The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
- Myelosuppression [see Warnings and Precautions (5.3)]
- Gastrointestinal Toxicity [see Warnings and Precautions (5.4)]
- Hepatotoxicity [see Warnings and Precautions (5.5)]
- Pulmonary Toxicity [see Warnings and Precautions (5.6)]
- Dermatologic Reactions [see Warnings and Precautions (5.7)]
- Renal Toxicity [see Warnings and Precautions (5.8)]
- Serious Infections [see Warnings and Precautions (5.11)]
- Neurotoxicity [see Warnings and Precautions (5.12)]
- Secondary Malignancies [see Warnings and Precautions (5.13)]
- Tumor Lysis Syndrome [see Warnings and Precautions (5.14)]
- Increased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)]
Because clinical trials and other studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.
The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n=128) with rheumatoid arthritis are listed below.
Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received corticosteroids. Hepatic histology was not examined in these short-term studies.
Elevated liver tests 15%, nausea/vomiting 10%
Incidence 3% to <10%:
Stomatitis, thrombocytopenia (platelet count < 100,000/mm3)
Incidence 1% to <3%:
Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count < 3000/mm3), pancytopenia, dizziness
Two other controlled trials of patients (n=680) with rheumatoid arthritis who received methotrexate 7.5 mg to 15 mg orally once weekly showed the following serious adverse reaction:
Other less common adverse reactions were: anemia, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge.
Polyarticular Juvenile Idiopathic Arthritis (pJIA)
The most common adverse reactions reported in patients 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m2 to 20 mg/m2 orally once weekly or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver tests 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea) 11%; stomatitis 2%; leukopenia 2%; headache 1.2%; alopecia 0.5%; dizziness 0.2%; rash 0.2%. Most patients received concomitant NSAIDs and some also received corticosteroids.
In two published series of adults with psoriasis (n=204, 248) who received methotrexate up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with rheumatoid arthritis, except for alopecia, photosensitivity, and “burning of skin lesions” (3% to 10% each). Painful plaque erosions have been reported.
The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure
Cardiovascular: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death
Eye: Optic neuropathy, blurred vision, ocular pain, conjunctivitis, xerophthalmia
Gastrointestinal: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration
Hematology: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia
Hepatobiliary: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis
Immune system: Anaphylaxis, anaphylactoid reactions, vasculitis
Musculoskeletal: Stress fracture, soft tissue and bone necrosis, arthralgia, myalgia, osteoporosis
Nervous system: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, and convulsions.
Renal: Azotemia, hematuria, proteinuria, cystitis
Reproductive: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction
Respiratory: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis
Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, erythematous rashes, pruritus, alopecia, skin ulceration, accelerated nodulosis, urticaria, pigmentary changes, ecchymosis, telangiectasia, photosensitivity, acne, furunculosis
Drugs that Increase Methotrexate Exposure
Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products.
If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with:
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anticoagulants, phenytoin, salicylates,
sulfonamides, sulfonylureas, and tetracyclines)
Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia.
Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions (5.10)].
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