Study: NCT00347919

Adverse event: Diarrhoea
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 2 affected / 73 at risk

Adverse event: Vomiting
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 1 affected / 73 at risk

Adverse event: Hepatic failure
Serious: yes
Organ System: Hepatobiliary disorders
Frequency: 1 affected / 73 at risk

Adverse event: Gastroenteritis
Serious: yes
Organ System: Infections and infestations
Frequency: 1 affected / 73 at risk

Adverse event: Femoral neck fracture
Serious: yes
Organ System: Injury, poisoning and procedural complications
Frequency: 1 affected / 73 at risk

Adverse event: Dehydration
Serious: yes
Organ System: Metabolism and nutrition disorders
Frequency: 3 affected / 73 at risk

Adverse event: Somnolence
Serious: yes
Organ System: Nervous system disorders
Frequency: 1 affected / 73 at risk

Adverse event: Dyspnoea
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 2 affected / 73 at risk

Adverse event: Epistaxis
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 1 affected / 73 at risk

Adverse event: Pleural effusion
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 1 affected / 73 at risk

Adverse event: Anaemia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 4 affected / 73 at risk

Adverse event: Abdominal distension
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 8 affected / 73 at risk

Adverse event: Abdominal pain
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 3 affected / 73 at risk

Adverse event: Abdominal pain upper
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 2 affected / 73 at risk

Adverse event: Constipation
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 4 affected / 73 at risk

Adverse event: Diarrhoea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 41 affected / 73 at risk

Adverse event: Dyspepsia
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 6 affected / 73 at risk

Adverse event: Nausea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 13 affected / 73 at risk

Adverse event: Stomatitis
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 5 affected / 73 at risk

Adverse event: Vomiting
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 6 affected / 73 at risk

Adverse event: Asthenia
Serious: no
Organ System: General disorders
Frequency: 9 affected / 73 at risk

Adverse event: Fatigue
Serious: no
Organ System: General disorders
Frequency: 7 affected / 73 at risk

Adverse event: Pyrexia
Serious: no
Organ System: Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Frequency: 7 affected / 73 at risk

Adverse event: Urinary tract infection
Serious: no
Organ System: Infections and infestations
Frequency: 7 affected / 73 at risk

Adverse event: Alanine aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 13 affected / 73 at risk

Adverse event: Aspartate aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 13 affected / 73 at risk

Adverse event: Blood bilirubin increased
Serious: no
Organ System: Investigations
Frequency: 3 affected / 73 at risk

Adverse event: Weight decreased
Serious: no
Organ System: Investigations
Frequency: 3 affected / 73 at risk

Adverse event: Blood alkaline phosphatase increased
Serious: no
Organ System: Investigations
Frequency: 10 affected / 73 at risk

Adverse event: Decreased appetite
Serious: no
Organ System: Metabolism and nutrition disorders
Frequency: 10 affected / 73 at risk

Adverse event: Back pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 5 affected / 73 at risk

Adverse event: Pain in extremity
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 8 affected / 73 at risk

Adverse event: Dizziness
Serious: no
Organ System: Nervous system disorders
Frequency: 6 affected / 73 at risk

Adverse event: Dysgeusia
Serious: no
Organ System: Nervous system disorders
Frequency: 1 affected / 73 at risk

Adverse event: Headache
Serious: no
Organ System: Nervous system disorders
Frequency: 7 affected / 73 at risk

Adverse event: Insomnia
Serious: no
Organ System: Psychiatric disorders
Frequency: 1 affected / 73 at risk

Adverse event: Proteinuria
Serious: no
Organ System: Renal and urinary disorders
Frequency: 2 affected / 73 at risk

Adverse event: Cough
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 5 affected / 73 at risk

Adverse event: Epistaxis
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 4 affected / 73 at risk

Adverse event: Oropharyngeal pain
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 4 affected / 73 at risk

Adverse event: Alopecia
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 3 affected / 73 at risk

Adverse event: Dermatitis acneiform
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 3 affected / 73 at risk

Adverse event: Dry skin
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 7 affected / 73 at risk

Adverse event: Pruritus
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 10 affected / 73 at risk

Adverse event: Rash
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 21 affected / 73 at risk

Adverse event: Hypertension
Serious: no
Organ System: Vascular disorders
Frequency: 4 affected / 73 at risk

Adverse event: Anaemia
Serious: yes
Organ System: Blood and lymphatic system disorders
Frequency: 2 affected / 76 at risk

Adverse event: Left ventricular dysfunction
Serious: yes
Organ System: Cardiac disorders
Frequency: 2 affected / 76 at risk

Adverse event: Diarrhoea
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 1 affected / 76 at risk

Adverse event: Oesophagitis
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 1 affected / 76 at risk

Adverse event: Fatigue
Serious: yes
Organ System: General disorders
Frequency: 1 affected / 76 at risk

Adverse event: Pyrexia
Serious: yes
Organ System: General disorders
Frequency: 1 affected / 76 at risk

Adverse event: Hypersensitivity
Serious: yes
Organ System: Immune system disorders
Frequency: 1 affected / 76 at risk

Adverse event: Gastroenteritis
Serious: yes
Organ System: Infections and infestations
Frequency: 1 affected / 76 at risk

Adverse event: Ejection fraction decreased
Serious: yes
Organ System: Investigations
Frequency: 3 affected / 76 at risk

Adverse event: Hyponatraemia
Serious: yes
Organ System: Metabolism and nutrition disorders
Frequency: 1 affected / 76 at risk

Adverse event: Dyspnoea
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 1 affected / 76 at risk

Adverse event: Pleural effusion
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 2 affected / 76 at risk

Adverse event: Pneumothorax
Serious: yes
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 1 affected / 76 at risk

Adverse event: Hypertension
Serious: yes
Organ System: Vascular disorders
Frequency: 1 affected / 76 at risk

Adverse event: Embolism
Serious: yes
Organ System: Vascular disorders
Frequency: 1 affected / 76 at risk

Adverse event: Anaemia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 4 affected / 76 at risk

Adverse event: Leukopenia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 6 affected / 76 at risk

Adverse event: Hypothyroidism
Serious: no
Organ System: Endocrine disorders
Frequency: 6 affected / 76 at risk

Adverse event: Abdominal distension
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 3 affected / 76 at risk

Adverse event: Abdominal pain
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 7 affected / 76 at risk

Adverse event: Abdominal pain upper
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 7 affected / 76 at risk

Adverse event: Diarrhoea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 52 affected / 76 at risk

Adverse event: Dyspepsia
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 8 affected / 76 at risk

Adverse event: Nausea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 23 affected / 76 at risk

Adverse event: Stomatitis
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 5 affected / 76 at risk

Adverse event: Vomiting
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 15 affected / 76 at risk

Adverse event: Asthenia
Serious: no
Organ System: General disorders
Frequency: 9 affected / 76 at risk

Adverse event: Fatigue
Serious: no
Organ System: General disorders
Frequency: 12 affected / 76 at risk

Adverse event: Pyrexia
Serious: no
Organ System: Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Frequency: 6 affected / 76 at risk

Adverse event: Urinary tract infection
Serious: no
Organ System: Infections and infestations
Frequency: 4 affected / 76 at risk

Adverse event: Alanine aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 25 affected / 76 at risk

Adverse event: Aspartate aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 26 affected / 76 at risk

Adverse event: Blood bilirubin increased
Serious: no
Organ System: Investigations
Frequency: 10 affected / 76 at risk

Adverse event: Crystal urine present
Serious: no
Organ System: Investigations
Frequency: 5 affected / 76 at risk

Adverse event: Electrocardiogram QT prolonged
Serious: no
Organ System: Investigations
Frequency: 4 affected / 76 at risk

Adverse event: Weight decreased
Serious: no
Organ System: Investigations
Frequency: 8 affected / 76 at risk

Adverse event: Blood alkaline phosphatase increased
Serious: no
Organ System: Investigations
Frequency: 9 affected / 76 at risk

Adverse event: Hyponatraemia
Serious: no
Organ System: Metabolism and nutrition disorders
Frequency: 4 affected / 76 at risk

Adverse event: Decreased appetite
Serious: no
Organ System: Metabolism and nutrition disorders
Frequency: 17 affected / 76 at risk

Adverse event: Back pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 4 affected / 76 at risk

Adverse event: Pain in extremity
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 9 affected / 76 at risk

Adverse event: Dizziness
Serious: no
Organ System: Nervous system disorders
Frequency: 4 affected / 76 at risk

Adverse event: Dysgeusia
Serious: no
Organ System: Nervous system disorders
Frequency: 12 affected / 76 at risk

Adverse event: Headache
Serious: no
Organ System: Nervous system disorders
Frequency: 6 affected / 76 at risk

Adverse event: Insomnia
Serious: no
Organ System: Psychiatric disorders
Frequency: 8 affected / 76 at risk

Adverse event: Proteinuria
Serious: no
Organ System: Renal and urinary disorders
Frequency: 8 affected / 76 at risk

Adverse event: Cough
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 7 affected / 76 at risk

Adverse event: Epistaxis
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 7 affected / 76 at risk

Adverse event: Oropharyngeal pain
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 5 affected / 76 at risk

Adverse event: Alopecia
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 11 affected / 76 at risk

Adverse event: Dermatitis acneiform
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 5 affected / 76 at risk

Adverse event: Dry skin
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 5 affected / 76 at risk

Adverse event: Hair colour changes
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 14 affected / 76 at risk

Adverse event: Pruritus
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 5 affected / 76 at risk

Adverse event: Rash
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 21 affected / 76 at risk

Adverse event: Skin hypopigmentation
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 4 affected / 76 at risk

Adverse event: Hypertension
Serious: no
Organ System: Vascular disorders
Frequency: 20 affected / 76 at risk

Adverse event: Febrile neutropenia
Serious: yes
Organ System: Blood and lymphatic system disorders
Frequency: 1 affected / 40 at risk

Adverse event: Thrombocytopenia
Serious: yes
Organ System: Blood and lymphatic system disorders
Frequency: 1 affected / 40 at risk

Adverse event: Diarrhoea
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 3 affected / 40 at risk

Adverse event: Abdominal pain upper
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 1 affected / 40 at risk

Adverse event: Colitis
Serious: yes
Organ System: Gastrointestinal disorders
Frequency: 1 affected / 40 at risk

Adverse event: Pyrexia
Serious: yes
Organ System: General disorders
Frequency: 4 affected / 40 at risk

Adverse event: Cholecystitis
Serious: yes
Organ System: Hepatobiliary disorders
Frequency: 1 affected / 40 at risk

Adverse event: Cellulitis
Serious: yes
Organ System: Infections and infestations
Frequency: 1 affected / 40 at risk

Adverse event: Upper limb fracture
Serious: yes
Organ System: Injury, poisoning and procedural complications
Frequency: 1 affected / 40 at risk

Adverse event: Ejection fraction decreased
Serious: yes
Organ System: Investigations
Frequency: 2 affected / 40 at risk

Adverse event: Alanine aminotransferase increased
Serious: yes
Organ System: Investigations
Frequency: 1 affected / 40 at risk

Adverse event: Aspartate aminotransferase increased
Serious: yes
Organ System: Investigations
Frequency: 1 affected / 40 at risk

Adverse event: Hepatic enzyme increased
Serious: yes
Organ System: Investigations
Frequency: 3 affected / 40 at risk

Adverse event: Dehydration
Serious: yes
Organ System: Metabolism and nutrition disorders
Frequency: 1 affected / 40 at risk

Adverse event: Hyponatraemia
Serious: yes
Organ System: Metabolism and nutrition disorders
Frequency: 1 affected / 40 at risk

Adverse event: Metastases to central nervous system
Serious: yes
Organ System: Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Frequency: 1 affected / 40 at risk

Adverse event: Dizziness
Serious: yes
Organ System: Nervous system disorders
Frequency: 1 affected / 40 at risk

Adverse event: Hydronephrosis
Serious: yes
Organ System: Renal and urinary disorders
Frequency: 1 affected / 40 at risk

Adverse event: Leukopenia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 2 affected / 40 at risk

Adverse event: Neutropenia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 2 affected / 40 at risk

Adverse event: Thrombocytopenia
Serious: no
Organ System: Blood and lymphatic system disorders
Frequency: 3 affected / 40 at risk

Adverse event: Left ventricular dysfunction
Serious: no
Organ System: Cardiac disorders
Frequency: 3 affected / 40 at risk

Adverse event: Tinnitus
Serious: no
Organ System: Ear and labyrinth disorders
Frequency: 2 affected / 40 at risk

Adverse event: Eye pain
Serious: no
Organ System: Eye disorders
Frequency: 2 affected / 40 at risk

Adverse event: Abdominal discomfort
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 2 affected / 40 at risk

Adverse event: Abdominal pain
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 11 affected / 40 at risk

Adverse event: Abdominal pain upper
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 3 affected / 40 at risk

Adverse event: Constipation
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 2 affected / 40 at risk

Adverse event: Diarrhoea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 34 affected / 40 at risk

Adverse event: Dry mouth
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 3 affected / 40 at risk

Adverse event: Dyspepsia
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 7 affected / 40 at risk

Adverse event: Nausea
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 28 affected / 40 at risk

Adverse event: Rectal haemorrhage
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 2 affected / 40 at risk

Adverse event: Stomatitis
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 5 affected / 40 at risk

Adverse event: Vomiting
Serious: no
Organ System: Gastrointestinal disorders
Frequency: 13 affected / 40 at risk

Adverse event: Asthenia
Serious: no
Organ System: General disorders
Frequency: 5 affected / 40 at risk

Adverse event: Chest discomfort
Serious: no
Organ System: General disorders
Frequency: 3 affected / 40 at risk

Adverse event: Chest pain
Serious: no
Organ System: General disorders
Frequency: 4 affected / 40 at risk

Adverse event: Fatigue
Serious: no
Organ System: General disorders
Frequency: 23 affected / 40 at risk

Adverse event: Mucosal inflammation
Serious: no
Organ System: General disorders
Frequency: 2 affected / 40 at risk

Adverse event: Pain
Serious: no
Organ System: General disorders
Frequency: 2 affected / 40 at risk

Adverse event: Hyperbilirubinaemia
Serious: no
Organ System: Hepatobiliary disorders
Frequency: 3 affected / 40 at risk

Adverse event: Urinary tract infection
Serious: no
Organ System: Infections and infestations
Frequency: 2 affected / 40 at risk

Adverse event: Paronychia
Serious: no
Organ System: Infections and infestations
Frequency: 3 affected / 40 at risk

Adverse event: Alanine aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 15 affected / 40 at risk

Adverse event: Aspartate aminotransferase increased
Serious: no
Organ System: Investigations
Frequency: 15 affected / 40 at risk

Adverse event: Blood thyroid stimulating hormone increased
Serious: no
Organ System: Investigations
Frequency: 7 affected / 40 at risk

Adverse event: Platelet count decreased
Serious: no
Organ System: Investigations
Frequency: 3 affected / 40 at risk

Adverse event: Weight decreased
Serious: no
Organ System: Investigations
Frequency: 5 affected / 40 at risk

Adverse event: Ejection fraction decreased
Serious: no
Organ System: Investigations
Frequency: 2 affected / 40 at risk

Adverse event: Blood alkaline phosphatase increased
Serious: no
Organ System: Investigations
Frequency: 5 affected / 40 at risk

Adverse event: Hypokalaemia
Serious: no
Organ System: Metabolism and nutrition disorders
Frequency: 4 affected / 40 at risk

Adverse event: Decreased appetite
Serious: no
Organ System: Metabolism and nutrition disorders
Frequency: 14 affected / 40 at risk

Adverse event: Arthralgia
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 6 affected / 40 at risk

Adverse event: Back pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 5 affected / 40 at risk

Adverse event: Musculoskeletal pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 4 affected / 40 at risk

Adverse event: Myalgia
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 3 affected / 40 at risk

Adverse event: Neck pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 3 affected / 40 at risk

Adverse event: Pain in extremity
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 4 affected / 40 at risk

Adverse event: Musculoskeletal chest pain
Serious: no
Organ System: Musculoskeletal and connective tissue disorders
Frequency: 3 affected / 40 at risk

Adverse event: Dizziness
Serious: no
Organ System: Nervous system disorders
Frequency: 7 affected / 40 at risk

Adverse event: Dysgeusia
Serious: no
Organ System: Nervous system disorders
Frequency: 12 affected / 40 at risk

Adverse event: Headache
Serious: no
Organ System: Nervous system disorders
Frequency: 11 affected / 40 at risk

Adverse event: Neuropathy peripheral
Serious: no
Organ System: Nervous system disorders
Frequency: 2 affected / 40 at risk

Adverse event: Insomnia
Serious: no
Organ System: Psychiatric disorders
Frequency: 5 affected / 40 at risk

Adverse event: Depression
Serious: no
Organ System: Psychiatric disorders
Frequency: 3 affected / 40 at risk

Adverse event: Haematuria
Serious: no
Organ System: Renal and urinary disorders
Frequency: 2 affected / 40 at risk

Adverse event: Breast pain
Serious: no
Organ System: Reproductive system and breast disorders
Frequency: 4 affected / 40 at risk

Adverse event: Cough
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 2 affected / 40 at risk

Adverse event: Dysphonia
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 2 affected / 40 at risk

Adverse event: Epistaxis
Serious: no
Organ System: Respiratory, thoracic and mediastinal disorders
Frequency: 13 affected / 40 at risk

Adverse event: Alopecia
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 10 affected / 40 at risk

Adverse event: Dermatitis acneiform
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 2 affected / 40 at risk

Adverse event: Dry skin
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 2 affected / 40 at risk

Adverse event: Hair colour changes
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 11 affected / 40 at risk

Adverse event: Nail disorder
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 3 affected / 40 at risk

Adverse event: Palmar-plantar erythrodysaesthesia syndrome
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 3 affected / 40 at risk

Adverse event: Pruritus
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 4 affected / 40 at risk

Adverse event: Rash
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 16 affected / 40 at risk

Adverse event: Rash macular
Serious: no
Organ System: Skin and subcutaneous tissue disorders
Frequency: 2 affected / 40 at risk

Adverse event: Hypertension
Serious: no
Organ System: Vascular disorders
Frequency: 15 affected / 40 at risk

Adverse event: Hot flush
Serious: no
Organ System: Vascular disorders
Frequency: 2 affected / 40 at risk