XATMEP SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling.

• Bone Marrow Suppression
• Serious Infections
• Renal Toxicity and Increased Toxicity with Renal Impairment
• Gastrointestinal Toxicity
• Hepatic Toxicity
• Pulmonary Toxicity
• Hypersensitivity and Dermatologic Reactions
• Secondary Malignancies
• Ineffective Immunization and Risks Associated with Live Vaccines
• Infertility
• Increased Toxicity Due to Third–Space Accumulation
• Soft Tissue and Bone Toxicity with Radiation Therapy

Clinical Trials Experience

Because clinical trials 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.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase methotrexate toxicity.

Polyarticular Juvenile Idiopathic Arthritis

The approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m²/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of 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%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m²/week in JIA, the published data for doses above 20 mg/m²/week are too limited to provide reliable estimates of adverse reaction rates.

Postmarketing Experience

Additional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system.

Blood And Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemia

Cardiovascular Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotension

Eye Disorders: Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmia

Gastrointestinal Disorders: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis

Hepatobiliary Disorders: Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevations

Immune System Disorders: Vasculitis, lymphomas, and anaphylactoid reactions

Infections: Fatal opportunistic infections (most commonly Pneumocystis jiroveci pneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, Herpes simplex hepatitis, and disseminated Herpes simplex

Metabolism: Hyperglycemia and tumor lysis syndrome

Musculoskeletal System: Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosis

Nervous System Disorders: Headaches, drowsiness, blurred vision, transient blindness, speech impairment (including dysarthria and aphasia), hemiparesis, paresis and convulsions have also occurred following administration of methotrexate.

Following low doses, there have been reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Renal Disorders: Azotemia, hematuria, proteinuria, cystitis

Reproductive Disorders: Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastia

Respiratory Disorders: Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitis

Skin Disorders: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.