METHOTREXATE, VIALS 8 Adverse Reactions

methotrexate, vials

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8.1 Adverse 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 7 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. 

Table 11: Adverse Drug Reactions by Organ System 

Table 11 provides an overview of adverse reactions observed with methotrexate use 

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, Injection site reaction, Injection site necrosis, 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.

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, alveolitis and pulmonary alveolar haemorrhage 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. 

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings 

(See 7 Warnings and Precautions: Monitoring and Laboratory Tests). 

8.5 Post-Market Adverse 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:

Table 12:  Post-Market Adverse Reactions

System Organ Class

Adverse Reaction

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

Endocrine Disorders

Diabetes

General Disorders and Administration Site Conditions

Pyrexia; Chills; Malaise; Fatigue; Injection site reaction; Injection site necrosis; Anaphylactic reactions

Gastrointestinal Disorders

Intestinal perforation; Noninfectious peritonitis; Glossitis; Nausea; Pancreatitis

Hepatobiliary Disorders

Hepatic failure

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

Musculoskeletal, Connective Tissue and Bone Disorders

Osteonecrosis

Nervous System Disorders

CSF pressure increased; Neurotoxicity; Arachnoiditis; Paraplegia; Stupor; Ataxia; Dementia; Dizziness; Paresthesia

Ophthalmologic Disorders

Transient blindness/vision loss

Pregnancy, Puerperium and Perinatal Conditions

Fetal death, Abortion

Renal and Urinary Disorders

Proteinuria

Reproductive System and Breast Disorders

Urogenital dysfunction

Respiratory, Thoracic and Mediastinal Disorders

Chronic interstitial pulmonary disease; Alveolitis; Dyspnea; Chest pain; Hypoxia; Cough; Plural effusion

Skin and Subcutaneous Tissue Disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS); Dermatitis; Petechiae

 

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8 Adverse Reactions

8.1 Adverse 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 7 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. 

Table 11: Adverse Drug Reactions by Organ System 

Table 11 provides an overview of adverse reactions observed with methotrexate use 

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, Injection site reaction, Injection site necrosis, 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.

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, alveolitis and pulmonary alveolar haemorrhage 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. 

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings 

(See 7 Warnings and Precautions: Monitoring and Laboratory Tests). 

8.5 Post-Market Adverse 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:

Table 12:  Post-Market Adverse Reactions

System Organ Class

Adverse Reaction

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

Endocrine Disorders

Diabetes

General Disorders and Administration Site Conditions

Pyrexia; Chills; Malaise; Fatigue; Injection site reaction; Injection site necrosis; Anaphylactic reactions

Gastrointestinal Disorders

Intestinal perforation; Noninfectious peritonitis; Glossitis; Nausea; Pancreatitis

Hepatobiliary Disorders

Hepatic failure

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

Musculoskeletal, Connective Tissue and Bone Disorders

Osteonecrosis

Nervous System Disorders

CSF pressure increased; Neurotoxicity; Arachnoiditis; Paraplegia; Stupor; Ataxia; Dementia; Dizziness; Paresthesia

Ophthalmologic Disorders

Transient blindness/vision loss

Pregnancy, Puerperium and Perinatal Conditions

Fetal death, Abortion

Renal and Urinary Disorders

Proteinuria

Reproductive System and Breast Disorders

Urogenital dysfunction

Respiratory, Thoracic and Mediastinal Disorders

Chronic interstitial pulmonary disease; Alveolitis; Dyspnea; Chest pain; Hypoxia; Cough; Plural effusion

Skin and Subcutaneous Tissue Disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS); Dermatitis; Petechiae

 

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