicable for specific infusion times.
Subcutaneous Administration
-When dispensing a vial of methotrexate to self-administer at home, ensure patient receives proper dosage and injection technique instructions, syringes, and needles. Ensure the instructions printed on the patient label include the dose in the unit of measure used for administration (e.g., mL) to minimize confusion. Dispense metric-only syringes with needles of appropriate length and gauge for subcutaneous administration in volumes most closely matching the prescribed dose volume.
-Otrexup, Rasuvo, and Reditrex are methotrexate formulations for subcutaneous use only.
-Both Otrexup and Rasuvo are single-use auto-injectors and Reditrex is a prefilled syringe. Otrexup and Reditrex are both yellow in color, and Rasuvo is yellow-to-brown in color. The formulation should not have lumps or particles floating in it.
-Administer Otrexup, Rasuvo and Reditrex in the abdomen or thigh; do NOT administer within 2 inches of the navel, on the arms, on any other areas of the body, or on skin that is tender, bruised, red, scaly, hard, or has scars or stretch marks.
-If self-injection is deemed appropriate, patients or caregivers should practice injections using a training device with guidance from a health care professional. See the manufacturer provided "Instructions for Use" as an aid for proper device use and administration.
Use of the Otrexup auto-injector:
-Immediately before use, twist cap to remove; flip the safety clip.
-Place needle end of Otrexup against thigh or stomach (abdomen) at a 90-degree angle and firmly push until you hear a click; hold for 3 seconds before removing the auto-injector.
-Press a cotton ball or gauze on the area for 10 seconds; do not rub the injection site.
-After use, the viewing window will be half-blocked with a red flag to show that the medicine was given. If the viewing window is not blocked, call your doctor, pharmacist, or 1-855-Otrexup (1-855-687-3987) for help. Do not inject another Otrexup dose without talking to your doctor.
Use of the Rasuvo auto-injector:
-Immediately prior to use, pull the yellow cap straight off. Do not twist the cap.
-Pinch a pad of skin surrounding a cleaned injection site (thigh or abdomen) with the thumb and forefinger. Position the uncapped transparent end of the auto-injector at a 90-degree angle to the skin. Without pressing the button, push firmly onto the skin until the stop point is felt which will unlock the yellow injection button.
-Press the yellow injection button until a click is heard which indicates the start of the injection. Hold Rasuvo against the skin until all medication is injected. This can take up to 5 seconds. It is not necessary to keep the button of the Rasuvo auto-injector pressed down after the injection has begun.
-To avoid incomplete injection, do not remove Rasuvo from the skin before the end of the injection. Look at the transparent control zone while injecting to make sure the entire dose is injected. When movement stops, the injection is complete.
-Pull straight up (perpendicular to the skin) to remove Rasuvo from the injection site. The protective needle shield should automatically move into place.
-Visually inspect the transparent control zone to ensure there is no liquid left in the syringe. If there is liquid left, not all the medicine was injected. The physician should be contacted. Do not use another Rasuvo unless advised by the doctor.
Use of the Reditrex prefilled syringe:
-Immediately prior to use, pull the needle cap straight off. Do not touch the plunger as the cap is removed. Always hold the syringe by the body of the syringe.
-Gently pinch an area of skin surrounding a cleaned injection site (thigh or abdomen) with the thumb and forefinger.
-Using a quick, dart-like motion, insert needle at a 45-degree angle into the pinched skin.
-Slowly push the plunger until all the liquid is injected and the syringe is empty.
-Once the plunger is pushed all the way in, the needle will automatically withdraw from the body and will automatically cover.
-Discard the prefilled syringe and needle in an appropriate sharps disposal container.
Intrathecal Administration
-Use only preservative-free methotrexate injection, which does not contain benzyl alcohol, for intrathecal use.
-If using methotrexate lyophilized powder for injection, reconstitute with preservative-free 0.9% Sodium Chloride Injection to a concentration of 1 mg/mL prior to withdrawing the appropriate dose.
Serious hypersensitivity reactions or anaphylaxis have occurred with methotrexate treatment; anaphylactoid reactions have also been reported in postmarketing experience with methotrexate. Immediately discontinue methotrexate and begin appropriate therapy if signs or symptoms of anaphylaxis or other serious hypersensitivity reactions occur.
Severe gastrointestinal (GI) toxicity may occur with methotrexate use. Interrupt or discontinue methotrexate for severe gastrointestinal toxicity including diarrhea and ulcerative stomatitis and begin appropriate supportive care; otherwise, hemorrhagic enteritis and death from GI perforation may occur. Also interrupt therapy for vomiting or other toxicities which may result in dehydration. Diarrhea occurred in up to 11% and nausea, vomiting, and stomatitis in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Anorexia was reported in less than 1% of methotrexate-treated patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680). Other GI adverse events that have been reported with methotrexate use include gingivitis, pharyngitis, hematemesis, melena, GI/peptic ulcer, GI bleeding, and pancreatitis.
Bone marrow suppression (e.g., anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and thrombocytopenia) has been reported with methotrexate use and may be severe or life-threatening. Obtain blood counts at baseline and at least monthly during treatment. Provide supportive care, withhold treatment, reduce the dose, or discontinue methotrexate as clinically appropriate; subcutaneous formulations of methotrexate should be stopped immediately if there is a significant drop in blood counts. Severe, prolonged myelosuppression is a dose-limiting toxicity of high-dose methotrexate in the absence of leucovorin rescue; however, with administration of leucovorin, the frequency and severity of these cytopenias is low. Thrombocytopenia defined as platelet count less than 100,000 cells/mm3 (3% to 10%), leukopenia defined as white blood cell (WBC) count less than 3,000 cells/mm3 (1% to 3%), and pancytopenia (1% to 3%) were reported in patients with rheumatoid arthritis (RA) who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 12- to 18-week double-blind studies (n = 128); decreased hematocrit was reported in less than 1% of methotrexate-treated RA patients in 2 other controlled trials (n = 680). Leukopenia occurred in 2% of pediatric patients with juvenile rheumatoid arthritis who received weekly oral doses of methotrexate (5 to 20 mg/m2 per week or 0.1 to 0.65 mg/kg per week). Agranulocytosis, aplastic anemia, eosinophilia, and lymphadenopathy have been reported in postmarketing experience with methotrexate.
Acute (e.g., elevated hepatic enzymes) and chronic (e.g., liver fibrosis and cirrhosis) hepatotoxicity has been reported with methotrexate use. Chronic toxicity generally occurs following prolonged use (2 years or more) and after a total dose of at least 1.5 grams; fatalities have been reported. Hepatic failure has also occurred with methotrexate use. In general, monitor liver function tests (LFTs) and albumin at baseline and every 1 to 2 months during treatment; increase the frequency of monitoring when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels. Interrupt or discontinue methotrexate treatment as clinically appropriate. Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not usually require modification of methotrexate therapy or appear to be predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation. Liver biopsies are recommended periodically for patients with psoriasis who receive long-term treatment because LFTs and albumin are often normal despite developing fibrosis or cirrhosis. In patients with rheumatoid arthritis (RA), persistent LFT abnormalities may precede a diagnosis of fibrosis or cirrhosis. Liver biopsies are recommended at baseline in patients with RA who are at increased risk of hepatotoxicity (e.g., history of excessive alcohol consumption, persistently abnormal LFTs, chronic hepatitis B or C infection); perform a liver biopsy for persistent LFT elevations or for decreased serum albumin levels. Consider discontinuing methotrexate therapy in patients who develop moderate fibrosis or any cirrhosis; discontinue therapy in patients with persistently elevated LFTs who refuse a liver biopsy. Elevated liver function tests (LFTs) were reported in 15% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 12- to 18-week double-blind studies (n = 128). Elevated LFTs occurred in 14% of pediatric patients with juvenile rheumatoid arthritis who received weekly oral doses of methotrexate (5 to 20 mg/m2 per week or 0.1 to 0.65 mg/kg per week). Liver fibrosis (7%) and cirrhosis (0.1%) were reported in patients with rheumatoid arthritis who had a liver biopsy before and/or after methotrexate treatment (n = 934); most cases of fibrosis (93.8%) were mild. Additional hepatobiliary disorders reported in postmarketing experience with methotrexate include acute hepatitis, hypoalbuminemia, and liver failure.
Infection has been reported with methotrexate use including pneumocystis jiroveci pneumonia as the most common opportunistic infection, invasive fungal infections, hepatitis B reactivation, tuberculosis (primary infection or reactivation) and disseminated Herpes zoster and cytomegalovirus infections; some infections were fatal. There have also been reports of disseminated vaccinia infections after smallpox immunizations as well as disseminated infections after administration of other live vaccines. Closely monitor patients for signs and symptoms of infection, such as fever and chills; an interruption or discontinuation of therapy may be necessary. Infection (general), upper respiratory infection, and fever each occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680). Other infections that have been reported with methotrexate use include pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster infection, and herpes simplex hepatitis; hypogammaglobulinemia has also been reported rarely.
Methotrexate can cause severe acute and chronic neurotoxicity which can be progressive, irreversible, and fatal. Monitor patients for signs of neurotoxicity and withhold or discontinue methotrexate if appropriate; discontinuation of therapy does not always result in complete recovery. Leukoencephalopathy has occurred with low, intermediate, and high-dose methotrexate regimens as well as with intrathecal therapy. The risk is increased with prior cranial radiation. However, chronic leukoencephalopathy which may be manifested by confusion, irritability, somnolence (drowsiness), ataxia, dementia, seizures, and coma has also been reported in patients who received repeated doses of high-dose methotrexate with leucovorin rescue, even without cranial radiation. A transient acute neurologic syndrome that included stroke-like encephalopathy with confusion, hemi-paresis, transient blindness, seizures, and coma has also been reported in patients treated with high-dose methotrexate; the exact cause is unknown. Management of methotrexate-induced leukoencephalopathy is usually supportive care, however there have been reports using theophylline or high-dose leucovorin. Generalized or focal seizures have occurred with intermediate-dose IV methotrexate (1 gram/m2) in pediatric patients with acute lymphoblastic leukemia; on imaging studies, these patients typically had leukoencephalopathy and/or microangiopathic calcifications. Acute chemical arachnoiditis has been reported in patients who received intrathecal methotrexate, with symptoms including headache, back pain, nuchal rigidity, and fever; sub-acute myelopathy with paraparesis/paraplegia involving one or more spinal nerve roots has also occurred with intrathecal administration. Dizziness (0.2% to 3%) and headache (1.2% or less) were reported in adult patients with rheumatoid arthritis (RA) and pediatric patients with juvenile RA who received weekly low-dose oral methotrexate. Speech impairment (e.g., dysarthria and aphasia) has been reported in postmarketing experience with methotrexate as well as transient subtle impaired cognition, mood alteration, and unusual cranial sensations following low doses; spinal radiculopathy has been reported with intrathecal use.
Methotrexate therapy can produce potentially fatal pulmonary toxicity including acute or chronic interstitial pneumonitis that can occur acutely at any time during therapy, has been reported at all dose levels, and is not always fully reversible. Obtain a chest x-ray at baseline. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Monitor patients for signs of pulmonary toxicity. Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis may require treatment interruption or discontinuation and careful investigation; additional symptoms include fever, dry cough, dyspnea, hypoxemia, and radiographic evidence of pulmonary infiltrates. Interstitial pneumonitis was reported in 1% of patients with rheumatoid arthritis (n = 680) who received oral methotrexate (7.5 to 15 mg weekly) in 2 controlled trials. Additionally, cough occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg weekly) in 2 other controlled studies (n = 680). Other respiratory adverse events that have been reported with methotrexate use include pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain, and thickening alveolitis.
Nephrotoxicity due to precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules (crystalluria/renal tubular obstruction) may occur with methotrexate use; irreversible acute renal failure (unspecified) has been reported. Obtain renal function tests at baseline, during treatment, and as clinically indicated in all patients who are receiving methotrexate; a dose reduction or discontinuation of methotrexate therapy may be necessary in patients with renal impairment or in patients experiencing nephrotoxicity. Follow recommendations for hydration, urinary alkalinization, leucovorin rescue, and glucarpidase as clinically appropriate. Dysuria occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680). Other renal adverse events that have been reported with methotrexate use include severe nephropathy or renal failure, azotemia, cystitis, proteinuria, and hematuria.
Severe and sometimes fatal skin reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme) have been reported following single or multiple doses of methotrexate at all dose levels and dosage forms. In some cases, the skin toxicity has occurred within days of methotrexate administration. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction. The composite term of rash/pruritus/dermatitis and alopecia were each reported in 1% to 3% of patients with rheumatoid arthritis (RA) who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 12- to 18-week double-blind studies (n = 128); hyperhidrosis was reported in less than 1% of methotrexate-treated RA patients in 2 other controlled trials (n = 680). Alopecia (0.5%) and rash (0.2%) occurred in pediatric patients with juvenile rheumatoid arthritis who received weekly oral doses of methotrexate (5 to 20 mg/m2 per week or 0.1 to 0.65 mg/kg per week). In 2 literature reports (n = 204; n = 248) in psoriasis patients treated with methotrexate doses ranging up to 25 mg per week for up to 4 years, alopecia, photosensitivity, and skin lesion burning were each reported in 3% to 10% of patients; painful plaque erosions were reported rarely in this analysis. Other dermatologic adverse events that have been reported with methotrexate use in postmarketing experience include accelerated nodulosis, erythematous rashes, urticaria, pigmentary changes, ecchymosis, telangiectasia, acne vulgaris, furunculosis, skin ulcer, vasculitis. Sunburn reactivation and radiation recall reaction have also been reported.
Tumor lysis syndrome (TLS) has been reported with methotrexate use, particularly in patients with rapidly growing tumors. In patients at risk for TLS, take appropriate measures (e.g., hydration, uric acid reducing agents) to prevent or alleviate this complication.
Chest pain (unspecified) occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled trials (n = 680). Other cardiac adverse events that have been reported in postmarketing experience with methotrexate include pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal thrombosis, thrombo-phlebitis, and pulmonary embolism). Methotrexate may also cause cardiac rhythm disturbances. The mechanism of the possible cardiac toxicity is unclear, and toxicity with a wide range of doses has been noted. A 36-year-old woman without cardiac structural disease or ischemia developed chest pain, sinus bradycardia, junctional escape beats, and ventricular tachycardia 2 hours after receiving methotrexate 12 g/m2 for osteosarcoma. The cardiac rhythm disturbances resolved within 48 hours without specific treatment (leucovorin dose was increased from 50 mg every 6 hours for 8 doses to 100 mg every 6 hours for a total of 12 doses) and did not recur with methotrexate 6 grams/m2 receipt 2 weeks later. However, the patient unexpectedly died at home 8 days after she received doxorubicin (total dose to date of 150 mg/m2) and cisplatin, which she got 1 month after the first methotrexate dose. According to the Naranjo scale for adverse drug reactions, a probable relationship existed between the cardiotoxicity observed and methotrexate use. In 2 other patients who received oral, weekly methotrexate doses for either psoriasis or rheumatoid arthritis, ventricular tachycardia or premature ventricular contractions (PVCs) occurred. Of interest, in the 1 patient with PVCs, the PVCs improved with methotrexate discontinuation and worsened with re-initiation.
Arthralgia occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680). Other musculoskeletal adverse events that have been reported in postmarketing experience with methotrexate include stress fracture (bone fractures), myalgia, osteoporosis, soft tissue necrosis, and osteonecrosis.
Ocular pain, blurred vision, conjunctivitis, optic neuropathy, xerophthalmia, and visual impairment and other changes including transient blindness have been reported in postmarketing experience with methotrexate. Ocular irritation occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week PO) in 2 controlled studies (n = 680). Ocular symptoms such as burning, pruritus, xerophthalmia, or a gritty sensation were noted in 4 patients who received methotrexate 150 to 250 mg/kg IV on an intermittent basis; no other concomitant chemotherapeutic drugs were received. Symptoms occurred 2 to 7 days after methotrexate receipt. Methylcellulose eye drops provided some symptomatic relief. Complete resolution of ocular irritation occurred in all 4 patients with methotrexate discontinuation. One patient developed ocular burning, pruritus, and mild blurred vision that began 5 to 7 days after his methotrexate dose of 250 mg/kg IV; he had been receiving this dose with leucovorin rescue every 3 weeks for 10 months before ocular symptoms developed. The symptoms persisted for 2 to 5 days after onset and quickly abated. Ophthalmic examination revealed normal vision and a normal lacrimal apparatus, conjunctivae, and lids; however, his reflex production of tears was decreased. Ocular irritation symptoms were reduced with a methotrexate dose reduction to 125 mg due to reduced kidney function; complete symptom resolution occurred with methotrexate discontinuation. Ocular toxicity may also be seen with low-dose weekly drug receipt. A patient developed reduced visual acuity after receiving weekly oral methotrexate (2.5 to 7.5 mg/week) for psoriatic arthritis for 8.5 years. The patient's full-field electroretinogram was markedly reduced; the electro-oculogram result was normal, and no retinal or vitreous pathology was found. Methotrexate appeared to have caused a reversible reduction in rod and cone function. The patient's visual acuity and retinal function improved but did not return to normal within 3 years of methotrexate cessation. In this patient, reduced visual acuity may have been a result of methotrexate-induced generalized photoreceptor or inner retina dysfunction. Methotrexate may also cause a reversible optic neuropathy. A 66-year-old woman had a reversible symmetric optic neuropathy with deep central scotomas (scotomata) and dyschromatopsia attributable to methotrexate treatment and abnormal folate metabolism. She had progressive bilateral visual loss over 5 weeks and had been taking methotrexate 2.5 mg PO three times per week for rheumatoid arthritis for the previous 10 months (total intake 322.5 mg) without folic acid supplementation. Her serum folate concentration was reduced at 1.6 ng/mL, but the vitamin B-12 concentration was normal. Methotrexate cessation and oral folic acid administration (5 mg daily) led to complete recovery of vision including color vision over 4 months. A genetic defect in folate metabolism may have existed in this patient, as her serum folate concentrations returned to normal during folic acid treatment but decreased to below normal once folic treatment was stopped. The timing of this patient's visual recovery implicates abnormal folate metabolism as the cause of the optic neuropathy. Demyelination does not appear to be the cause, as both the visual evoked potential latencies and the brain magnetic resonance imaging (MRI) were normal after visual recovery. Methotrexate appeared to have precipitated the visual loss, as folate administration led to a dramatic resolution of the optic neuropathy with normalization of the visual evoked potentials and visual fields. Visual symptoms developed in another patient who was receiving low-dose methotrexate for psoriasis; her serum folate concentration was not recorded. Methotrexate appeared to have affected optic nerve function, as optic disc swelling and slight optic disc atrophy were noted. Her paracentral relative visual field defects corresponded to methotrexate dose changes. Another patient was diagnosed with methotrexate-induced optic atrophy. She presented with progressive visual loss in each eye and developed bilateral central scotomas, transient optic disk swelling, and optic atrophy. Her serum folate concentration was normal. Discontinuation of methotrexate reduced, but did not eliminate, the visual field defects. Further, a suspected case of toxic posterior optic neuropathy was noted in a patient who had an acute unilateral central visual field defect; a diagnosis of demyelinating retrobulbar optic neuritis was excluded. The patient received methotrexate 15 mg IM once weekly for psoriatic arthritis and received folate supplementation. The scotoma incompletely resolved after methotrexate cessation; improvement of her visual field defects were noted six weeks after discontinuing methotrexate, and continued improvement occurred over 6 months after drug cessation. Consider the possibility of a toxic optic neuropathy including methotrexate-induced posterior optic neuropathy in any patient in whom painless visual loss develops, especially if folate supplementation is not used.
Epistaxis occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680).
Tinnitus occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680).
Hyperglycemia and diabetes mellitus have been reported in postmarketing experience with methotrexate.
Fatigue and malaise have frequently been reported with methotrexate use.
Vaginal discharge occurred in less than 1% of patients with rheumatoid arthritis who received low-dose oral pulse methotrexate (7.5 to 15 mg per week) in 2 controlled studies (n = 680). Other genital system adverse events that have been reported in postmarketing experience with methotrexate include gonadal suppression (e.g., defective oogenesis, spermatogenesis inhibition, transient oligospermia), impotence (erectile dysfunction), libido decrease, menstrual dysfunction, gynecomastia, and infertility.
Fetal death and teratogenesis have been reported following methotrexate use in pregnant women in case reports, literature reviews, and observational studies. Women who are pregnant or who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Exposure to methotrexate during the first trimester of pregnancy in women has been associated with an increased incidence of spontaneous fetal abortion and congenital anomalies, including facial dysmorphism, central nervous system abnormalities, skull anomalies, intellectual impairment, and cardiac anomalies. Intrauterine growth restriction and functional abnormalities have been reported with methotrexate exposures in the second and third trimesters. In a prospective multicenter study, the rate of spontaneous abortion/miscarriage in pregnant women exposed to 30 mg per week or less of methotrexate was 42.5% compared to 22.5% in unexposed patients with autoimmune disease and 17.3% in unexposed patients with non-autoimmune disease. Of the live births, the rate of major birth defects was higher in women exposed to methotrexate after conception than in unexposed patients with autoimmune disease (adjusted odds ratio [OR], 1.8) and unexposed patients with non-autoimmune disease (adjusted OR, 3.1); major birth defects associated with methotrexate-exposed pregnancies were not always consistent with methotrexate-associated adverse developmental outcomes. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A new primary malignancy consisting of lymphoma or other lymphoproliferative disease may occur in patients treated with methotrexate at all dose levels. Lymphoproliferative disease that occurs during therapy with low-dose methotrexate may completely regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate if lymphoproliferative disease occurs; if it does not regress, institute appropriate treatment.
Methotrexate interferes with folate and homocysteine metabolism, which may lead to vitamin B6 deficiency, vitamin B12 deficiency, and folate deficiency. Monitoring patients for these deficiencies is recommended, especially during long-term use. Supplementation with folic acid during use of methotrexate for oncology indications is not recommended. However, for non-oncology indications, folic acid supplementation may be helpful in preventing adverse nutrient depletion. Supplementation with vitamin B6 and vitamin B12 may be beneficial in all patients taking methotrexate in lowering Hcy levels and preventing nutrient depletion.
Methotrexate is contraindicated in patients with a history of serious hypersensitivity reactions or anaphylaxis to the drug. Immediately discontinue methotrexate and begin appropriate therapy if signs or symptoms of anaphylaxis or other serious hypersensitivity reaction occur.
Serious rash and occasionally fatal dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Reactions were noted after single or multiple low, intermediate, or high doses of methotrexate in patients with neoplastic and non-neoplastic diseases. Recovery has been reported with methotrexate discontinuation. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.
Methotrexate is a radiation sensitizer. Methotrexate given concurrently with radiation therapy may increase the risk of soft tissue necrosis and osteonecrosis. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Psoriasis lesions may be aggravated by the concurrent use of methotrexate and ultraviolet radiation therapy. Patients with prior radiation dermatitis or sunburn may experience recall reactions during methotrexate therapy. Due to methotrexate-induced photosensitivity, patients should wear protective clothing and use sunscreen during sunlight (UV) exposure. Monitor patients for signs of dermatologic toxicity and withhold or permanently discontinue methotrexate depending on the severity of the reaction.
Methotrexate causes bone marrow suppression including neutropenia which can be severe and life-threatening; unexpectedly severe and sometimes fatal bone marrow suppression and aplastic anemia have been reported with concomitant administration of methotrexate along with some nonsteroidal anti-inflammatory drugs. Treatment with Otrexup, Rasuvo or Reditrex is contraindicated in patients with pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) and should be used with caution, if at all, in patients with pre-existing hematopoietic impairment. Methotrexate should be used with extreme caution in the presence of active infection; potentially fatal infection may also occur with methotrexate therapy including opportunistic infections and reactivation of latent viral infections; if a patient presents with pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered. Obtain blood counts at baseline and at least monthly during treatment; monitor more frequently during initial dosing, dose changes, or during periods of increased risk of elevated methotrexate blood levels. Monitor patients for possible clinical complications of myelosuppression including signs and symptoms of infection. Provide supportive care, withhold treatment, reduce the dose, or discontinue methotrexate as clinically appropriate; subcutaneous formulations of methotrexate should be stopped immediately if there is a significant drop in blood counts. Withhold or discontinue methotrexate in patients who develop serious infections.
Administration of methotrexate requires an experienced clinician whose knowledge and experience include the use of antimetabolite therapy due to the potential for serious or fatal adverse reactions. Subcutaneous methotrexate should only be used in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Toxic effects may be related in frequency and severity to dose or frequency of administration, but have been seen at all doses and can occur at any time during therapy; most adverse reactions are reversible if detected early and appropriate corrective measures are taken, although deaths have been reported. Patients should be closely monitored for toxicities and should be informed by their physician of the risks involved in treatment. In patients receiving high-dose IV methotrexate, administer IV fluids and urine alkalinization before the first dose, continuing throughout treatment, to maintain adequate hydration and urine output as well as a urinary pH of 7 or higher. Administer leucovorin rescue in all patients receiving methotrexate injection at doses greater than 500 mg/m2, and consider the use of leucovorin for patients receiving doses between 100 mg/m2 to 400 mg/m2. Monitor methotrexate concentrations at baseline and periodically (every 1 to 2 months) during treatment with subcutaneous or oral administration; monitor methotrexate levels at least daily in patients receiving high-dose IV methotrexate, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function.
The use of methotrexate in HIV-seropositive patients has been associated with rapid progression of immunosuppression, some with fatal outcomes. Treatment with Otrexup, Rasuvo, or Reditrex is contraindicated in patients who have overt or laboratory evidence of immunodeficiency syndromes (i.e., acquired immunodeficiency syndrome (AIDS)); other formulations of methotrexate should not be used in this population unless absolutely necessary.
Methotrexate therapy can produce potentially fatal pulmonary toxicity including acute or chronic interstitial pneumonitis. Risk factors in rheumatoid arthritis patients include diabetes mellitus, older age, rheumatoid pleuropulmonary involvement, and previous use of the disease modifying drugs sulfasalazine, gold, or penicillamine; and hypoalbuminemia; in nondiabetic patients, hypoalbuminemia and previous use of disease modifying drugs are the most important risk factors. A history of pulmonary disease, extra-articular manifestations of rheumatoid arthritis, tobacco smoking (men only), and non-sedentary occupations (women only) have also been suggested as risk factors for methotrexate-induced pulmonary toxicity. Methotrexate-induced lung disease may occur acutely at any time during therapy, has been reported at all dose levels, and is not always fully reversible. Obtain a chest x-ray at baseline. Pulmonary function tests may be useful if toxicity is suspected, especially if baseline measurements are available. Monitor patients for signs of pulmonary toxicity. Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis may require treatment interruption or discontinuation and careful investigation; additional symptoms include fever, dry cough, dyspnea, hypoxemia, and radiographic evidence of pulmonary infiltrates.
Methotrexate is metabolized by the liver and undergoes enterohepatic circulation. Treatment with Otrexup, Rasuvo, or Reditrex is contraindicated in patients with alcoholism, alcoholic liver disease, or other chronic hepatic disease. Avoid the use of other formulations of methotrexate in patients with chronic liver disease unless the benefits clearly outweigh the risks; the safety of methotrexate in patients with liver disease is unknown. Methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis, and liver failure but generally only after prolonged use (2 years or more). Risk factors for hepatotoxicity include alcoholism, obesity, diabetes mellitus, steatohepatitis, hyperlipidemia, previous significant exposure to liver toxins, family history of inheritable liver disease, duration of therapy, and advanced age. In rheumatoid arthritis (RA) patients, age at first use of methotrexate and duration of methotrexate therapy have been reported as risk factors for hepatotoxicity; previously mentioned risk factors may also have a role. In general, monitor liver function tests (LFTs) and albumin at baseline and every 1 to 2 months during treatment; increase the frequency of monitoring when initiating or changing therapy, or during periods of increased risk of elevated methotrexate levels. Interrupt or discontinue methotrexate treatment as clinically appropriate. Acutely, liver enzyme elevations are frequently seen, but elevations are usually transient, asymptomatic, and do not usually require modification of methotrexate therapy or appear to be predictive of subsequent hepatic disease. Persistent abnormalities and/or hypoalbuminemia may be indicators of serious hepatotoxicity and require further evaluation as they may precede fibrosis or cirrhosis. However, in patients with psoriasis, LFTs and albumin are often normal despite developing fibrosis or cirrhosis which may be detectable only by biopsy; for this reason, periodic liver biopsies are recommended for psoriatic patients undergoing long-term treatment. Hepatotoxicity in these patients appears to be a function of the cumulative dose and generally occurs after a cumulative dose of 1.5 g or more. Manufacturer recommendations for liver biopsy in psoriatic patients are to obtain biopsies prior to therapy or shortly after initiating therapy (i.e., within 2 to 4 months), at a methotrexate cumulative dose of 1.5 g, and after each additional 1 to 1.5 g of methotrexate. However, psoriasis guidelines suggest that every 3.5 to 4 g instead of 1 to 1.5 g of cumulative methotrexate may be a more appropriate interval for liver biopsy in patients without preexisting risk factors for hepatotoxicity. The joint American Academy of Dermatology and National Psoriasis Foundation guidelines recommend a noninvasive assessment of liver fibrosis (e.g., serologic tests and liver stiffness assessment by transient elastography) at baseline rather than a liver biopsy, regardless of the presence of risk factors. Consider a GI or hepatology consult or imaging with vibration-controlled transient elastography, or both, for abnormal baseline laboratory results or risk factors for fibrosis; an annual GI/hepatology consult and/or vibration-controlled transient elastography should occur if methotrexate is continued despite abnormal baseline results. Moderate fibrosis or any cirrhosis should lead to discontinuation of the methotrexate; mild fibrosis normally suggests a repeat biopsy at 6 months. Pretreatment liver biopsy should be performed in RA patients with a history of excessive alcohol consumption, persistently abnormal baseline LFTs, or chronic hepatitis B or C infection. During treatment of rheumatoid arthritis, liver biopsy should be performed if there are persistent LFT abnormalities or if there is a decrease in serum albumin below the normal range (in the setting of well-controlled rheumatoid arthritis). Methotrexate may be continued with monitoring for RA patients if the liver biopsy shows mild changes (Roenigk grades I, II, or IIIa); it should be discontinued in any patient with persistently abnormal LFTs who refuses liver biopsy, or in patients with moderate to severe changes on biopsy (Roenigk grade IIIb or IV).
Methotrexate is eliminated primarily by the kidney and clearance is dependent on dosage and route of administration. Patients who have renal impairment or renal disease or are receiving concurrent nephrotoxic drugs are at risk for increased toxicity due to prolonged elevated methotrexate serum concentrations. Irreversible acute renal failure and nephrotoxicity may occur following high-dose intravenous (IV) methotrexate therapy, although it has also been reported in patients receiving subcutaneous and oral administration of methotrexate. Nephrotoxicity is primarily caused by the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Obtain renal function tests at baseline and monitor for toxicity in all patients who are receiving methotrexate; a dose reduction or discontinuation of methotrexate therapy may be necessary in patients with renal impairment or in patients experiencing nephrotoxicity. Monitor renal function periodically during treatment (e.g., every 1 to 2 months) and as clinically indicated in patients receiving oral or subcutaneous formulations of methotrexate and more frequently when initiating or changing therapy or in patients with conditions that might increase the risk of elevated methotrexate levels (e.g., dehydration). In patients receiving high-dose IV methotrexate, alkalinize the urine before the first dose, continuing throughout treatment to maintain a urinary pH of 7 or higher; this pH is necessary to prevent precipitation of methotrexate or its metabolites in the renal tubules. Administer hydration and leucovorin rescue as recommended. Monitor serum creatinine and electrolytes at baseline and at least daily during therapy; also monitor methotrexate concentrations at least daily, adjusting hydration and leucovorin dosing as needed. Consider the use of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromole per liter) and delayed methotrexate clearance due to impaired renal function. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective methotrexate clearance has been reported with acute, intermittent hemodialysis using a high-flux filter.
Methotrexate elimination is reduced in patients with third space effusions (e.g., ascites or pleural effusion) and methotrexate levels may be elevated for a prolonged period resulting in increased toxicity. Remove significant third space fluid prior to treatment. Carefully monitor such patients for toxicity; a dose reduction or discontinuation of therapy may be necessary.
Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome (TLS) in patients with rapidly growing tumors. Institute appropriate treatment for prevention and management of TLS prior to starting treatment with methotrexate.
Methotrexate should be used with extreme caution in patients with GI disease such as peptic ulcer disease or ulcerative colitis as they are at greater risk of developing severe gastrointestinal toxicity. Interrupt or discontinue methotrexate for severe gastrointestinal toxicity including diarrhea and ulcerative stomatitis and begin appropriate supportive care; otherwise, hemorrhagic enteritis and death from GI perforation may occur. Also interrupt therapy for vomiting or other toxicities which may result in dehydration. Unexpectedly severe, sometimes fatal gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) and some nonsteroidal anti-inflammatory drugs (NSAIDs).
Vaccination during methotrexate therapy may be ineffective because the antibody response is suboptimal. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated infections (e.g., vaccinia) after administration of live vaccines in patients receiving methotrexate. Hypogammaglobinemia has been reported rarely. Update immunizations prior to initiation of methotrexate therapy according to guidelines; the interval between live vaccines and initiation of methotrexate should be in accordance with vaccination guidelines for patients on immunosuppressive agents. In pediatric patients with juvenile idiopathic arthritis (JIA), data suggests non-live vaccines are, in general, adequately immunogenic and safe. Live-attenuated vaccines can be safely and effectively administered to JIA patients receiving methotrexate, unless they are also receiving additional immunosuppressive drugs or biologics. In these cases, evidence regarding safety is lacking. Live-attenuated booster vaccinations can be considered on an individual basis. There is no data regarding a safe time interval for administration of live vaccines after cessation of methotrexate.
Ensure correct formulation selection of preservative-free methotrexate injection for intrathecal administration, administration to neonates or low-birth weight infants, and administration to patients with known benzyl alcohol hypersensitivity; do not use benzyl alcohol-containing formulations for high-dose methotrexate regimens unless immediate treatment is required and preservative-free formulations are not available. Benzyl alcohol is present in preservative-containing injection formulations and can cause severe central nervous system toxicity or metabolic acidosis. Fatal gasping syndrome (including symptoms of gasping respiration, hypotension, bradycardia, and cardiovascular collapse) has been reported in neonates who received IV solutions containing benzyl alcohol. High-dose therapy is indicated for osteosarcoma; leucovorin rescue and careful monitoring are necessary. Hold subsequent methotrexate doses until hematologic parameters, hepatic function, and renal function have recovered.
A new primary malignancy, specifically malignant lymphomas or other lymphoproliferative disease, may occur in patients treated with methotrexate at all dose levels. Lymphoproliferative disease that occurs during therapy with low-dose methotrexate may completely regress following withdrawal of methotrexate and thus, may not require cytotoxic treatment. Discontinue methotrexate if lymphoproliferative disease occurs; if it does not regress, institute appropriate treatment.
Methotrexate can cause severe acute and chronic neurotoxicity including leukoencephalopathy which can be progressive, irreversible, and fatal; generalized and focal seizures have occurred in pediatric patients. Prior or concurrent cranial irradiation has been associated with an increased risk of leukoencephalopathy. Monitor patients for signs of neurotoxicity and withhold or discontinue treatment with methotrexate when appropriate. Avoid the intrathecal use of methotrexate injection that contains benzyl alcohol due to the risk of serious neurotoxicity.
Folate deficiency may increase the incidence of methotrexate-related adverse reactions. Administer folic acid or folinic acid to patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriasis to decrease the risk of adverse reactions. However, avoid the use of products containing folic acid or folinic acid in patients with neoplastic diseases unless clinically indicated, as they may also decrease the clinical effectiveness of methotrexate.
Cautious dose selection is recommended for geriatric patients (age 65 or older) who may be at increased risk of adverse reactions due to a higher frequency of decreased renal or hepatic function, reduced folate stores, concomitant disease, or concomitant drug therapy. Closely monitor these patients for early signs of hepatic, bone marrow, and renal toxicity; serum methotrexate levels may also be helpful including in patients receiving treatment for non-neoplastic diseases. Since decline in renal function may be associated with increases in adverse reactions and serum creatinine measurements may overestimate renal function in the elderly, more accurate methods (i.e., creatinine clearance) should be considered. Based on postmarketing experience, the incidence of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. Clinical studies of methotrexate did not include sufficient numbers of geriatric patients 65 years of age and older to determine whether they respond differently than younger patients.
Methotrexate is contraindicated for use during pregnancy in women who are being treated for nonmalignant diseases (e.g., psoriasis, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis). Pregnancy should be avoided by females of reproductive potential during methotrexate treatment and for at least 6 months after the last dose; however, because the benzyl alcohol preservative can cross the placenta, use the preservative-free formulation of IV methotrexate if treatment of a neoplastic disease is necessary during pregnancy. Methotrexate can cause intrauterine fetal death and/or congenital anomalies when administered to pregnant women based on case reports, literature reviews, and observational studies. Women who are pregnant or who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Exposure to methotrexate during the first trimester of pregnancy in women has been associated with an increased incidence of spontaneous abortions and congenital anomalies, including facial dysmorphism, central nervous system abnormalities, skull anomalies, intellectual impairment, and cardiac anomalies. Intrauterine growth restriction and functional abnormalities have been reported with methotrexate exposures in the second and third trimesters. In a prospective multicenter study, the rate of spontaneous abortion/miscarriage in pregnant women exposed to 30 mg per week or less of methotrexate was 42.5% compared to 22.5% in unexposed patients with autoimmune disease and 17.3% in unexposed patients with non-autoimmune disease. Of the live births, the rate of major birth defects was higher in women exposed to methotrexate after conception than in unexposed patients with autoimmune disease (adjusted odds ratio [OR], 1.8) and unexposed patients with non-autoimmune disease (adjusted OR, 3.1); major birth defects associated with methotrexate-exposed pregnancies were not always consistent with methotrexate-associated adverse developmental outcomes. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
Counsel patients about the reproductive risk and contraception requirements during methotrexate treatment. Pregnancy testing should be performed before starting methotrexate in female patients of reproductive potential. These patients should use effective contraception during methotrexate therapy and for at least 6 months after the final methotrexate dose. Women who become pregnant while receiving methotrexate should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during methotrexate therapy and for at least 3 months after the final methotrexate dose due to the risk of male-mediated teratogenicity; methotrexate may cause chromosomal damage to sperm cells. Methotrexate may cause infertility; oligospermia in men and menstrual irregularity or dysfunction in women have been reported during methotrexate therapy and after stopping therapy. It is not known whether infertility is reversible in affected female or male patients.
Due to the potential for serious adverse reactions in nursing infants from methotrexate, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. Methotrexate has been detected in human breast milk with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production, however previous American Academy of Pediatrics recommendations considered methotrexate incompatible with breast-feeding.
For the treatment of acute lymphocytic leukemia (ALL):
NOTE: Methotrexate has been designated as an orphan drug by the FDA for the treatment of ALL.
-for the treatment of ALL, as part of a combination chemotherapy regimen:
Intravenous dosage:
Adults: 10 to 5,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. As maintenance therapy following remission, methotrexate has been administered as 2.5 mg/kg IV every 14 days.
Infants, Children, and Adolescents: 10 to 5,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. As maintenance therapy following remission, methotrexate has been administered as 2.5 mg/kg IV every 14 days.
Intramuscular dosage:
Adults: 20 to 30 mg/m2 intramuscularly (IM) per week; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. As maintenance therapy following remission, methotrexate has been administered IM twice weekly for a total weekly dose of 30 mg/m2.
Infants, Children, and Adolescents: 20 to 30 mg/m2 intramuscularly (IM) per week; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. As maintenance therapy following remission, methotrexate has been administered IM twice weekly for a total weekly dose of 30 mg/m2.
Oral dosage:
Adults: 20 mg/m2 orally once weekly as maintenance therapy following remission. Dosage may be adjusted to maintain a target absolute neutrophil count and/or for hematologic toxicity.
Infants, Children, and Adolescents: 20 mg/m2 orally once weekly as maintenance therapy following remission. Dosage may be adjusted to maintain a target absolute neutrophil count and/or for hematologic toxicity.
For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: The recommended dose, infusion time, and dosing schedule of methotrexate varies depending on which specific type of NHL is being treated and its use as a single agent or as part of combination therapy; therefore, refer to individual protocols for specific dosage and schedule.
-for the treatment of NHL, in combination with other therapies:
Intravenous dosage:
Adults: 10 to 8,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. Methotrexate 1,000 mg/m2 or 3,000 mg/m2 as an IV infusion over 24 hours followed by leucovorin rescue has been studied.
Infants, Children, and Adolescents: 10 to 8,000 mg/m2 IV; dose and schedule are individualized based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy (500 mg/m2 IV or greater); consider leucovorin rescue following intermediate-dose methotrexate therapy (100 to less than 500 mg/m2 IV). Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. Methotrexate 1,000 mg/m2 or 3,000 mg/m2 as an IV infusion over 24 hours followed by leucovorin rescue has been studied.
Oral dosage:
Adults: 2.5 mg orally 2 to 4 times per week (maximum, 10 mg per week) has been administered in patients with relapsed or refractory NHL, as part of a metronomic combination chemotherapy regimen.
-for the treatment of cutaneous NHL:
Intravenous dosage:
Adults: 5 to 75 mg IV a single agent; recommended dosage varies based on individual protocols.
Infants, Children, and Adolescents: 5 to 75 mg IV a single agent; recommended dosage varies based on individual protocols.
-for the treatment of central nervous system NHL:
Intravenous dosage:
Adults: 8,000 mg/m2 IV infusion over 4 hours as a single agent or 3,000 to 8,000 mg/m2 in combination with immunochemotherapy; dose and schedule are based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy. Additionally, give IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment.
Infants, Children, and Adolescents: 8,000 mg/m2 IV infusion over 4 hours as a single agent or 3,000 to 8,000 mg/m2 in combination with immunochemotherapy; dose and schedule are based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment. Administer leucovorin rescue following high-dose methotrexate therapy. Additionally, give IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment.
Intrathecal dosage:
Adults: 12 to 15 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
Children 9 years and older and Adolescents: 12 to 15 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
Children 3 to 8 years: 12 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
Children 2 years: 10 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
Children 1 year: 8 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
Infants: 6 mg intrathecally; dosing frequency varies based on use (i.e., prophylaxis or treatment) and other factors including individual protocols.
For the treatment of head and neck cancer:
-for the treatment of squamous cell cancer of the head and neck:
Intravenous dosage:
Adults: 40 mg/m2 IV once weekly; 60 mg/m2 IV once weekly has also been recommended by the manufacturer. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized phase 3 clinical trial (n = 277), patients with recurrent and metastatic squamous cell cancer of the head and neck (SCCHN) were randomized to treatment with cisplatin (100 mg/m2 IV) plus fluorouracil (1,000 mg/m2 CIV on days 1 through 4) every 3 weeks, carboplatin (300 mg/m2 IV) plus fluorouracil (1,000 mg/m2 CIV on days 1 through 4) every 4 weeks, or methotrexate 40 mg/m2 IV weekly. Treatment with combination chemotherapy significantly improved the overall response rate (32% vs. 21% vs. 10%) but was also associated with significantly increased hematologic and nonhematologic toxicity and no improvement in overall survival. In another phase 3 clinical trial, patients with recurrent or metastatic SCCHN were randomized to treatment with once-daily gefitinib (250 mg or 500 mg) or methotrexate 40 mg/m2 IV once weekly. Treatment with gefitinib did not improve overall survival compared with methotrexate (5.6 months vs. 6 months vs. 6.7 months).
For the treatment of bladder cancer*:
-as neoadjuvant treatment for muscle-invasive bladder cancer, in combination with other chemotherapy agents*:
Intravenous dosage:
Adults: Neoadjuvant therapy with methotrexate as a part of MCV, MVAC, and with cisplatin has been studied. Methotrexate 30 mg/m2 IV bolus and vinblastine 4 mg/m2 IV bolus on days 1 and 8 plus cisplatin 100 mg/m2 IV infusion on day 2 repeated every 21 days (MCV regimen) for 3 cycles prior to local radical treatment (LRT) with cystectomy, full-dose external-beam radiotherapy, or preoperative radiotherapy and cystectomy resulted in a nonsignificantly higher 3-year overall survival (OS) rate compared with LRT alone (55.5% vs. 50%; hazard ratio (HR) = 0.85; 95% CI, 0.71 to 1.02; p = 0.075) in a randomized phase III trial in 976 patients; however, the 10-year OS rate was significantly improved in the MCV arm in a long-term analysis (36% vs. 30%; HR = 0.84; 0.72 to 0.99; p = 0.037). Folinic acid 15 mg orally or IV every 6 hours for 4 doses was given 24 hours after each methotrexate dose. Five treatment-related deaths occurred in the MCV arm. In another randomized, phase III trial in 317 patients, neoadjuvant therapy with methotrexate 30 mg/m2 on days 1, 15, and 22 in combination with vinblastine 3 mg/m2 IV on days 2, 15, and 22; doxorubicin 30 mg/m2 on day 2; and cisplatin 70 mg/m2 on day 2 repeated every 28 days (MVAC regimen) for 3 cycles followed by radical cystectomy led to a nonsignificantly improved median OS time (77 vs. 46 months; adjusted p = 0.06 ) compared with radical cystectomy alone, although significantly more patients were pathologically free from disease at cystectomy in the MVAC arm (48% vs. 15%; p < 0.001). Similarly, 3 cycles of methotrexate 250 mg/m2 IV (with leucovorin 15 mg orally every 6 hours for 8 doses starting 24 hours after each methotrexate dose) plus cisplatin 100 mg/m2 IV administered every 3 weeks prior to cystectomy did not significantly improve the 5-year OS rate compared with cystectomy alone (53% vs. 46%) despite a significantly improved rate of tumor downstaging (to T0) (26.4% vs. 11.5%; p = 0.001).
-as first-line chemotherapy for the treatment of advanced or metastatic bladder cancer, in combination with vinblastine, doxorubicin, and cisplatin*:
Intravenous dosage:
Adults: 30 mg/m2 IV on days 1, 15, and 22 in combination with vinblastine, doxorubicin, and cisplatin repeated every 28 days (MVAC regimen) for up to 6 cycles has been evaluated in patients with advanced or metastatic transitional cell carcinoma of the bladder in 2 randomized, phase III trials. Some patients received granulocyte colony-stimulating factor (G-CSF) following chemotherapy.
For the adjuvant treatment of early breast cancer, in combination with fluorouracil and cyclophosphamide (CMF):
Intravenous dosage:
Adults: 40 mg/m2 IV plus fluorouracil 600 mg/m2 IV on days 1 and 8, in combination with cyclophosphamide 100 mg/m2 by mouth on days 1 through 14, repeated every 28 days for 6 cycles.
For the treatment of lung cancer, especially squamous cell or small cell lung cancer (SCLC):
Intravenous dosage:
Adults: Many different regimens exist; common combination regimens include: methotrexate 20 mg/m2 IV as a single dose with cisplatin, doxorubicin, and cyclophosphamide, every 28 days; methotrexate 40 mg/m2 IV for one dose with etoposide and cisplatin; and methotrexate 100 mg/m2 IV for one dose along with cyclophosphamide, vincristine, and doxorubicin.
Oral dosage:
Adults: 10 mg/m2 PO twice weekly x 4 doses every 3 weeks in combination with lomustine and cyclophosphamide.
For the treatment or prophylaxis of leukemic meningitis:
-for the treatment of leukemic meningitis:
Intrathecal dosage:
Adults: 12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Elderly patients: 12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. A dose reduction may be necessary in elderly patients. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Children 9 years and older and Adolescents: 12 to 15 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Children 3 to 8 years: 12 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Children 2 years: 10 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Children 1 year: 8 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
Infants: 6 mg intrathecally at intervals of 2 or more days up to twice weekly; however, intervals of less than 1 week may result in increased subacute toxicity. Dosing frequency may vary based on individual protocols. Continue treatment for 1 dose after the cerebrospinal fluid cell count returns to normal.
-for prophylaxis of leukemic meningitis:
Intrathecal dosage:
Adults: 12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
Elderly patients: 12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols. A dose reduction may be necessary in geriatric patients.
Children 9 years and older and Adolescents: 12 to 15 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
Children 3 to 8 years: 12 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
Children 2 years: 10 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
Children 1 year: 8 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
Infants: 6 mg intrathecally; administer no more than once weekly. Dosing frequency may vary based on individual protocols.
For the treatment of osteogenic sarcoma:
NOTE: Methotrexate has been designated an orphan drug by the FDA for the treatment of osteogenic sarcoma.
-for the treatment of osteosarcoma, as part of a combination chemotherapy regimen:
Intravenous dosage (Preservative-free solutions only):
Adults: 12 g/m2 (maximum dose, 20 g) IV over 4 hours; dose and schedule are individualized based on factors such as patient comorbidities, disease state, and prior treatments. Administer leucovorin rescue following high-dose methotrexate therapy. Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. If the initial dose does not produce a peak serum methotrexate concentration of 1,000 micromolar at the end of the methotrexate infusion, increase to methotrexate 15 g/m2 IV for subsequent treatments. When used in combination with other chemotherapy agents, high-dose methotrexate followed by leucovorin rescue resulted in prolonged relapse-free survival in patients with non-metastatic osteosarcoma who had undergone surgical resection or amputation for the primary tumor.
Infants, Children, and Adolescents: 12 g/m2 (maximum dose, 20 g) IV over 4 hours; dose and schedule are individualized based on factors such as patient comorbidities, disease state, and prior treatments. Administer leucovorin rescue following high-dose methotrexate therapy. Administer IV fluids and alkalinize urine to a urinary pH of 7 or higher prior to the first dose and continue during treatment. When used in combination with other chemotherapy agents, high-dose methotrexate followed by leucovorin rescue resulted in prolonged relapse-free survival in patients with non-metastatic osteosarcoma who had undergone surgical resection or amputation for the primary tumor.
For the treatment of desmoid tumor* or aggressive fibromatosis not amenable to surgery or radiotherapy, in combination with vinblastine:
Intravenous dosage:
Adults: 30 mg/m2/dose IV in combination with vinblastine 6 mg/m2/dose IV every 7 to 10 days for 1 year resulted in a partial response (PR) rate of 40% and a minor response or stable disease in 60% in a phase II study in 30 patients (age range, 4 to 68 years) with recurrent or primary inoperable aggressive fibromatosis. At a median follow-up of 75 months (range, 14 to 125 months), 29 patients were alive and the overall actuarial progression-free interval at 5 and 10 years was 67%.
Infants >= 7 months, Children, and Adolescents: 30 mg/m2/dose IV in combination with vinblastine 6 mg/m2/dose IV every 7 to 10 days for 1 year resulted in a partial response (PR) rate of 40% and a minor response or stable disease in 60% in a phase II study of 30 patients (age range, 4 to 68 years). At a median follow-up of 75 months (range, 14 to 125 months), 29 patients were alive and the overall actuarial progression-free interval at 5 and 10 years was 67%. In another phase II study of 26 children, methotrexate 30 mg/m2/dose IV and vinblastine 5 mg/m2/dose IV weekly for 26 weeks then every other week for an additional 26 weeks led to an ORR of 19.2% and a 3-year progression-free survival rate of 32.5%. Serious adverse effects in this study included grade 4 neutropenia (n=5), mood alteration (n=1), and uncomplicated generalized seizure (n=1).
For the treatment of gestational trophoblastic disease including choriocarcinoma and hydatidiform mole:
-for gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole:
Oral or Intramuscular dosage:
Adults: 15-30 mg PO/IM once daily for 5 days. Repeat after 1 or more weeks, dependent on the response or toxicity.
-for high-risk gestational trophoblastic disease in combination with leucovorin, etoposide, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen):
Intravenous dosage:
Adults: 100 mg/m2 IV push on day 1, followed by 200 mg/m2 IV infusion over 12 hours on day 1 in combination with leucovorin, etoposide, actinomycin D, cyclophosphamide, and vincristine (EMA-CO regimen), repeated every 2-3 weeks depending on toxicity. Leucovorin 15 mg PO/IM every 12 hours for 4 doses should begin on day 2, 24 hours after initiating methotrexate infusion. Multiple studies have been reported with cure rates ranging from 70-90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as three consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2-3 additional courses after complete hCG response.
-for high-risk gestational trophoblastic disease in combination with leucovorin, etoposide, actinomycin D, and cisplatin (EMA-EP regimen):
Intravenous dosage:
Adults: 100 mg/m2 IV push on day 1, followed by 200 mg/m2 IV infusion over 12 hours on day 1 in combination with leucovorin, etoposide, actinomycin D, and cisplatin (EMA-EP regimen), repeated every 2-3 weeks depending on toxicity. Leucovorin 15 mg PO/IM every 12 hours for 4 doses should begin on day 2, 24 hours after initiating methotrexate infusion. Studies in patients with chemorefractory high-risk gestational trophoblastic disease have shown response rates of > 90% with salvage treatment with EMA-EP. Consider growth-factor support to maintain dose-intensity and prevent hematological toxicity.
For the treatment of active Crohn's disease*:
Intramuscular or Subcutaneous dosage:
Adults: 15 to 25 mg IM or subcutaneously once weekly. Guidelines suggest methotrexate for treatment of active Crohn's disease and for maintenance treatment of luminal Crohn's disease after steroid-induced remission. Consider folic acid supplementation during treatment.
Oral dosage:
Adults: 12.5 to 15 mg PO once weekly. Guidelines suggest oral methotrexate as adjunctive therapy for reducing immunogenicity against biologic therapy. Data demonstrating efficacy of oral methotrexate for maintaining remission of Crohn's disease are lacking. Due to potential gastrointestinal absorption issues, guidelines recommend parenteral therapy for active and maintenance therapy. It is perceived that patients with normal small bowel absorption may be started on or switched from parenteral to oral methotrexate; however, controlled efficacy data are lacking for this approach.
For the treatment of ectopic pregnancy*:
Intramuscular dosage (single-dose regimen):
Adults: 50 mg/m2 IM as a single dose on day 1. Measure hCG concentration on post-treatment days 4 and 7. If hCG decreases by 15% or more between days 4 and 7, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 4 and 7, administer additional 50 mg/m2 IM and repeat hCG. If hCG does not decrease after 2 doses, may consider surgical management. If hCG plateaus or increases during follow-up testing, consider administering additional methotrexate for treatment of a persistent ectopic pregnancy.
Adolescents: 50 mg/m2 IM as a single dose on day 1. Measure hCG concentration on post-treatment days 4 and 7. If hCG decreases by 15% or more between days 4 and 7, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 4 and 7, administer additional 50 mg/m2 IM and repeat hCG. If hCG does not decrease after 2 doses, consider surgical management. If hCG plateaus or increases during follow-up testing, may consider administering additional methotrexate for treatment of a persistent ectopic pregnancy.
Intramuscular dosage (2-dose regimen):
Adults: 50 mg/m2 IM on days 1 and 4. Measure hCG concentration on post-treatment days 4 and 7. If hCG decreases by 15% or more between days 4 and 7, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 4 and 7, administer additional 50 mg/m2 IM on day 7 and repeat hCG on day 11. If hCG decreases by 15% or more between days 7 and 11, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 7 and 11, administer additional 50 mg/m2 IM on day 11 and repeat hCG on day 14. If hCG does not decrease after 4 doses, consider surgical management. If hCG plateaus or increases during follow-up, may consider administering additional methotrexate for treatment of persistent ectopic pregnancy.
Adolescents: 50 mg/m2 IM on days 1 and 4. Measure hCG concentration on post-treatment days 4 and 7. If hCG decreases by 15% or more between days 4 and 7, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 4 and 7, administer additional 50 mg/m2 IM on day 7 and repeat hCG on day 11. If hCG decreases by 15% or more between days 7 and 11, continue to monitor hCG weekly until at nonpregnant concentration; however, if hCG decreases by less than 15% between days 7 and 11, administer additional 50 mg/m2 IM on day 11 and repeat hCG on day 14. If hCG does not decrease after 4 doses, consider surgical management. If hCG plateaus or increases during follow-up, may consider administering additional methotrexate for treatment of persistent ectopic pregnancy.
Intramuscular dosage (fixed multiple-dose regimen):
Adults: 1 mg/kg/dose IM on days 1, 3, 5, 7; alternate with leucovorin on days 2, 4, 6, 8. Measure hCG concentration on methotrexate dose days; if hCG decreases by 15% of more at any measurement, discontinue methotrexate and measure hCG weekly until at nonpregnant concentration. If hCG does not decrease after 4 doses, consider surgical management. If hCG plateaus or increases during follow-up, may consider administering additional methotrexate for treatment of persistent ectopic pregnancy.
Adolescents: 1 mg/kg/dose IM on days 1, 3, 5, 7; alternate with leucovorin on days 2, 4, 6, 8. Measure hCG concentration on methotrexate dose days; if hCG decreases by 15% of more at any measurement, discontinue methotrexate and measure hCG weekly until at nonpregnant concentration. If hCG does not decrease after 4 doses, consider surgical management. If hCG plateaus or increases during follow-up, may consider administering additional methotrexate for treatment of persistent ectopic pregnancy.
For the treatment of rheumatoid arthritis:
Oral dosage:
Adults: 7.5 to 15 mg PO once weekly, initially. Increase the dose to at least 15 mg/week to achieve optimal response. Doses more than 20 mg/week result in an increased risk of adverse reactions. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Responses are typically observed 3 to 6 weeks after initiation; however, responses have occurred up to 12 weeks after initiation.
Subcutaneous dosage:
Adults: 7.5 to 15 mg subcutaneously once weekly, initially. Increase the dose to at least 15 mg/week to achieve optimal response. Doses more than 20 mg/week result in an increased risk of adverse reactions. Responses are typically observed 3 to 6 weeks after initiation; however, responses have occurred up to 12 weeks after initiation.
For the treatment of active juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) (i.e., polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis with predominant joint inflammation):
Oral dosage:
Children and Adolescents: 10 mg/m2/dose PO once weekly initially. Individualize dosage and titrate gradually to achieve optimal clinical response. Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. At high doses (more than 15 mg/m2/week), the parenteral route is preferred due to decreased oral bioavailability and increased gastrointestinal side effects of the oral formulation. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.
Subcutaneous dosage (Otrexup ONLY):
Children and Adolescents: 10 mg/m2/dose subcutaneously once weekly initially (Otrexup). Titrate doses gradually to achieve optimal clinical response. Otrexup Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. Use another methotrexate formulation in patients who require doses less than 10 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.
Subcutaneous dosage (Rasuvo ONLY):
Children and Adolescents : 10 mg/m2/dose subcutaneously once weekly initially. Titrate doses gradually to achieve an optimal clinical response. Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. Use another methotrexate formulation in patients who require doses less than 7.5 mg per week, doses more than 30 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.
Subcutaneous dosage (Reditrex ONLY):
Children and Adolescents: 10 mg/m2/dose subcutaneously once weekly initially (Reditrex). Titrate doses gradually to achieve optimal clinical response. Reditrex Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. Use another methotrexate formulation in patients who require doses less than 7.5 mg per week, doses more than 25 mg per week, high-dose regimens, or dose adjustments of less than 2.5 mg increments. Therapeutic response usually begins within 3 to 6 weeks and improvement may continue for at least another 12 weeks. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. SWITCHING FROM OTHER ROUTES: Methotrexate bioavailability may differ when switching from oral to subcutaneous methotrexate; specific dosage guidance for switching between formulations has not been provided by the manufacturer. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alpha inhibitor is recommended.
Intramuscular dosage:
Children and Adolescents: 10 mg/m2/dose IM once weekly initially. Tailor dose to the individual patient and adjust gradually to achieve optimal response. Max: Although there is experience with doses up to 30 mg/m2/week, doses more than 15 mg/m2/week have not shown additional therapeutic benefit and doses more than 20 mg/m2/week may increase the risk of toxicity. The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least two years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks. GUIDELINES: Monitor a complete blood count with differential, liver function tests, and albumin and serum creatinine concentrations every 4 to 8 weeks initially, and then every 12 to 16 weeks, unless risk factors for toxicity are present. Methotrexate can be discontinued after 6 months of stable remission. If response to monotherapy is inadequate, combination therapy with a TNF-alfa inhibitor is recommended.
For the treatment of severe psoriasis:
Oral dosage:
Adults: 7.5 to 25 mg PO once weekly as a single dose or in 3 divided doses over 24 hours. May consider a test dose of 2.5 to 5 mg followed by a complete blood count in 5 to 7 days; if there is no evidence of myelosuppression or hepatotoxicity, then the weekly dose can be increased as needed. The FDA-approved dose is 10 to 25 mg PO once weekly. Adjust dose gradually to achieve optimal clinical response. Max: 30 mg/week. Decrease dose to the lowest dose that maintains adequate response once adequate control is achieved. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. The addition of topical calcipotriene to standard dose methotrexate therapy is recommended for the treatment of moderate to severe psoriasis; it may lead to lower cumulative doses of methotrexate and increased time to relapse after methotrexate discontinuation.
Adolescents*: 7.5 to 25 mg PO once weekly as a single dose or in 3 divided doses over 24 hours. May consider a test dose of 2.5 to 5 mg followed by a complete blood count in 5 to 7 days; if there is no evidence of myelosuppression or hepatotoxicity, then the weekly dose can be increased as needed. Adjust dose gradually to achieve optimal clinical response. Max: 25 mg/week. Decrease dose to the lowest dose that maintains adequate response once adequate control is achieved. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Guidelines recommend methotrexate as an effective systemic therapy for moderate to severe plaque psoriasis and other psoriasis subtypes or pustular psoriasis in children.
Children*: 0.2 to 0.3 mg/kg/dose (Max: 25 mg/dose) PO once weekly, initially. May increase the dose by 1.25 to 5 mg/week as needed until an effective dose is attained. Dose range: 0.2 to 0.7 mg/kg/week. Max: 25 mg/week. Slowly taper the dose after 2 to 3 months of sustained clearance. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Guidelines recommend methotrexate as an effective systemic therapy for moderate to severe plaque psoriasis and other psoriasis subtypes or pustular psoriasis in children.
Subcutaneous dosage:
Adults: 7.5 to 25 mg subcutaneously once weekly. May consider a test dose of 2.5 to 5 mg followed by a complete blood count in 5 to 7 days; if there is no evidence of myelosuppression or hepatotoxicity, then the weekly dose can be increased as needed. The FDA-approved dose is 10 to 25 mg subcutaneously once weekly. Adjust dose gradually to achieve optimal clinical response. Max: 30 mg/week. Decrease dose to the lowest dose that maintains adequate response once adequate control is achieved. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. The addition of topical calcipotriene to standard dose methotrexate therapy is recommended for the treatment of moderate to severe psoriasis; it may lead to lower cumulative doses of methotrexate and increased time to relapse after methotrexate discontinuation.
Adolescents*: 7.5 to 25 mg IM once weekly as a single dose or in 3 divided doses over 24 hours. May consider a test dose of 2.5 to 5 mg followed by a complete blood count in 5 to 7 days; if there is no evidence of myelosuppression or hepatotoxicity, then the weekly dose can be increased as needed. Adjust dose gradually to achieve optimal clinical response. Max: 25 mg/week. Decrease dose to the lowest dose that maintains adequate response once adequate control is achieved. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Guidelines recommend methotrexate as an effective systemic therapy for moderate to severe plaque psoriasis and other psoriasis subtypes or pustular psoriasis in children.
Children*: 0.2 to 0.3 mg/kg/dose (Max: 25 mg/dose) subcutaneously once weekly, initially. May increase the dose by 1.25 to 5 mg/week as needed until an effective dose is attained. Dose range: 0.2 to 0.7 mg/kg/week. Max: 25 mg/week. Slowly taper the dose after 2 to 3 months of sustained clearance. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. Guidelines recommend methotrexate as an effective systemic therapy for moderate to severe plaque psoriasis and other psoriasis subtypes or pustular psoriasis in children.
Intravenous or Intramuscular dosage:
Adults: 10 to 25 mg IV or IM once weekly. Adjust dose gradually to achieve optimal clinical response. Max: 30 mg/week. Decrease dose to the lowest dose that maintains adequate response once adequate control is achieved. Administer folic acid or leucovorin (folinic acid) to reduce the risk of adverse reactions. The addition of topical calcipotriene to standard dose methotrexate therapy is recommended for the treatment of moderate to severe psoriasis; it may lead to lower cumulative doses of methotrexate and increased time to relapse after methotrexate discontinuation.
For the treatment of active psoriatic arthritis*:
Oral or Subcutaneous dosage:
Adults: Efficacy not established; off-label use has long been recommended in treatment guidelines. 7.5 mg PO once weekly initially, then slowly titrate to the common target dose of 15 mg PO once weekly. In patients with persistently active psoriatic arthritis (PsA), the dosage can be increased to 20 mg/week PO and then to 25 mg/week PO if needed. Usual target efficacious dose: 15 mg to 25 mg/week PO. Similar dosages have been given subcutaneously, using appropriate subcutaneous formulations. Despite a long history of use, specific evidence for MTX monotherapy in the treatment of PsA is not robust and remains inconclusive. In the MIPA trial, a low-dose MTX regimen was not more effective than placebo for synovitis (ACR20, etc.) and the only beneficial effect of MTX was for patient and assessor global symptom scores and skin scores. The authors note that trials continue to study the role of MTX along with biologics in PsA patients (combination therapy). GUIDELINES: Guidelines state that in treatment-naive PsA patients, methotrexate may be considered instead of a TNF-alpha blocker if the patient does not have severe PsA, does not have severe psoriasis, prefers oral therapy, the patient expresses concern over starting a biologic as the first therapy, or has contraindications to TNF-inhibiting (TNFi) biologics (e.g., congestive heart failure, previous serious infections, recurrent infections, or demyelinating disease). Methotrexate may also be beneficial in patients with PsA who also have plaque psoriasis (skin involvement), and is the preferred conventional DMARD in such patients when conventional DMARDs are chosen. Experts note that the impact of MTX on radiologic damage due to PsA remains unproven, but that in some healthcare environments, MTX must be used before treatments of proven effectiveness (e.g., TNFi agents) are prescribed.
For the treatment of systemic lupus erythematosus (SLE)*:
Oral dosage:
Adults: 7.5 to 25 mg/week PO once weekly or in 2 divided doses.
Children and Adolescents: 15 to 20 mg/m2/week (Max: 25 mg/week) PO once weekly or in 2 divided doses.
Intramuscular or Subcutaneous dosage:
Adults: 7.5 to 25 mg/week IM or subcutaneously once weekly or in 2 divided doses.
Children and Adolescents: 15 to 20 mg/m2/week (Max: 25 mg/week) IM or subcutaneously once weekly or in 2 divided doses.
For the treatment of sarcoidosis*:
Oral dosage:
Adults: 5 to 10 mg PO once weekly, initially. Increase the dose to 10 to 15 mg PO once weekly after 8 weeks if inadequate response and based on tolerability. Max: 20 mg/week.
For the treatment of carcinomatous meningitis*:
Intrathecal dosage (Preservative-free solutions only):
Adults: 10 mg intrathecally twice weekly for 4 weeks followed by 10 mg intrathecally once weekly for 4 doses then every other week for 4 doses (with leucovorin 10 mg orally every 6 hours for 8 doses starting 24 hours after each methotrexate dose) led to a nonsignificantly different response rate (20% vs. 26%) compared with liposomal cytarabine in a multicenter, randomized study. Unless contraindicated, all patients also received dexamethasone 4 mg twice daily on days 1 to 5 of each treatment cycle. The median overall survival (OS) times were not significantly different in the methotrexate and liposomal cytarabine arms (78 vs. 105 days); however, treatment with intrathecal liposomal cytarabine was associated with significantly improved progression-free survival (PFS) in a multivariate analysis. The median time to neurological progression was significantly shortened in patients who received methotrexate compared with liposomal cytarabine (30 vs. 58 days). In a multicenter, randomized trial in 100 patients with neoplastic meningitis from solid tumors, PFS time was not significantly different with intracerebrospinal fluid methotrexate or liposomal cytarabine therapy (37.5 vs. 35 days). In an unplanned retrospective subgroup analysis, PFS was significantly increased when methotrexate was given intraventricularly (via a ventricular reservoir) compared with intralumbar administration (43 vs. 19 days). Methotrexate 10 mg intrathecally on days 1 and 4 repeated weekly for 8 weeks was compared with intrathecal thiotepa in a randomized trial in 52 patients with previously untreated neoplastic meningitis. The median OS times were 15.9 weeks in the methotrexate arm and 14.1 weeks in the thiotepa arm. After 8 weeks of therapy, no patient experienced a complete response or improvement. Eight patients in each treatment arm converted from a positive to a negative cytology after therapy. Patients in the methotrexate arm experienced significantly more neurologic and skin/mucous membrane toxicity compared with patients in the thiotepa arm.
For the treatment of locally advanced or metastatic penile cancer* in combination with cisplatin and bleomycin:
Intravenous dosage:
Adults: 25 mg/m2 IV bolus on days 1 and 8 in combination with cisplatin 75 mg /m2 IV on day 1 and bleomycin 10 units/m2 IV on days 1 and 8, repeated every 21 days. Treatment was given for 6 cycles if a complete remission was achieved. Patients who achieved stable disease or a partial response, continued treatment until disease progression. Bleomycin was discontinued after a maximum cumulative dose of 200 units/m2 was given.
For the treatment of mycosis fungoides:
Intravenous dosage:
Adults: 5 to 50 mg IV once weekly as a single agent has resulted in clinical responses in 50% of patients with early stage disease; the dosage may be reduced or discontinued based on patient response and/or hematologic toxicity. Methotrexate 15 to 37.5 mg IV twice weekly has been used in patient who had a poor response with weekly therapy. Higher doses of methotrexate with leucovorin rescue have also been given in patient with advanced stage disease.
Infants, Children, and Adolescents: 5 to 50 mg IV once weekly as a single agent has resulted in clinical responses in 50% of patients with early stage disease; the dosage may be reduced or discontinued based on patient response and/or hematologic toxicity. Methotrexate 15 to 37.5 mg IV twice weekly has been used in patient who had a poor response with weekly therapy. Higher doses of methotrexate with leucovorin rescue have also been given in patient with advanced stage disease.
Oral dosage:
Adults: 25 to 75 mg orally once weekly as a single agent or methotrexate 10 mg/m2 orally twice weekly as part of a combination chemotherapy regimen.
For the treatment of dermatomyositis* and polymyositis*:
Subcutaneous dosage:
Adults: 7.5 mg subcutaneously once weekly, initially. Increase dosage by 2.5 mg/week up to 25 mg subcutaneously once weekly; if no improvement after 4 weeks, may consider increasing dosage by 5 mg/week up to 60 mg subcutaneously once weekly.
Infants, Children, and Adolescents: 15 to 20 mg/m2/dose or 1 mg/kg/dose (Max: 40 mg/dose) subcutaneously once weekly. Subcutaneous administration is preferred over oral administration.
Oral dosage:
Adults: 7.5 mg PO once weekly, initially. Increase dosage by 2.5 mg/week up to 25 mg PO once weekly.
Infants, Children, and Adolescents: 15 to 20 mg/m2/dose or 1 mg/kg/dose (Max: 40 mg/dose) PO once weekly. Subcutaneous administration is preferred over oral administration.
For the treatment of atopic dermatitis*:
Oral dosage:
Adults: 7.5 to 25 mg PO once weekly. Taper or discontinue therapy once clearance or near-clearance is achieved and maintained, with maintenance of remission with emollients and topical agents and/or phototherapy. May consider discontinuing therapy in nonresponders on a sufficient dose (15 mg/week or more) after a 12- to 16-week trial.
Children and Adolescents: 0.2 to 0.7 mg/kg/dose (Max: 25 mg/dose) PO once weekly. Taper or discontinue therapy once clearance or near-clearance is achieved and maintained, with maintenance of remission with emollients and topical agents and/or phototherapy. May consider discontinuing therapy in nonresponders on a sufficient dose after a 12- to 16-week trial.
Intramuscular or Subcutaneous dosage:
Adults: 7.5 to 25 mg IM or subcutaneously once weekly. Taper or discontinue therapy once clearance or near-clearance is achieved and maintained, with maintenance of remission with emollients and topical agents and/or phototherapy. May consider discontinuing therapy in nonresponders on a sufficient dose (15 mg/week or more) after a 12- to 16-week trial.
Children and Adolescents: 0.2 to 0.7 mg/kg/dose (Max: 25 mg/dose) IM or subcutaneously once weekly. Taper or discontinue therapy once clearance or near-clearance is achieved and maintained, with maintenance of remission with emollients and topical agents and/or phototherapy. May consider discontinuing therapy in nonresponders on a sufficient dose after a 12- to 16-week trial.
For the treatment of chronic gout or gouty arthritis in combination with pegloticase in persons refractory to conventional therapy:
Oral dosage:
Adults: 15 mg PO once weekly coadministered with pegloticase every 2 weeks and folic acid or leucovorin (folinic acid) supplementation. Start methotrexate and folic acid or leucovorin (folinic acid) supplementation at least 4 weeks prior to starting and continue throughout treatment with pegloticase. The optimal duration of pegloticase treatment has not been established. Pegloticase is not recommended for asymptomatic hyperuricemia.
For the treatment of graft-versus-host disease (GVHD)*:
-for the treatment of acute GVHD*:
Oral dosage:
Children and Adolescents: 5 to 10 mg/m2/dose PO once weekly. Guidelines suggest methotrexate as a third-line treatment option for steroid-refractory acute GVHD.
Intravenous dosage:
Adults: 5 mg/m2/dose IV once weekly or 5 to 10 mg IV every 3 to 4 days. Max: 20 mg/week. Guidelines suggest methotrexate as a third-line treatment option for steroid-refractory acute GVHD.
Children and Adolescents: 5 to 10 mg/m2/dose IV once weekly. Guidelines suggest methotrexate as a third-line treatment option for steroid-refractory acute GVHD.
-for the treatment of chronic GVHD*:
Oral dosage:
Adults: 5 to 10 mg/m2/dose PO once weekly. Guidelines suggest methotrexate as a second- or third-line treatment option for refractory chronic GVHD, mainly for skin and oral manifestations of chronic GVHD.
Children and Adolescents: 5 to 10 mg/m2/dose PO once weekly. Guidelines suggest methotrexate as a second- or third-line treatment option for refractory chronic GVHD, mainly for skin and oral manifestations of chronic GVHD.
Intravenous dosage:
Adults: 5 to 10 mg/m2/dose IV once weekly. Guidelines suggest methotrexate as a second- or third-line treatment option for refractory chronic GVHD, mainly for skin and oral manifestations of chronic GVHD.
Children and Adolescents: 5 to 10 mg/m2/dose IV once weekly. Guidelines suggest methotrexate as a second- or third-line treatment option for refractory chronic GVHD, mainly for skin and oral manifestations of chronic GVHD.
For the treatment of temporal arteritis*:
Oral dosage:
Adults: 7.5 to 15 mg PO once weekly in combination with a tapering course of glucocorticoids.
For the treatment of polymyalgia rheumatica*:
Oral dosage:
Adults: 7.5 to 10 mg PO once weekly in combination with a glucocorticoid.
Therapeutic Drug Monitoring:
Guidelines for High-Dose Methotrexate with Leucovorin Rescue
Guidelines for high-dose methotrexate with leucovorin rescue are protocol specific. Refer to protocol for specific recommendations on hydration and leucovorin dosing and duration.
NOTE: Delay the administration of high-dose methotrexate until recovery if the white blood cell count is less than 1,500 cells/microliter (microL), the neutrophil count is less than 200 cells/microL, the platelet count is less than 75,000 cells/microL, the serum bilirubin level is greater than 1.2 mg/dL, the ALT level is greater than 450 units, or the serum creatinine is abnormal or creatinine clearance is 60 mL/min or less. Do not administer high-dose methotrexate if mucositis is present until there is evidence of healing. Drain any pleural effusion dry prior to high-dose methotrexate infusion.
For normal methotrexate elimination (defined as a serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hour): leucovorin 15 mg PO/IV/IM every 6 hours for 60 hours (10 doses starting at 24 hours after start of the methotrexate infusion).
For delayed late methotrexate elimination (defined as a serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration): continue leucovorin 15 mg PO/IV/IM every 6 hours until methotrexate level is less than 0.05 micromolar.
For delayed early methotrexate elimination and/or evidence of acute renal injury (defined as a serum methotrexate level of 50 micromolar or more at 24 hours; 5 micromolar or more at 48 hours after administration; or a serum creatinine level that doubles or more than doubles at 24 hours after methotrexate administration): leucovorin 150 mg IV every 3 hours until the methotrexate level is less than 1 micromolar, then leucovorin 15 mg IV every 3 hours until the methotrexate level is less than 0.05 micromolar.
Other abnormalities in methotrexate elimination or abnormalities in renal function resulting in significant toxicity: extend leucovorin rescue for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy.
Consider administration of glucarpidase in patients who have toxic plasma methotrexate concentrations (greater than 1 micromol/L) and delayed methotrexate clearance due to impaired renal function.
Maximum Dosage Limits:
NOTE: The suggested maximum tolerated dose (MTD) for methotrexate is dependent on the disease state, performance status, and other chemotherapy agents or radiation given in combination.
NOTE: The correct dose of methotrexate in the treatment of neoplastic disease will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.
-Adults
For psoriasis 30 mg/week PO; for rheumatoid arthritis 20 mg/week PO. See specific injection product for maximal weekly injection doses, as these vary by product and route given.
In the treatment of neoplastic disease the maximum tolerated dose of methotrexate varies significantly from 80 to 900 mg/m2 IV without leucovorin rescue therapy and 900 to 30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses greater than 30 mg/m2 are generally not recommended due to poor absorption.
-Geriatric
The maximum tolerated doses of methotrexate may be lower in elderly patients. See adult maximum listings.
-Children
For polyarticular juvenile idiopathic arthritis: 20 to 30 mg/m2/week (0.65 to 1 mg/kg/week) is a usual maximum dose.
In the treatment of neoplastic disease, the maximum tolerated dose of methotrexate varies significantly from 80 to 900 mg/m2 IV without leucovorin rescue therapy and 900 to 30,000 mg/m2 IV with leucovorin rescue. The maximum intrathecal dose of methotrexate is 15 mg. Oral doses greater than 30 mg/m2 are generally not recommended due to poor absorption.
Patients with Hepatic Impairment Dosing
Subcutaneous formulations of methotrexate are contraindicated in patients with alcoholic liver disease or other chronic liver disease. Closely monitor other patients with hepatic impairment for adverse reactions; consider reducing the dose of methotrexate or consider alternative treatments. The safety of methotrexate in patients with hepatic impairment is unknown.
Patients with Renal Impairment Dosing
Carefully monitor patients with creatinine clearance (CrCl) less than 90 mL/min for adverse reactions; consider reducing the dose of methotrexate or consider alternative treatments as appropriate. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, effective clearance has been reported with acute, intermittent hemodialysis using a high-flux dialyzer. Treatment should be individualized for the patient and the disease being treated. The following is an example dosing nomogram that has been suggested when methotrexate is used for the treatment of neoplastic diseases:
-CrCl 60 mL/minute or higher: No dosage adjustment needed.
-CrCl 46 to 60 mL/minute: Administer 65% of standard dose.
-CrCl 31 to 45 mL/minute: Administer 50% of standard dose.
-CrCl 30 mL/minute or less: Not recommended.
*non-FDA-approved indication
Acalabrutinib: (Moderate) Coadministration of acalabrutinib and methotrexate may increase methotrexate exposure and increase the risk for methotrexate toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Methotrexate is a BCRP transporter substrate.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Acetaminophen; Aspirin: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Acetaminophen; Ibuprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Acitretin: (Contraindicated) The combination of methotrexate and acitretin is contraindicated. An increased risk of hepatitis has been reported from the combined use of methotrexate and the retinoid etretinate. Acitretin is the principal active component of etretinate. Although no longer available commercially in the United States, etretinate has been shown to increase methotrexate serum concentrations and cases of hepatotoxicity (e.g., hepatitis) have also been reported in patients receiving etretinate and methotrexate concomitantly.
Acyclovir: (Moderate) Avoid concomitant use of methotrexate with acyclovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Acyclovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with acyclovir may result in decreased renal function as well as increased methotrexate plasma concentrations.
Adalimumab: (Minor) Methotrexate reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively; however, data do not suggest the need for dose adjustment for either drug.
Adefovir: (Major) Avoid concomitant use of methotrexate with adefovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Adefovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with adefovir may result in decreased renal function as well as increased methotrexate plasma concentrations.
Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL-2 in combination with chemotherapy agents have not been established; however, concurrent or sequential use of these agents is common but results in various pharmacodynamic drug interaction risks. Aldesleukin is associated with serious adverse reactions affecting many organ systems. Concurrent administration of antineoplastic agents possessing nephrotoxic, myelotoxic, or hepatotoxic effects (e.g., methotrexate), may increase toxicity in these organ systems.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Allopurinol: (Minor) In vitro studies have shown that allopurinol administered one hour prior to methotrexate may decrease the therapeutic effects of methotrexate.
Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Alteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Amikacin: (Major) Avoid concomitant use of methotrexate with amikacin due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Amikacin and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with amikacin may result in decreased renal function as well as increased methotrexate plasma concentrations.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Aminolevulinic Acid: (Major) Methotrexate may increase the photosensitizing effects of photosensitizing agents used for photodynamic therapy.
Aminosalicylate sodium, Aminosalicylic acid: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Amlodipine; Celecoxib: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Amoxicillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Amoxicillin; Clavulanic Acid: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Amphotericin B lipid complex (ABLC): (Major) Avoid concomitant use of methotrexate with amphotericin B due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Amphotericin B and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with amphotericin B may result in decreased renal function as well as increased methotrexate plasma concentrations.
Amphotericin B liposomal (LAmB): (Major) Avoid concomitant use of methotrexate with amphotericin B due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Amphotericin B and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with amphotericin B may result in decreased renal function as well as increased methotrexate plasma concentrations.
Amphotericin B: (Major) Avoid concomitant use of methotrexate with amphotericin B due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Amphotericin B and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with amphotericin B may result in decreased renal function as well as increased methotrexate plasma concentrations.
Ampicillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Ampicillin; Sulbactam: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Apixaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Asparaginase Erwinia chrysanthemi: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3 to 24 hours prior to L-asparaginase, L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased.
Aspirin, ASA: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Butalbital; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Caffeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Dipyridamole: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Aspirin, ASA; Oxycodone: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Atenolol; Chlorthalidone: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Azilsartan; Chlorthalidone: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Basiliximab: (Minor) Because basiliximab is an immunosuppressant, additive effects may be seen with other immunosuppressives such as methotrexate.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Betrixaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Bexarotene: (Major) Concomitant use of systemic retinoids, such as bexarotene, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Bismuth Subsalicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates. (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Bupivacaine; Meloxicam: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Celecoxib: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Celecoxib; Tramadol: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chloramphenicol: (Minor) Chloramphenicol may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Chloramphenicol may also displace methotrexate from protein binding sites leading to increased methotrexate levels.
Chlorothiazide: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Chlorthalidone: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cholestyramine: (Major) The bile-acid sequestrant cholestyramine is well-known to cause drug interactions by binding and decreasing the oral administration of many drugs. Cholestyramine enhances the clearance of methotrexate from the systemic circulation. This interaction has been used therapeutically in patients with methotrexate toxicity. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.
Choline Salicylate; Magnesium Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Cidofovir: (Major) Avoid concomitant use of methotrexate with cidofovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Cidofovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with cidofovir may result in decreased renal function as well as increased methotrexate plasma concentrations.
Ciprofloxacin: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant ciprofloxacin use. Ciprofloxacin may inhibit methotrexate renal tubular transport potentially resulting in increased methotrexate serum concentrations.
Cisplatin: (Moderate) Closely monitor renal function and watch for methotrexate-related adverse reactions if concomitant use of cisplatin and methotrexate is necessary. Cisplatin and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with cisplatin may result in decreased renal function as well as increased methotrexate plasma concentrations.
Clofarabine: (Major) Avoid the concomitant use of clofarabine and methotrexate due to the risk of additive hepatotoxicity. Coadministration may also increase the risk of additive nephrotoxicity. Additionally, taking these drugs together may alter clofarabine concentrations; clofarabine and methotrexate are both substrates of OAT1 and OAT3.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cyclosporine: (Moderate) Cyclosporine should be used cautiously with nephrotoxic drugs, such as methotrexate, as cyclosporine itself can cause structural kidney damage. Additive nephrotoxicity can occur if these drugs are administered together. Monitor renal function and fluid status carefully. Additionally, concurrent administration of methotrexate and cyclosporine in patients with rheumatoid arthritis can elevate methotrexate concentrations and decrease the levels of the 7-hydroxy-methotrexate metabolite. Of 20 patients with rheumatoid arthritis that received methotrexate and cyclosporine, the mean peak methotrexate concentration increased 26%, the mean methotrexate AUC increased 18%, and the AUC of the 7-hydroxy-methotrexate metabolite decreased 80% as compared with patients that received methotrexate alone. Cyclosporine concentrations do not appear to be altered, but data is from only 6 patients. Monitoring of methotrexate and cyclosporine concentrations during concurrent cyclosporine therapy is recommended.
Cytarabine, ARA-C: (Minor) Pre-treatment with methotrexate enhances Ara-CTP formation resulting in increased cytarabine induced cytotoxicity. Simultaneous administration of cytarabine and methotrexate is associated with increased retention of Ara-CTP within the cell.
Dabigatran: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Daclatasvir: (Minor) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with daclatasvir, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
Dantrolene: (Moderate) Concomitant administration of methotrexate and dantrolene may result in elevated methotrexate concentrations. Elevated methotrexate concentrations were noted in a girl who received oral dantrolene a day before intravenous methotrexate 12 g/m2 (18 grams). The methotrexate concentration was 418 micromol/L twenty-four hours after the dose. The threshold value of 0.2 micromol/L was reached 324 hours after the start of the methotrexate infusion despite administration of carboxypeptidase-G2, an enzyme that hydrolyzes methotrexate to nontoxic metabolites, at hours 54 and 78. Three weeks later, a methotrexate dose of 10 grams was well-tolerated with a standard decrease in plasma concentrations. The clearance of methotrexate may have been impaired by dantrolene or the metabolite 5-hydroxydantrolene. Also, altered protein binding may have occurred; both dantrolene and methotrexate bind to albumin.
Dapsone: (Major) Drugs with similar pharmacologic activity, such as dapsone, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Demeclocycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Dexlansoprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Dichlorphenamide: (Major) Concomitant use of dichlorphenamide and methotrexate is not recommended because of an increased risk of methotrexate-related adverse effects. This combination should be avoided, since increased methotrexate exposure may cause severe toxicity. Monitor closely for signs of methotrexate toxicity if coadministration cannot be avoided, including signs and symptoms of bone marrow toxicity/ immunosuppression (sore throat, fever, reduced blood counts, unusual bruising or bleeding) and liver toxicity, as examples. Increased methotrexate exposure is possible. Methotrexate is a sensitive OAT1 substrate. Dichlorphenamide inhibits OAT1.
Diclofenac: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Diclofenac; Misoprostol: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Dicloxacillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Diflunisal: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
Diphenhydramine; Ibuprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Diphenhydramine; Naproxen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Direct Oral Anticoagulants (DOACs): (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Doxycycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Edoxaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Elbasvir; Grazoprevir: (Moderate) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors. (Minor) Administering methotrexate with elbasvir; grazoprevir may result in elevated methotrexate plasma concentrations. Methotrexate is a substrate for the breast cancer resistance protein (BCRP); both elbasvir and grazoprevir are BCRP inhibitors.
Eltrombopag: (Moderate) Eltrombopag is an inhibitor of OATP1B1 and Breast Cancer Resistance Protein (BCRP). Drugs that are substrates for these transporters, such as methotrexate, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for increased methotrexate toxicity if these drugs are coadministered. In a clinical study, administration of a single dose of rosuvastatin, another substrate of both OATP1B1 and BCRP, in combination with eltrombopag increased plasma rosuvastatin AUC by 55% and the Cmax by 103%. A 50% rosuvastatin dosage reduction was recommended.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Esomeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone has been associated with hepatotoxicity; caution is recommended in combining 17-alpha-alkylated androgens in combination with other medications that have potential hepatotoxic effects (e.g., methotrexate). Monitor liver function periodically; if liver function becomes abnormal or clinical symptoms (e.g., jaundice) develop, discontinue the androgen and determine the etiology. Androgen-induced jaundice is reversible whtih medication discontinuation.
Ethanol: (Major) Alcohol may increase the risk for liver-related side effects of methotrexate. Patients should be advised to avoid intake of alcohol-containing beverages during methotrexate therapy. Patients who are noncompliant with alcohol restrictions should not receive methotrexate.
Etodolac: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Fenoprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Floxuridine: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Floxuridine is metabolized to 5-FU. Like 5-FU, the scheduling of floxuridine and methotrexate when used together is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
Fluorouracil, 5-FU: (Minor) Methotrexate given 3 to 24 hours before 5-FU increases the formation of fluorouridine triphosphate and enhances cell kill and toxicity. When 5-FU is given within 24 hours prior to methotrexate, the cytotoxicity of methotrexate is decreased. Thus, the scheduling of these agents in combination is critical. It appears that the more favorable sequence is administering methotrexate prior to 5-FU due to increased RNA toxicity of 5-FU.
Flurbiprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Folic Acid, Vitamin B9: (Moderate) Folic acid may compete with methotrexate for entry into cells. However, in some situations, folic acid supplementation may be used to decrease adverse reactions such as mouth sores in patients receiving methotrexate for arthritis and other non-malignant diseases. Folic acid, vitamin B9, is NOT effective for methotrexate rescue therapy since folic acid requires dihydrofolate reductase for bioactivation and methotrexate inhibits this enzyme. Therefore folic acid should not be used to prevent toxicity of moderate- to high-dose methotrexate therapy.
Food: (Moderate) Concurrent administration of oral methotrexate with food may delay the absorption of methotrexate and decrease the maximum serum concentration. (Moderate) Food or drink that acidifies the urine such as cola can cause elevated methotrexate concentrations. In a patient, acute renal failure was noted 24 hours after drug receipt despite baseline normal renal function. The patient had repeated episodes of reduced urinary pH despite sodium bicarbonate administration. The urinary pH went from 8.5 to 6.5 after the patient consumed 330 ml of Coca-Cola. Urinary pH was maintained at 8 or higher once the patient stopped consuming cola. The plasma methotrexate concentration fell and urinary function eventually returned to normal. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and creatinine concentrations are essential for safe methotrexate administration.
Foscarnet: (Major) Avoid concomitant use of methotrexate with foscarnet due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Foscarnet and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with foscarnet may result in decreased renal function as well as increased methotrexate plasma concentrations.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Fosphenytoin: (Major) Avoid concomitant use of methotrexate and fosphenytoin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; fosphenytoin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Fostamatinib: (Moderate) Monitor for methotrexate toxicities that may require methotrexate dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; methotrexate is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the BCRP substrate AUC by 95% and Cmax by 88%.
Furosemide: (Moderate) Furosemide undergoes significant renal tubular secretion. Concomitant administration of furosemide with other drugs that undergo significant renal tubular secretion, such as methotrexate, may result in decreased effect of furosemide and, conversely, decreased elimination of the other drug. High dose treatment of both furosemide and other drugs that undergo renal tubular secretion may result in increased toxicity of both drugs.
Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as methotrexate, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
Gentamicin: (Major) Avoid concomitant use of methotrexate with gentamicin due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Gentamicin and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with gentamicin may result in decreased renal function as well as increased methotrexate plasma concentrations.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and methotrexate as coadministration may increase serum concentrations of methotrexate and increase the risk of adverse effects. Methotrexate is a substrate of breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and methotrexate as coadministration may increase serum concentrations of methotrexate and increase the risk of adverse effects. Methotrexate is a substrate of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of BCRP.
Glimepiride: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Glipizide: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Glipizide; Metformin: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Glyburide: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Glyburide; Metformin: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Golimumab: (Moderate) The safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Hydrocodone; Ibuprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Hydroxychloroquine: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant hydroxychloroquine use. Concomitant use may increase the risk for methotrexate toxicity.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Ibrutinib: (Moderate) Use ibrutinib and methotrexate together with caution; plasma concentrations of methotrexate may increase resulting in increased toxicity. Ibrutinib is a BCRP inhibitor in vitro; methotrexate is a BCRP substrate with a narrow therapeutic index.
Ibuprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Ibuprofen; Famotidine: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Ibuprofen; Oxycodone: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Ibuprofen; Pseudoephedrine: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Indomethacin: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Infliximab: (Moderate) Rheumatoid arthritis patients who received methotrexate in combination with infliximab had higher serum concentrations of infliximab as compared to those who received infliximab alone. Many serious infections during infliximab therapy have occurred in patients who received concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposed patients to infections. The impact of concurrent infliximab therapy and immunosuppression on the development of malignancies is unknown. In clinical trials, the use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and appeared to reduce infusion reactions.
Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Isotretinoin: (Moderate) Concomitant use of systemic retinoids, such as isotretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.
Itraconazole: (Moderate) Systemic exposure of methotrexate, a substrate of the drug transporter breast cancer resistance protein (BCRP), may be increased when administered concurrently with itraconazole, a BCRP inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of methotrexate; monitor patients for potential adverse effects.
Ketoprofen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Ketorolac: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Lamotrigine: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant lamotrigine use. Concomitant use may have additive antifolate effects. Methotrexate inhibits dihydrofolate reductase, and lamotrigine is a weak inhibitor of dihydrofolate reductase.
Lansoprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Leflunomide: (Major) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs. The potential for hepatotoxicity should also be considered when such medications would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure. In a small phase III study of leflunomide with methotrexate, 33% of the patients had LFT enzyme elevations of 2-fold the upper limit of normal (ULN) or greater. All of these resolved with either continuation of the medications with dosage adjustment or leflunomide discontinuation. Furthermore, 3.8% of 133 patients with normal LFTs on methotrexate had an ALT serum concentration at least 3 times the ULN with leflunomide addition. In contrast, 0.8% of 130 patients with placebo addition met the criteria. If leflunomide and methotrexate are used concomitantly, the American College of Rheumatology guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Also, laboratory monitoring for leflunomide needs to be conducted.
Levomefolate: (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Lithium: (Major) Avoid concomitant use of methotrexate with lithium due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Lithium and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with lithium may result in decreased renal function as well as increased methotrexate plasma concentrations.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as methotrexate. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Mafenide: (Moderate) Concurrent use of mafenide and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
Magnesium Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Mefenamic Acid: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Meloxicam: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Methenamine; Sodium Salicylate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Methoxsalen: (Major) Methotrexate may increase the photosensitizing effects of photosensitizing agents used for photodynamic therapy.
Methyltestosterone: (Moderate) Methyltestosterone has been associated with hepatotoxicity; caution is recommended in combining 17-alpha-alkylated androgens in combination with other medications that have potential hepatotoxic effects (e.g., methotrexate). Monitor liver function periodically; if liver function becomes abnormal or clinical symptoms (e.g., jaundice) develop, discontinue the androgen and determine the etiology. Androgen-induced jaundice is reversible whtih medication discontinuation.
Metolazone: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Minocycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Nabumetone: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Nafcillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Naproxen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Naproxen; Esomeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Naproxen; Pseudoephedrine: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Natalizumab: (Major) The concomitant use of natalizumab and immunosuppressives may further increase the risk of infections, including progressive multifocal leukoencephalopathy (PML), over the risk observed with use of natalizumab alone. Prior treatment with an immunosuppressant is also a risk factor for PML. Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as methotrexate. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
Neomycin: (Moderate) Oral neomycin has been shown to inhibit the gastrointestinal absorption of methotrexate. Caution is warranted with concomitant use.
Nitisinone: (Moderate) Monitor for increased methotrexate-related adverse effects if coadministered with nitisinone. Increased methotrexate exposure is possible. Nitisinone inhibits OAT3. Methotrexate is an OAT3 substrate.
Nonsteroidal antiinflammatory drugs: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Omadacycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Omeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities. (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Osimertinib: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with osimertinib is necessary. Methotrexate is a BCRP substrate and osimertinib is a BCRP inhibitor.
Oxacillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with methotrexate due to the risk of increased oxaliplatin-related adverse reactions. Methotrexate is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents.
Oxaprozin: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Pantoprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Paromomycin: (Minor) Paromomycin may decrease the absorption and bioavailability of oral methotrexate. Paromomycin may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
Pegaspargase: (Major) L-Asparaginase with methotrexate has shown both therapeutic synergistic and antagonistic effects depending upon the schedule of administration of these agents. When methotrexate is given 3-24 hours prior to L-Asparaginase Escherichia coli, the L-asparaginase blocks the antifolate effects of methotrexate and decreases methotrexate toxicity. If L-asparaginase is given prior to methotrexate, the efficacy of methotrexate is decreased. This could be due to inhibition of protein synthesis preventing progression to the S-phase of the cell cycle. Alternatively, L-asparaginase pretreatment may inhibit methotrexate polyglutamation, which is required for intracellular retention of methotrexate. Cells are refractory to methotrexate for up to 10 days following a single dose of L-asparaginase. During the period following L-asparaginase protein inhibition, there is a period of increased DNA synthesis that leads to increased sensitivity to methotrexate. Since the active component of pegaspargase is L-asparaginase, the same drug-drug interactions reported with L-asparaginase would be expected with pegaspargase. It is recommended to give L-asparaginase or pegaspargase at least 10-14 days prior to methotrexate or shortly after methotrexate administration.
Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Penicillin G Benzathine: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Penicillin G Benzathine; Penicillin G Procaine: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Penicillin G Procaine: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Penicillin G: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Penicillin V: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Penicillins: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with methotrexate. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Phenytoin: (Major) Avoid concomitant use of methotrexate and phenytoin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; phenytoin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Photosensitizing agents (topical): (Major) Methotrexate may increase the photosensitizing effects of photosensitizing agents used for photodynamic therapy.
Pioglitazone; Glimepiride: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Piperacillin; Tazobactam: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Piroxicam: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Porfimer: (Major) Avoid coadministration of porfimer with methotrexate due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like methotrexate may increase the risk of a photosensitivity reaction.
Pretomanid: (Major) Avoid coadministration of pretomanid with methotrexate, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity; methotrexate exposure may also increase. Monitor for methotrexate-related adverse events, such as myelosuppression, and evidence of hepatotoxicity if coadministration is necessary. Consider methotrexate dose reduction if needed. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications. Pretomanid inhibits the OAT3 transporter in vitro, and methotrexate is a substrate of OAT3.
Probenecid: (Contraindicated) Probenecid inhibits renal elimination of methotrexate, which can cause increased plasma levels and toxicity of methotrexate. In addition, methotrexate can increase uric acid production. Probenecid has also been associated with decreased clearance of methotrexate from the CSF. Concomitant use of methotrexate and probenecid is not recommended because of the increased risk of uric acid neuropathy. If coadministration is necessary, patients receiving this combination should be closely monitored.
Probenecid; Colchicine: (Contraindicated) Probenecid inhibits renal elimination of methotrexate, which can cause increased plasma levels and toxicity of methotrexate. In addition, methotrexate can increase uric acid production. Probenecid has also been associated with decreased clearance of methotrexate from the CSF. Concomitant use of methotrexate and probenecid is not recommended because of the increased risk of uric acid neuropathy. If coadministration is necessary, patients receiving this combination should be closely monitored.
Proton pump inhibitors: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Pyrimethamine: (Major) Drugs with similar pharmacologic activity, such as pyrimethamine, may lead to additive antifolate effects and bone marrow suppression when used with methotrexate. Concurrent use of pemetrexed and methotrexate is unlikely, however, the combination should be avoided.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Rabeprazole: (Major) Avoid concomitant use of methotrexate and proton pump inhibitors (PPIs) due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions; consider temporary withdrawal of the PPI in some patients receiving high-dose methotrexate. Concomitant use of methotrexate, primarily at high dose, and PPIs may increase and prolong serum concentrations of methotrexate, possibly leading to methotrexate toxicities.
Regorafenib: (Moderate) Monitor for an increase in methotrexate-related adverse reactions if coadministration with regorafenib is necessary. Methotrexate is a BCRP substrate and regorafenib is a BCRP inhibitor.
Reteplase, r-PA: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and methotrexate. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Rituximab: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
Rituximab; Hyaluronidase: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
Rivaroxaban: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Rolapitant: (Major) Avoid the concurrent use of methotrexate and rolapitant if possible; if coadministration is necessary, monitor methotrexate levels and watch for methotrexate-related adverse effects. Methotrexate is a substrate of the Breast Cancer Resistance Protein (BCRP), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration.
Ropeginterferon alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as methotrexate. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
Salicylates: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Salsalate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Sapropterin: (Moderate) Significant increases in serum phenylalanine concentrations have been noted after methotrexate infusions of 58 g/m2 to 46 patients with an unknown PKU status. Increased concentrations occurred at the end of the infusion in 95% of methotrexate cycles, but large inter-individual variations in the concentrations existed. Individual predispositions may exist, as maximal phenylalanine concentrations were of the same magnitude in a given patient. Phenylalanine concentrations returned to baseline concentrations 24 hours after the end of the methotrexate infusion. Methotrexate has been shown to decrease endogenous tetrahydrobiopterin (BH4) concentrations by inhibiting the enzyme dihydropteridine reductase; a similar reaction could be expected in patients receiving sapropterin. Dihydropteridine reductase recycles quinonoid dihydropterin (q-BH2) back to the active cofactor BH4. Reduction of BH4 could make management of hyperphenylalaninemia more difficult. Drugs that inhibit folate metabolism should be used with caution in patients taking sapropterin.
Sarecycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir with methotrexate. Taking these medications together may increase the plasma concentrations of methotrexate. Methotrexate is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is an BCRP inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Stiripentol: (Moderate) Consider a dose reduction of methotrexate when coadministered with stiripentol. Coadministration may increase plasma concentrations of methotrexate resulting in an increased risk of adverse reactions. Methotrexate is a substrate of BCRP; stiripentol may inhibit BCRP at clinically relevant concentrations.
Sulfadiazine: (Moderate) Concurrent use of sulfadiazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid concomitant use of methotrexate and sulfamethoxazole due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim. Methotrexate is approximately 50% protein bound; sulfamethoxazole is highly protein-bound. Sulfamethoxazole may displace methotrexate from its protein binding sites and compete with the renal transport of methotrexate, increasing methotrexate plasma concentrations. (Major) Avoid concomitant use of methotrexate and trimethoprim due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim.
Sulfasalazine: (Moderate) Concurrent use of sulfasalazine and methotrexate may increase the incidence of methotrexate-related adverse events. Methotrexate is partially bound to albumin, and toxicity may be increased because of displacement by sulfonamides.
Sulfonylureas: (Major) Avoid concomitant use of methotrexate and sulfonylureas due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; sulfonylureas are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Sulindac: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Sumatriptan; Naproxen: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Tacrolimus: (Major) Avoid concomitant use of methotrexate with tacrolimus due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tacrolimus and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tacrolimus may result in decreased renal function as well as increased methotrexate plasma concentrations.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and methotrexate due to the potential for increased plasma concentrations of methotrexate increasing the risk of adverse effects. Methotrexate dose adjustment may be needed with coadministration. Methotrexate is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Tedizolid: (Moderate) If possible, stop use of oral methotrexate temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for methotrexate-associated adverse events. Methotrexate plasma concentrations may be increased when oral methotrexate is administered concurrently with oral tedizolid. Methotrexate is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as methotrexate may result in additive effects.
Tenecteplase: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Tenofovir Alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Tenofovir Alafenamide: (Major) Avoid concomitant use of methotrexate with tenofovir alafenamide due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir alafenamide and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir alafenamide may result in decreased renal function as well as increased methotrexate plasma concentrations.
Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Teriflunomide: (Major) Teriflunomide is an inhibitor of the hepatic uptake transporter organic anion transporting polypeptide OATP1B1 and the renal uptake organic anion transporter OAT3, while methotrexate is a substrate of both of these transporters. Concomitant use may produce greater potential for hepatotoxicity. The potential for hepatotoxicity should also be considered when such medications would be prescribed after teriflunomide administration has ceased, if the patient has not received the teriflunomide elimination procedure.
Tetracycline: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Tetracyclines: (Moderate) Monitor for methotrexate-related adverse reactions during concomitant tetracyclines use. Tetracyclines may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Theophylline, Aminophylline: (Moderate) Methotrexate may decrease the clearance of aminophylline. Aminophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations. (Moderate) Methotrexate may decrease the clearance of theophylline. Theophylline levels should be closely monitored when used concurrently with methotrexate. In a small number of patients with either leukemia or lymphoma and acute methotrexate neurotoxicity, theophylline attenuated methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations.
Thiazide diuretics: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Thrombolytic Agents: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Tobramycin: (Major) Avoid concomitant use of methotrexate with tobramycin due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tobramycin and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tobramycin may result in decreased renal function as well as increased methotrexate plasma concentrations.
Tolmetin: (Major) Do not administer nonsteroidal anti-inflammatory drugs (NSAIDs) before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when NSAIDs are administered concomitantly with lower doses of methotrexate as they have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Despite potential interactions, patients with rheumatoid arthritis (RA) are often receiving concurrent treatment with NSAIDs without apparent problems. However, these doses are lower than those used in psoriasis or malignancy; higher methotrexate doses may lead to unexpected toxicity in combination with NSAIDs. NSAIDs may be continued in patients with RA receiving treatment with methotrexate, although the possibility of increased toxicity has not been fully explored.
Tolvaptan: (Major) Avoid concomitant use of methotrexate with tolvaptan due to the increased risk of severe methotrexate-related adverse reactions; additive hepatotoxicity may also occur. If concomitant use is unavoidable, closely monitor for adverse reactions. Tolvaptan and methotrexate are both hepatotoxic drugs; concomitant use of methotrexate with hepatotoxic drugs may increase methotrexate plasma concentrations. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic drugs has not been evaluated; however, hepatotoxicity has been reported in such cases.
Tretinoin, ATRA: (Moderate) Concomitant use of systemic retinoids, such as tretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy. Topical retinoid products do not appear to pose this increased risk for liver problems.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Trimethoprim: (Major) Avoid concomitant use of methotrexate and trimethoprim due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Increased bone marrow suppression has been reported in patients receiving methotrexate and sulfamethoxazole; trimethoprim.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Valacyclovir: (Major) Avoid concomitant use of methotrexate with valacyclovir due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Valacyclovir and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with valacyclovir may result in decreased renal function as well as increased methotrexate plasma concentrations.
Valproic Acid, Divalproex Sodium: (Major) Avoid concomitant use of methotrexate with valproic acid due to the increased risk of severe methotrexate-related adverse reactions; additive hepatotoxicity may also occur. If concomitant use is unavoidable, monitor valproic acid concentrations as well as for adverse reactions or loss of valproic acid efficacy. Concomitant use may decrease valproic acid concentrations and increase methotrexate plasma concentrations. Valproic acid and methotrexate are both hepatotoxic drugs; concomitant use of methotrexate with hepatotoxic drugs may increase methotrexate plasma concentrations. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic drugs has not been evaluated; however, hepatotoxicity has been reported in such cases.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant thiazide diuretic use. Thiazide diuretics may decrease renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Vancomycin: (Major) Avoid concomitant use of methotrexate with vancomycin due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. Recent exposure to vancomycin, in the absence of overt renal impairment, may also adversely affect methotrexate excretion and increase risk of toxicity. If concomitant use is unavoidable, closely monitor for adverse reactions. Vancomycin and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with vancomycin may result in decreased renal function as well as increased methotrexate plasma concentrations. In a case report, two patients who had received a methotrexate-containing chemotherapy regimen initially displayed appropriate methotrexate clearance. However, administration of vancomycin in between chemotherapy treatment cycles appears to have caused markedly prolonged methotrexate clearance (i.e., 170 to 231 hours to reach serum methotrexate concentrations of less than 0.2 micro-M). Subclinical renal impairment was documented in both cases following vancomycin administration, which eventually resolved; subsequent methotrexate cycles, of the same dose, showed appropriate clearance.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with methotrexate is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like methotrexate may increase the risk of a photosensitivity reaction.
Vincristine Liposomal: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vincristine. When given 0 to 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell. Since the window of opportunity for a synergistic interaction is short, the effects in vivo are clinically not seen. Therapeutic synergism is noted when methotrexate is given 8 to 48 hours before vincristine. The mechanism for this interaction has not been clearly defined.
Vincristine: (Major) Monitor for increased serum concentrations and toxicities of methotrexate when administered concurrently with vincristine. When given 0 to 1 hour prior to methotrexate, vincristine increases the cellular retention of methotrexate by inhibiting methotrexate efflux from the cell. Since the window of opportunity for a synergistic interaction is short, the effects in vivo are clinically not seen. Therapeutic synergism is noted when methotrexate is given 8 to 48 hours before vincristine. The mechanism for this interaction has not been clearly defined.
Vitamin B Complex Supplements: (Moderate) Folic acid may compete with methotrexate for entry into cells. However, in some situations, folic acid supplementation may be used to decrease adverse reactions such as mouth sores in patients receiving methotrexate for arthritis and other non-malignant diseases. Folic acid, vitamin B9, is NOT effective for methotrexate rescue therapy since folic acid requires dihydrofolate reductase for bioactivation and methotrexate inhibits this enzyme. Therefore folic acid should not be used to prevent toxicity of moderate- to high-dose methotrexate therapy.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of methotrexate with penicillins due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions.
Voriconazole: (Moderate) Advise patients to avoid strong, direct sunlight during concomitant methotrexate and voriconazole use due to increased risk of skin toxicity. Methotrexate is associated with ultraviolet (UV) reactivation and voriconazole has been associated with photosensitivity skin reaction.
Warfarin: (Major) Avoid concomitant use of methotrexate and warfarin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; warfarin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Methotrexate competitively inhibits dihydrofolate reductase, which is the enzyme responsible for converting folic acid to reduced folate cofactors (i.e., tetrahydrofolate). Reduced folates are required for metabolic transfer of 1-carbon units in the synthesis of thymidylate and purine nucleotides. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues that have a high rate of cellular metabolism such as malignant cells, bone marrow, fetal cells, hair follicles, buccal and intestinal mucosa, and cells of the urinary bladder are generally more sensitive to the effects of methotrexate. Methotrexate is cycle-specific and inhibits cells primarily in the S-phase. At doses greater than 30 mg/m2, methotrexate inhibits cells in the S-phase and slows the entry of cells from G1- into S-phase. Methotrexate may inhibit protein synthesis due to the reduction of reduced folate cofactors. This may be the mechanism by which higher doses of methotrexate arrest cells in the G1-phase. The duration of exposure to methotrexate once the initial threshold for cytotoxicity is exceeded is a critical factor in the cellular toxicity of methotrexate. Therefore, prolonged exposure even at low plasma concentrations of methotrexate may result in serious toxicity and increased cytotoxicity.
Methotrexate may enter the cell by one of two transport systems. The primary process by which methotrexate enters the cell is the reduced-folate carrier that has a high affinity for reduced folates and methotrexate, and the second is the human folate receptor, which has a higher affinity for folic acid and reduced folates than methotrexate. Methotrexate may also enter the cell by passive diffusion, but this mechanism is not usually critical unless methotrexate is given at high doses (serum concentrations greater than 100 micromol). Once inside the cell, methotrexate undergoes polymerization of the glutamic acid side chain, similar to endogenous folates, to form methotrexate polyglutamate (MTX-PG). While both methotrexate and MTX-PG competitively inhibit dihydrofolate reductase, MTX-PG has enhanced binding to and inhibition of the enzyme and due to its large size, has reduced efflux out of the cell as compared to the parent compound. As compared with the parent drug, polyglutamate derivatives also have a greater ability to inhibit other folate-dependent enzymes such as thymidylate synthetase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase. The process of polyglutamation happens more readily in tumor cells than in benign mammalian cells, which partially explains selectivity of methotrexate for tumor cells. Formation of MTX-PG is dependent upon intracellular methotrexate concentrations and the duration of exposure. High-dose methotrexate therapy takes advantage of these mechanisms to overcome resistance to conventional dose therapy. The high extracellular concentrations achieved with high-dose therapy may facilitate the entry of methotrexate into the cell and may bypass resistance secondary to changes in membrane transport systems. Due to increased methotrexate exposure and intracellular concentrations, the formation of MTX-PG may be increased with high-dose methotrexate therapy.
Methotrexate resistance may develop through a number of mechanisms. Resistance may be due to decreased intracellular influx of methotrexate, decreased binding of methotrexate to dihydrofolate reductase, or increased activity or concentration of dihydrofolate reductase. A fourth mechanism, decreased formation of MTX-PG, can also occur and may be important for resistance to high-dose methotrexate. Reduced MTX-PG formation is time dependent with resistance occurring only during short-term exposure (less than 24 hours) but not during prolonged exposure. Decreased intracellular transport of methotrexate and increased synthesis of dihydrofolate reductase are common mechanisms of acquired resistance to methotrexate. Myelocytic leukemia blast cells are intrinsically resistant to methotrexate. The resistance seems to be due to decreased retention of methotrexate in cells as a result of reduced polyglutamation.
The mechanism of action in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and in psoriasis is unknown. Methotrexate has immunosuppressive properties and can thus, exhibit anti-inflammatory activity. The efficacy of methotrexate for rheumatoid arthritis is likely multifactorial; however, inhibition of AICAR transformylase appears to be a main mechanism, as an inverse relationship between urinary AICA concentrations and disease activity has been noted. The enzyme AICAR transformylase which is inhibited by methotrexate catalyzes the last step in the de novo biosynthesis of inosine monophosphate, which may cause immunosuppression. Also, AICA or its metabolites may be immunotoxic. Furthermore, inhibition of AICAR transformylase by methotrexate and its metabolites leads to AICA riboside accumulation, which inhibits adenosine deaminase. This results in increased adenosine concentrations which inhibit lymphocyte proliferation by the interaction of adenosine with A2 and A3 receptors. Therefore, at low doses, methotrexate may selectively inhibit replication and function of T and B lymphocytes. In addition, methotrexate can suppress the secretion of interleukin-1, interferon-gamma, and tumor necrosis factor, increase the secretion of interleukin-4, impair the release of histamine from basophils, and decrease chemotaxis of neutrophils.
Methotrexate may be given orally, IV, IM, subcutaneously, or intrathecally. After IV administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate is 50% bound to serum plasma proteins. It may be displaced from plasma albumin by various compounds including chloramphenicol, phenytoin, tetracyclines, salicylates, and sulfonamides. Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally; high CSF concentrations of the drug may be attained by intrathecal administration. In dogs, synovial fluid concentrations after oral dosing were higher in inflamed joints than in joints without inflammation. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joints to the level of normal joints.
After absorption, methotrexate undergoes hepatic and intracellular metabolism to a polyglutamated form (MTX-PG), which can be converted back to methotrexate by hydrolase enzymes. The retention of MTX-PG varies with the cells of different tissues and tumors. A small amount of methotrexate is metabolized to 7-hydroxymethotrexate by aldehyde oxidase. Methotrexate also undergoes minor metabolism to 7-hydroxymethotrexate; this may account for 7% to 33% of the drug excreted during the terminal phase of elimination. Accumulation may become significant following high doses. The aqueous solubility of 7-hydroxymethotrexate is 3-to 5-fold lower than the solubility of methotrexate. In addition, methotrexate is subject to metabolism by intestinal flora after oral administration to an inactive metabolite, DAMPA. However, this metabolite may cross-react with radioimmunoassays for methotrexate. When methotrexate is given at low doses (30 mg/m2) metabolites account for less than 10% of the drug excreted. When the same dose is given orally, approximately 35% of the dose is excreted as metabolites. This has lead to the conclusion that the majority of methotrexate metabolism occurs primarily in the GI tract and through enterohepatic circulation. The terminal half-life of methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, rheumatoid arthritis, or low-dose antineoplastic therapy (less than 30 mg/m2). Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Following IV administration of high-dose methotrexate, the terminal half-life is 8 to 15 hours. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. Methotrexate can exit slowly from third space accumulations resulting in prolonged terminal plasma half-life and toxicity.
Renal excretion by glomerular filtration and active tubular secretion is the primary route of elimination and is dependent upon dosage and route of administration. After IV administration, 80% to 90% of an administered dose is excreted unchanged in the urine within 24 hours. Biliary excretion accounts for less than 10% of methotrexate elimination. The rate of methotrexate clearance varies widely and is generally decreased at higher doses. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent on the duration of exposure rather than the peak level achieved; delayed drug clearance has been identified as a major factor responsible for methotrexate toxicity. Pharmacokinetic monitoring of serum methotrexate concentrations may help identify patients at high risk for toxicity and guide leucovorin dosing.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Oral Route
Oral absorption of methotrexate appears to be dose dependent. Peak plasma concentrations are attained within 0.75 to 6 hours following administration. Single oral doses greater than 80 mg/m2 may not be completely absorbed, possibly due to a saturation effect, while lower doses are well absorbed; there appears to be a plateau effect on bioavailability at doses of 15 mg or higher. At an oral dose of 30 mg/m2 or less, the mean bioavailability of methotrexate is about 60%; the absorption of doses greater than 40 mg/m2 has been reported to be significantly less than that of lower doses. Oral administration with food did not affect the AUC of methotrexate; however, the Cmax decreased by 50% and absorption was delayed. In addition, oral methotrexate is subject to first-pass metabolism in the liver that may decrease bioavailability and systemic exposure. Among adults with rheumatoid arthritis who got a median dose of 30 mg weekly (range, 25 mg to 40 mg) orally and subcutaneously, the mean bioavailability after oral administration was 0.64 (range, 0.21 to 0.96) as compared with subcutaneous administration. After administration of 12.5 to 25 mg to patients with Crohn's disease, the mean systemic exposure per milligram of methotrexate was 261 nmol x hour/L when given orally and 281 nmol x hour/L when given orally with 5 mg of oral folic acid, as compared to 360 nmol x hour/L when given subcutaneously.
Intramuscular Route
Methotrexate is generally completely absorbed from parenteral routes of administration, with a Tmax of 30 to 60 minutes after IM injection. Similar blood concentrations were obtained after IM or subcutaneous administration of weekly doses of 7.5 mg to 22.5 mg to 8 patients; 4 had rheumatoid arthritis, 2 had psoriatic arthritis, 1 had polymyositis, and 1 had Wegener's granulomatosis.
Subcutaneous Route
The bioavailability of a subcutaneous methotrexate formulation (Otrexup) was similar to IM administration at the same dose in patients with rheumatoid arthritis; systemic exposure of methotrexate was higher with subcutaneous administration of Otrexup compared to oral administration at the same dose. The bioavailability of Otrexup was 17% and 13% higher compared with oral methotrexate at doses of 10 mg and 15 mg, respectively; the bioavailability of Otrexup was 31% and 36% higher compared with oral methotrexate at doses of 20 mg and 25 mg, respectively. Otrexup absorption is similar when administered in the abdomen or thigh. In a relative bioavailability study of a different subcutaneous formulation of methotrexate (Rasuvo) in healthy subjects, the AUC of methotrexate at doses of 7.5 mg, 15 mg, 22.5 mg, and 30 mg was 35%, 49%, 51%, and 68% higher than the same dose of orally administered methotrexate, respectively. In another relative bioavailability study in psoriasis patients, the AUC of Rasuvo at a dose of 30 mg was similar to the same dose of methotrexate administered IM. The bioavailability of another subcutaneous methotrexate prefilled syringe formulation (Reditrex) was similar to IM or subcutaneous methotrexate administration at the same doses. Systemic exposure of subcutaneous methotrexate doses of 10 mg, 15 mg, 20 mg, and 25 mg was higher than that of oral methotrexate by 17%, 13%, 31%, and 36%, respectively. Reditrex absorption is similar when administered in the abdomen or thigh. After administration of 12.5 mg to 25 mg to patients with Crohn's disease, the mean systemic exposure per milligram of methotrexate was 360 nanomole (nmol) x hour/L when given subcutaneously, as compared to 261 nmol x hour/L when given orally and 281 nmol x hour/L when given orally with 5 mg of oral folic acid.
Other Route(s)
Intrathecal injection
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration. After intrathecal injection of methotrexate, absorption into the systemic circulation occurs slowly and may result in prolonged plasma concentrations. A pharmacokinetic analysis which included 2 patients (ages 9 and 17 years) demonstrated that intrathecal administration of a dose of 12 mg/m2 produced plasma concentrations 24 hours post-dose that were 10-fold greater than those after oral administration. Pharmacologically significant plasma concentrations were present more than twice as long with intrathecal administration compared to oral administration. The duration of maintenance of significant plasma concentrations of methotrexate following intrathecal administration exceeded 24 hours in both patients and reached 48 hours in 1 patient. Plasma half-lives were 1.9 and 5 to 9.9 hours following oral and intrathecal administration, respectively.
-Special Populations
Renal Impairment
Renal excretion is the primary route of elimination of methotrexate, therefore patients with renal impairment may have altered pharmacokinetics; consider adjustment of dosage regimens in such patients. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance rates vary widely and are generally decreased at higher doses. When a patient has delayed drug elimination due to compromised renal function, methotrexate serum concentrations may remain elevated for prolonged periods and may increase risk for toxicity. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. In general, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.
Pediatrics
Plasma methotrexate concentrations are highly variable in pediatric patients. Oral absorption appears to be dose dependent and ranged from 23% to 95% in pediatric patients with leukemia; a 20-fold difference between the highest and lowest peak levels has been reported (Cmax, 0.11 to 2.3 micromolar after a 20 mg/m2 dose). The mean serum concentrations were 0.59 micromolar (microM) (range, 0.03 to 1.4 microM) at 1 hour, 0.44 microM (range, 0.01 to 1 microM) at 2 hours, and 0.29 microM (range, 0.06 to 0.58 microM) at 3 hours following oral methotrexate doses of 6.4 to 11.2 mg/m2 per week in pediatric patients with juvenile rheumatoid arthritis (JRA). The terminal half-life values ranged from 0.7 to 5.8 hours in pediatric patients with acute lymphocytic leukemia (ALL) (dose range, 6.3 to 30 mg/m2) and from 0.9 to 2.3 hours in patients with JRA (dose range, 3.75 to 26.2 mg/m2).