Adverse Drug Reaction Overview
In general, the incidence and severity of acute side effects are related to dose, frequency of administration, and the duration of the exposure to significant blood levels of methotrexate to the target organs. The most serious reactions are discussed under WARNINGS AND PRECAUTIONS section. The most frequently reported adverse reactions include ulcerative stomatitis, leucopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. Ulcerations of the oral mucosa are usually the earliest signs of toxicity.
Adverse Drug Reactions by Organ System
| Blood and lymphatic system disorders: | Leucopenia, anemia, aplastic anemia, thrombopenia, pancytopenia, agranulocytosis, lymphadenopathy and lymphoproliferative disorders (including reversible), neutropenia and eosinophilia have also been observed. |
| Cardiac disorders: | Pericarditis and pericardial effusion (damage to heart, rarely). |
| Eye disorders: | Conjunctivitis, blurred vision, serious visual changes of unknown etiology, and transient blindness/vision loss. |
| Gastrointestinal disorders: | Gingivitis, stomatitis, enteritis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, pancreatitis, intestinal perforation, non-infectious peritonitis, glossitis. |
| General disorders and administration site conditions: | Anaphylactoid reactions, vasculitis, fever, conjunctivitis, infection, sepsis, nodulosis, hypogammaglobulinaemia, and sudden death. |
| Hepatobiliary disorders: | Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations, hepatic failure. |
| Infection: | Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, and disseminated H. simplex, cytomegalovirus infection, including cytomegaloviral pneumonia. |
| Metabolism and nutrition disorders: | Diabetes mellitus. |
| Musculoskeletal, connective tissue and bone disorders: | Stress fractures, soft tissue necrosis, osteonecrosis, arthralgia, myalgia and osteoporosis. |
| Neoplasms benign, malignant and unspecified (including cysts and polyps): | Tumour lysis syndrome. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate, and thus may not require cytotoxic treatment. Discontinue Methotrexate Injection USP first and, if the lymphoma does not regress, appropriate treatment should be instituted. |
| Nervous system: | Cerebrospinal fluid pressure increased, neurotoxicity, arachnoiditis, paresthesia, headache, dizziness, drowsiness, speech impediment including dysarthria and aphasia; hemiparesis, paresis and convulsions. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations, leukoencephalopathy, or encephalopathy. |
| Renal and urinary disorders: | Renal failure, severe nephropathy or renal failure, azotemia, dysuria, cystitis, hematuria, urogenital dysfunction. Proteinuria has also been observed. |
| Reproductive system and breast disorders: | Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge and gynecomastia; infertility, abortion, fetal defects, loss of libido/impotence. |
| Respiratory, thoracic and mediastinal disorders: | Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, pulmonary fibrosis, Pneumocystis carinii pneumonia, pleural effusion. Dyspnea, chest pain, hypoxia, respiratory fibrosis, pharyngitis, and chronic interstitial obstructive pulmonary disease and alveolitis have occasionally occurred. |
| Skin disorders: | Erythema, pruritus, photosensitisation, petechiae, loss of hair, skin necrosis, exfoliative dermatitis, painful erosion of psoriatic plaques, herpes zoster, vasculitis, urticaria, pigmentary changes, acne, ecchymosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), furunculosis and telangiectasia. Drug reaction with eosinophilia and systemic symptoms. |
| Vascular disorders: | Hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), vasculitis. |
Adverse Reactions Reported in Rheumatoid Arthritis:
- Alopecia (common)
- Diarrhea (common)
- Dizziness (common)
- Elevated liver enzymes (very common)
- Leucopenia (common)
- Nausea/vomiting (very common)
- Pancytopenia (common)
- Rash/pruritus/dermatitis (common)
- Stomatitis (common)
- Thrombocytopenia (common)
Adverse Reactions in Psoriasis:
The adverse reaction rates reported are very similar to those in the rheumatoid arthritis studies. Rarely, painful psoriatic plaque erosions may appear.
Abnormal Hematologic and Clinical Chemistry Findings
See WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests section.
Post-Market Adverse Drug Reactions
Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse events have also been reported during post-marketing experience with methotrexate:
|
System Organ Class |
Adverse Reaction |
|
Infections and Infestations |
Infections (including fatal sepsis); Pneumonia; Pneumocystis carinii pneumonia; Nocardiosis; Histoplasmosis; Cryptococcosis; Herpes zoster; H. simplex hepatitis; Disseminated H. simplex; Cytomegalovirus infection (including cytomegaloviral pneumonia); Reactivation of hepatitis B infection; Worsening of hepatitis C infection |
|
Blood and Lymphatic System Disorders |
Agranulocytosis; Pancytopenia; Leukopenia; Neutropenia; Lymphadenopathy and lymphoproliferative disorders (including reversible); Eosinophilia; Anemia megaloblastic; Renal vein thrombosis; Lymphoma; Aplastic anemia; Hypogammaglobulinemia |
|
Nervous System Disorders |
CSF pressure increased; Neurotoxicity; Arachnoiditis; Paraplegia; Stupor; Ataxia; Dementia; Dizziness; Paresthesia |
|
Respiratory, Thoracic and Mediastinal Disorders |
Chronic interstitial pulmonary disease; Alveolitis; Dyspnea; Chest pain; Hypoxia; Cough; Plural effusion |
|
Gastrointestinal Disorders |
Intestinal perforation; Noninfectious peritonitis; Glossitis; Nausea; Pancreatitis |
|
Hepatobiliary Disorders |
Hepatic failure |
|
Skin and Subcutaneous Tissue Disorders |
Drug reaction with eosinophilia and systemic symptoms; Dermatitis; Petechiae |
|
Musculoskeletal, Connective Tissue and Bone Disorders |
Osteonecrosis |
|
Renal and Urinary Disorders |
Proteinuria |
|
Pregnancy, Puerperium and Perinatal Conditions |
Fetal death, Abortion |
|
Reproductive System and Breast Disorders |
Urogenital dysfunction |
|
General Disorders and Administration Site Conditions |
Pyrexia; Chills; Malaise; Fatigue; Anaphylactic reactions |
|
Endocrine Disorders |
Diabetes |
|
Ophthalmologic Disorders |
Transient blindness/vision loss |