6 ADVERSE REACTIONS
The following adverse reactions are described, or described in greater detail, in other sections:
- Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
- Myelosuppression [see Warnings and Precautions (5.4)]
- Serious Infections [see Warnings and Precautions (5.5)]
- Renal Toxicity [see Warnings and Precautions (5.6)]
- Hepatotoxicity [see Warnings and Precautions (5.7)]
- Neurotoxicity [see Warnings and Precautions (5.8)]
- Gastrointestinal Toxicity [see Warnings and Precautions (5.9)]
- Pulmonary Toxicity [see Warnings and Precautions (5.10)]
- Dermatologic Reactions [see Warnings and Precautions (5.11)]
- 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)]
6.1 Clinical Trials Experience
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.
Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness.
The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n=128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies.
Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%.
Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm3).
Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3000/mm3), pancytopenia, dizziness.
Two other controlled trials of patients (n=680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions:
Incidence 1%: Interstitial pneumonitis.
Other less common adverse reactions: Decreased hematocrit, 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 approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m2 per week to 20 mg/m2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function 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%.
In two published series of adult psoriasis patients (n=204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%). Painful plaque erosions have been reported.
6.2 Postmarketing Experience
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.
Blood and lymphatic system disorders: Aplastic anemia, lymphadenopathy, hypogammaglobulinemia
Cardiovascular disorders: Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension, sudden death
Eye disorders: Optic neuropathy, blurred vision, ocular irritation, conjunctivitis, xerophthalmia
Gastrointestinal disorders: Hemorrhagic enteritis, intestinal perforation, gingivitis, pancreatitis, pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding
Hepatobiliary disorders: Acute hepatitis, decreased serum albumin, fibrosis, cirrhosis, liver failure
Immune system disorders: Anaphylaxis, anaphylactoid reactions, vasculitis
Musculoskeletal disorders: Stress fracture, soft tissue necrosis, arthralgia, myalgia, osteoporosis
Nervous system disorders: Headaches, drowsiness, blurred vision, speech impairment (including dysarthria and aphasia), transient cognitive dysfunction, mood alteration, unusual cranial sensations, paresis, encephalopathy, leukoencephalopathy, and convulsions. Also, spinal radiculopathy with intrathecal use
Renal disorders: Severe renal toxicity including renal failure, azotemia, hematuria, proteinuria, cystitis
Reproductive disorders: Defective oogenesis or spermatogenesis, loss of libido, impotence, gynecomastia, menstrual dysfunction
Respiratory disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening, alveolitis
Skin disorders: 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