Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) Plus Taxane-Based Therapy in Patients With Locally Recurrent or Metastatic Breast Cancer. (NCT NCT00448591)

Last Updated: 2015-05-25

Results Overview

Adverse events (including laboratory abnormalities) were assessed by the investigator according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) grading systems.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2296 participants

Primary outcome timeframe

Day 1 of Cycles 1, 2, 3, 4, 5, and 6 up to 6 months after the last bevacizumab infusion

Results posted on

2015-05-25

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab Participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (iv) on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) until disease progression, unacceptable toxicity or withdrawal, along with Taxane-based chemotherapy or in combination with other chemotherapy as prescribed.
Overall Study STARTED	2296
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	2296

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab Participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (iv) on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) until disease progression, unacceptable toxicity or withdrawal, along with Taxane-based chemotherapy or in combination with other chemotherapy as prescribed.
Overall Study Withdrawal by Subject	178
Overall Study Progressive Disease	1382
Overall Study Adverse Event	382
Overall Study Protocol Violation	41
Overall Study Lost to Follow-up	19
Overall Study Treatment Regimen Completed	70
Overall Study Other	154
Overall Study Termination of Study	70

Baseline Characteristics

A Study of Avastin (Bevacizumab) Plus Taxane-Based Therapy in Patients With Locally Recurrent or Metastatic Breast Cancer.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on day 1 of each 3 week cycle, or 10 mg/kg iv on day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) until disease progression, unacceptable toxicity or withdrawal, along with Taxane-based chemotherapy as prescribed
Age, Continuous	53.2 years STANDARD_DEVIATION 11.0 • n=99 Participants
Sex: Female, Male Female	2252 Participants n=99 Participants
Sex: Female, Male Male	12 Participants n=99 Participants

PRIMARY outcome

Timeframe: Day 1 of Cycles 1, 2, 3, 4, 5, and 6 up to 6 months after the last bevacizumab infusion

Population: Safety Population

Adverse events (including laboratory abnormalities) were assessed by the investigator according to the National Cancer Institute - Common Toxicity Criteria (NCI-CTC) grading systems.

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) Any AE	95.4 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) CTC grade 3, 4 or 5 AE	57.6 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) Bevacizumab-related AE	64.2 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) Any Serious AE	29.7 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) Bevacizumab-related serious SAE	7.6 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) All deaths	53.1 percentage of participants
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Related to Bevacizumab, Death, and AEs of Special Interest (AESIs) AESIs	71.8 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 4, final visit and every 3 months during follow-up until disease progression or death up to 45 months

Population: ITT Population

Disease progression was assessed by the investigator per standard clinical practice using Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Percentage of Participants With Disease Progression	72.44 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 4, final visit and every 3 months during follow-up until disease progression or death up to 45 months

Population: ITT Population

TTP was defined as the time period from the start of first-line therapy to investigator-assessed disease progression. Tumor assessments were performed according to standard clinical practice using NCI criteria. Participants who had not progressed at the time of analysis (including those who died before progressive disease \[PD\]) or who were lost to follow-up were censored at the last bevacizumab administration date. Time to disease progression was determined by Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Time to Progression (TTP)	9.7 months Interval 9.4 to 10.1

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 4, final visit and every 3 months during follow-up until disease progression or death up to 45 months

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Percentage of Participants With Recorded Death	53.14 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 4, Final Visit and every 3 months during follow-up until death up to 45 months

Population: ITT Population

Overall Survival was defined as the time from start of first-line therapy to death due to any cause. Participants for whom no death was captured in the clinical database were censored at the last date they were known to be alive. Median time to overall survival was calculated by Kaplan Meier estimates.

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Overall Survival	25.2 months Interval 24.0 to 26.3

SECONDARY outcome

Timeframe: Baseline, Day 1 of Cycle 4, final visit and every 3 months during follow-up until disease progression or death up to 45 months

Population: ITT Population

Best overall response is defined as the best response shown throughout the study. Tumor assessment was performed by the investigator using standard clinical practice.

Outcome measures

Outcome measures
Measure	Bevacizumab n=2264 Participants Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) along with Taxane-based chemotherapy as prescribed
Percentage of Participants by Best Overall Response to Treatment Complete response	9.0 percentage of participants
Percentage of Participants by Best Overall Response to Treatment Partial response	45.1 percentage of participants
Percentage of Participants by Best Overall Response to Treatment Stable disease	32.4 percentage of participants
Percentage of Participants by Best Overall Response to Treatment Progressive disease	9.1 percentage of participants
Percentage of Participants by Best Overall Response to Treatment Not evaluable	0.1 percentage of participants
Percentage of Participants by Best Overall Response to Treatment Assessment not done	4.2 percentage of participants

Adverse Events

Bevacizumab

Serious events: 672 serious events

Other events: 2095 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bevacizumab n=2264 participants at risk Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) until disease progression, unacceptable toxicity or withdrawal, along with Taxane-based chemotherapy as prescribed
Ear and labyrinth disorders Deafness	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.40% 9/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Abdominal pain	0.31% 7/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Nausea	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Constipation	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Rectal haemorrhage	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Febrile neutropenia	5.2% 117/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Neutropenia	4.3% 98/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Febrile bone marrow aplasia	0.62% 14/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Pneumonia	0.75% 17/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Infection	0.66% 15/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Sepsis	0.75% 17/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Device related infection	0.71% 16/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Vomiting	0.88% 20/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Diarrhoea	0.57% 13/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.0% 23/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.93% 21/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Pyrexia	1.1% 26/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Hypertension	0.71% 16/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Deep vein thrombosis	0.53% 12/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Neutrophil count decreased	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Anaemia	0.35% 8/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Leukopenia	0.35% 8/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Thrombocytopenia	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Agranulocytosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Bone marrow failure	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Lymphopenia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Thrombotic microangiopathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Blood and lymphatic system disorders Thrombotic thrombocytopenic purpura	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Urinary tract infection	0.40% 9/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Neutropenic sepsis	0.35% 8/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Anal abscess	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Abscess limb	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Diverticulitis	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Erysipelas	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Bronchitis	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Cellulitis	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Febrile infection	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Lower respiratory infection	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Abscess	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Appendicitis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Catheter site infection	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Herpes zoster	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Lung infection	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Soft tissue infection	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Abscess soft tissue	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Anal infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Arthritis infective	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Catheter sepsis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Clostridial infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Clostridium difficile colitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Endocarditis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Escherichia infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Gastroenteritis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Gastrointestinal infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Infected cyst	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Influenza	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Kidney infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Klebsiella sepsis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Laryngitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Liver abscess	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Neutropenic infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Osteomyelitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Otitis media	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Parotid abscess	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Perianal abscess	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Periodontal infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Peritonsillar abscess	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Postoperative wound infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Pseudomonas infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Pyelonephritis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Renal cyst infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Respiratory moniliasis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Septic shock	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Sinusitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Skin infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Staphylococcal sepsis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Tonsillitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Tooth infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Tuberculous pleurisy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Upper respiratory tract infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Urosepsis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Varicella	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Viral infection	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Wound abscess	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Depression	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Confusional state	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Acute psychosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Drug abuse	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Insomnia related to another mental condition	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Major depression	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Mental disorder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Mastectomy	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Hepatectomy	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Breast lump removal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Catheter removal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Hip surgery	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Laryngeal operation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Surgical and medical procedures Thoractomy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Skin ulcer	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Drug eruption	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Intertrigo	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Leukocytoclastic vasculitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Pruritus	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Skin necrosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Skin toxicity	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Diplopia	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Blindness	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Keratitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Pupils unequal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Retinal detachment	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bladder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Reproductive system and breast disorders Pelvic pain	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Reproductive system and breast disorders Uterine disorder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Reproductive system and breast disorders Uterine haemorrhage	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine prolapse	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Immune system disorders Hypersensitivity	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Stomatitis	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Anal fistula	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal perforation	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Subileus	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Ascites	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Colitis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Diarrhoea haemorrhagic	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Haematemesis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Intestinal perforation	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Large intestine perforation	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Peritonitis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Abdominal pain upper	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Anal fissure	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Colitis ulcerative	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Dental caries	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Diverticulum intestinal haemorrhagic	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Duodenal perforation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Duodenal ulcer	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Dysphagia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Enteritis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastric haemorrhage	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastric perforation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastritis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal disorder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal obstruction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal pain	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gastrointestinal toxicity	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gingivitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Haematochezia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Ileal perforation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Intestinal obstruction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Irritable bowel syndrome	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Melaena	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Oesophageal fistula	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Oesophageal stenosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Oesophagitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Pancreatitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Pneumoperitoneum	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Proctalgia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Proctocolitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Sigmoiditis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.40% 9/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.40% 9/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Nasal septum perforation	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Aspiration	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Hypoventilation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Non-cardiogenic pulmonary oedema	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pharyngeal inflammation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Pulmonary thrombosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Impaired healing	0.40% 9/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Chest pain	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders General physical health deterioration	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Asthenia	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Fatigue	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Malaise	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Pain	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Death	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Oedema peripheral	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Aplasia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Discomfort	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Extravasation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Hyperthermia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Mucosal inflammation	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Necrosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Pelvic mass	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Thrombosis	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Venous thrombosis limb	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Haemorrhage	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Hypertensive crisis	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Peripheral ischaemia	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Phlebitis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Venous thrombosis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Aortic stenosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Axillary vein thrombosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Haemodynamic instability	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Thrombophlebitis superficial	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Vena cava thrombosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Headache	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Cerebrovascular accident	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Convulsion	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Facial palsy	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Cerebral haemorrhage	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Dizziness	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Hemiparesis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Neuropathy peripheral	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Paraesthesia	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Syncope	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Transient ischaemic attack	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Cerebral ischaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Cerebral microangiopathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Cranial nerve paralysis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Dementia alzheimer's type	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Epilepsy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Intracranial pressure increased	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Movement disorder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Optic neuritis retrobulbar	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Paraplegia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Peripheral motor neuropathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Pneumocephalus	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Presyncope	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Reversible ischaemic neurological deficit	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiac failure	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiac failure congestive	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Myocardial infarction	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Atrial fibrillation	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Angina unstable	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiac arrest	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Palpitations	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Acute myocardial infarction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Arrhythmia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Atrial flutter	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiogenic shock	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiomyopathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Cardiotoxicity	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Congestive cardiomyopathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Coronary artery disease	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Diastolic dysfunction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Myocardial ischaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Pericardial effusion	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Sinus tachycardia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Tachycardia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Cardiac disorders Ventricular arrhythmia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Cholecystitis	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hepatic failure	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hyperbilirubinaemia	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Cholangitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Cholecystitis acute	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hepatic atrophy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hepatic functional abnormal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hepatitis toxic	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Hepatotoxicity	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Jaundice hepatocellular	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Hepatobiliary disorders Portal vein thrombosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Proteinuria	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Nephrotic syndrome	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Renal failure	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Haematuria	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Hydronephrosis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Hydroureter	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Obstrucive uropathy	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Renal colic	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Ureteric obstruction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Urethral pain	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations White blood cell count decreased	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Haemoglobin decreased	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Platelet count decreased	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Transaminases increased	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Granulocyte count decreased	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Neutrophil count abnormal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Scan myocardial perfusion abnormal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations White blood cell count abnormal	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Fall	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Humerus fracture	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Femoral neck fracture	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Femur fracture	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Head injury	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Joint dislocation	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Procedural pain	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Contusion	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Device breakage	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Device leakage	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Fracture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Haemothorax	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Hepatic rupture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Medical device complication	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Patella fracture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Procedural complication	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Radiation injury	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Radiation oesophagitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Radius fracture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Rib fracture	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Subcutaneous haematoma	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Thrombosis in device	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Wound	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Injury, poisoning and procedural complications Wound dehiscence	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Back pain	0.35% 8/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.27% 6/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Pathological fracture	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Bone pain	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Pain in extremity	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Arthralgia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Bone disorder	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Fistula	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Joint destruction	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Neck pain	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Osteitis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Osteolysis	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Dehydration	0.22% 5/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypercalcaemia	0.18% 4/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypokalaemia	0.13% 3/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Anorexia	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Metabolic acidosis	0.09% 2/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Diabetes mellitus	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Gout	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hyperkalaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypernatraemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypocalcaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypoglycaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hyponatraemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hypovolaemia	0.04% 1/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.

Other adverse events

Other adverse events
Measure	Bevacizumab n=2264 participants at risk Participants received bevacizumab 15 mg/kg iv on Day 1 of each 3 week cycle, or 10 mg/kg iv on Day 1 of each 2 week cycle (weekly equivalent dose of 5 mg/kg/week) until disease progression, unacceptable toxicity or withdrawal, along with Taxane-based chemotherapy as prescribed
Gastrointestinal disorders Stomatitis	29.0% 657/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Nausea	29.5% 667/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Diarrhoea	27.1% 613/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Constipation	18.3% 415/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Vomiting	15.5% 352/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Fatigue	49.1% 1111/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Pyrexia	15.9% 361/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Alopecia	41.3% 934/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Nail disorder	12.0% 272/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Neutrophil count decreased	25.9% 587/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations White blood cell count decreased	25.0% 566/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Haemoglobin decreased	18.4% 416/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Alanine aminotransferase increased	12.9% 293/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Aspartate aminotransferase increased	11.4% 259/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Epistaxis	38.3% 867/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Cough	14.9% 338/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea	13.8% 312/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Neuropathy	19.7% 446/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Headache	18.1% 409/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Arthralgia	15.0% 339/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Back pain	13.5% 305/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Myalgia	11.9% 270/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Pain in extremity	12.2% 277/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Bone pain	10.9% 247/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Vascular disorders Hypertension	33.6% 760/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Anorexia	18.7% 423/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Renal and urinary disorders Proteinuria	27.3% 618/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Metabolism and nutrition disorders Hyperglycaemia	6.4% 144/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Eye disorders Lacrimation increased	9.4% 212/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Psychiatric disorders Insomnia	6.0% 136/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Abdominal pain	9.3% 210/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Abdominal pain upper	6.8% 153/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Gingival bleeding	5.8% 131/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Gastrointestinal disorders Dyspepsia	5.3% 119/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	8.7% 198/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
General disorders Oedema peripheral	8.9% 202/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	10.3% 234/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Skin and subcutaneous tissue disorders Rash	9.1% 207/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Blood alkaline phosphatase increased	8.9% 202/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Gamma-glutamyltransferase increased	8.1% 184/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Platelet count decreased	7.3% 166/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Investigations Blood lactate dehydrogenase increased	5.0% 114/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Respiratory, thoracic and mediastinal disorders Dysphonia	6.6% 149/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Dysgeusia	7.4% 168/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Neuropathy peripheral	7.3% 165/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Paraesthesia	7.0% 158/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Nervous system disorders Dizziness	5.3% 120/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Urinary tract infection	6.3% 142/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.
Infections and infestations Nasopharyngitis	5.5% 124/2264 • Adverse events were recorded throughout the study from date of first dose of drug administration until follow up visits.

Additional Information

Medical Communications

Hoffmann- LaRoche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER