Rheumatoid arthritis toxicity criteria and severity descriptors

Toxicity criteria and severity descriptors for PBS-listed rheumatoid arthritis biological agents.

Toxicity criteria and severity descriptors for the listing of biological agents for rheumatoid arthritis on the PBS.

ALT - alanine aminotransferase
AST - aspartate aminotransferase
BP - blood pressure
ECG - electrocardiogram
IV - intravenous
NIH - National Institutes of Health
ULN - upper limit of normal
WCC - white cell count

Azathioprine

Only valid for adult patients. Azathioprine must be at a dose of at least 1 mg per kg per day.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools per day over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Ç Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Pulmonary
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)
Infection Severe, systemic infection, requiring IV antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Cyclosporin

Only valid for adult patients. Cyclosporin must be at a dose of at least 2 mg per kg per day.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Cardiovascular
Hypertension Recurrent or persistent rise of > 20 mmHg diastolic BP or rise to > 150 over 90 on 2 occasions if BP previously normal 2 (or higher)
Fluid retention Symptomatic, limiting function, unresponsive to therapy or requiring drug discontinuation 3 (or higher)
Dermatology or skin
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Weight gain or loss 20% or more weight gain or loss 3 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Musculoskeletal
Muscle weakness Symptomatic and interfering with function 2 (or higher)
Neurology or senses
Ataxia (incoordination) Mild symptoms interfering with function but not interfering with activities of daily living 2 (or higher)
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria > 1.0 g per24 hours, elevated urine protein-creatinine ratios, (dipstick protein ++ or greater), confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine > 1.5 ULN or creatinine clearance < 30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)
Hyperkalaemia Potassium > 6 mmol per L 3 (or higher)
Infection Severe, systemic infection, requiring IV antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Sodium aurothiomalate

Only valid for adult patients. Sodium aurothiomalate must be at a dose of at least 50 mg weekly.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Eosinophilia Persistent or unexplained eosinophilia > 1 x 109 per L
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Neurology or senses
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Syncope (fainting) Present 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Vision - cornea or retina Symptomatic corneal or lenticular changes present 1 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment. 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (for example, cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging
(refer Searles McKendry criteria)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria > 1.0 g per 24 hours, elevated urine protein-creatinine ratios, (dipstick protein ++ or greater), confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine > 1.5 ULN or creatinine clearance < 30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)

Hydroxychloroquine

Only valid for adult patients. Hydroxychloroquine must be at a dose of at least 200 mg daily.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Musculoskeletal
Muscle weakness Symptomatic and interfering with function 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Neuropathy - motor Objective weakness interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Vision - cornea or retina Symptomatic corneal or retinal changes present 1 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)

Leflunomide

Only valid for adult patients. Leflunomide must be at a dose of at least 10 mg daily.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Cardiovascular
Arrhythmia Symptomatic and requiring therapy 3 (or higher)
Hypertension Recurrent or persistent rise of > 20 mmHg diastolic BP or rise to > 150 over 90 on 2 occasions if BP previously normal 2 (or higher)
Fluid retention Symptomatic, limiting function, unresponsive to therapy or requiring drug discontinuation 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Weight gain or loss 20% or more weight gain or loss 3 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (for example, cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging (refer Searles McKendry criteria) Refer Searles McKendry criteria
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria > 1.0 g per 24 hours, elevated urine protein-creatinine ratios, (dipstick protein ++ or greater), confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine > 1.5 ULN or creatinine clearance < 30 mL permin 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)
Hypokalaemia Potassium < 3 mmol per L 3 (or higher)
Infection Severe, systemic infection, requiring IV antimicrobial treatment or hospitalisation 3 (or higher)
Secondary malignancy Secondary malignancy present 4

Methotrexate

Only valid for adult patients. Methotrexate must be at a dose of at least 20 mg weekly.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Cardiovascular
Pericardial effusion or pericarditis Pericarditis (pericardial rub, ECG changes or chest pain) 2 (or higher)
Thrombosis or embolism Requiring anticoagulant therapy 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased, and symptoms do not improve with at least 2 of the following measures:
  1. reduction of the methotrexate dose
  2. folinic acid or folic acid supplementation
  3. switching from oral to intramuscular dosing
  4. dividing the methotrexate dose over 12 hours

A minimum of 3 doses of methotrexate should have been trialled

2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Musculoskeletal
Osteonecrosis
(avascular necrosis)
Symptomatic and interfering with function 2 (or higher)
Osteoporosis Symptomatic and requiring treatment 3 (or higher)
Neurology or senses
Decreased level of consciousness Somnolence or sedation interfering with function but not interfering with activities of daily living 2 (or higher)
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Vision Symptomatic and interfering with function but not interfering with activities of daily living 2 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment. 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary symptoms - new or worsening (probable drug-induced pneumonitis) Development of syndrome consistent with drug-induced pneumonitis (for example, cough, dyspnoea, fever, hypoxaemia) with lung infiltrates on imaging
(refer Searles McKendry criteria)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine > 1.5 ULN or creatinine clearance < 30 mL per min 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fatigue, malaise Severe, loss of ability to perform some activities 3 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)
Infection Severe, systemic infection, requiring IV antimicrobial treatment or hospitalisation 3 (or higher)
Nodulosis (following introduction of methotrexate therapy) Development of multiple new nodules causing significant local pressure symptoms and distress to patient
Secondary malignancy Secondary malignancy present 4

Sulfasalazine

Only valid for adult patients. Sulfasalazine must be at a dose of at least 2 g daily.

Adverse event Brief description of minimum grade NIH common toxicity criteria grade
Blood or bone marrow
Anaemia Haemoglobin < 80 g per L 3 (or higher)
Leukopenia Total WCC < 3 x 109 per L 2 (or higher)
Thrombocytopenia Platelets < 50 x 109 per L 3 (or higher)
Neutropenia Total neutrophils < 1.0 x 109 per L 3 (or higher)
Dermatology or skin
Alopecia Pronounced hair loss 2 (or higher)
Rash or desquamation Scattered macular or papular eruption or erythema with pruritis or other associated symptoms covering < 50% of body surface or localised desquamation or other lesions covering < 50% of body 2 (or higher)
Gastrointestinal
Diarrhoea Increase of 4-6 stools perday over pretreatment 2 (or higher)
Nausea Oral intake significantly decreased 2 (or higher)
Pancreatitis Abdominal pain with pancreatic enzyme elevation 3 (or higher)
Stomatitis Painful erythema, oedema or ulcers but able to eat or swallow 2 (or higher)
Vomiting 2 or more episodes per 24 hours over pretreatment 2 (or higher)
Hepatic
Bilirubin > 1.5 x ULN 2 (or higher)
Transaminases ALT or AST > 2.5 x ULN or ALT or AST > 1.5 x ULN on 3 occasions over a 3-month period 2 (or higher)
Serum alkaline phosphatase 2.5 x ULN 2 (or higher)
Neurology or senses
Headaches (severe) Severe pain; pain or analgesics severely interfere with activities of daily living 3 (or higher)
Hearing Tinnitus or hearing loss not requiring hearing aid or treatment 2 (or higher)
Mood alteration Moderate mood alteration interfering with function but not interfering with activities of daily living 2 (or higher)
Neuropathy - sensory Objective sensory loss or paraesthesia interfering with function but not interfering with activities of daily living 2 (or higher)
Seizure(s) Seizures in which consciousness is altered 3 (or higher)
Pulmonary
Cough (severe) Severe cough or coughing spasm, poor control or unresponsive to treatment. Evidence of reversal on cessation of treatment 3 (or higher)
Pneumonitis or pulmonary infiltrates Radiographic changes, respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Pulmonary fibrosis Respiratory function test abnormalities and requiring steroids or diuretics 2 (or higher)
Renal
Haematuria Macroscopic (or dipstick +++) confirmed on 2 separate occasions 2 (or higher)
Proteinuria > 1.0 g per24 hours, elevated urine protein-creatinine ratios, (dipstick protein ++ or greater), confirmed on 2 separate occasions 2 (or higher)
Renal impairment Creatinine > 1.5 ULN or creatinine clearance < 30 mL permin 2 (or higher)
Other
Allergic reaction Urticaria, drug fever > 38 °C or bronchospasm 2 (or higher)
Fever (in the absence of neutropenia) Body temp > 39 °C (oral or tympanic) 2 (or higher)

Page last updated: 25 January 2016

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