Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy

• ClinicalTrials.gov Identifier: NCT00556374
• Recruitment Status: Completed
• First Posted: November 12, 2007
• Results First Posted: November 6, 2015
• Last Update Posted: July 27, 2023
• Sponsor: Amgen
• Collaborator: Austrian Breast and Colorectal Cancer Study Group
• Information provided by (Responsible Party): Amgen

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Supportive Care
• Condition: Breast Cancer
• Interventions: Drug: Placebo; Biological: Denosumab; Drug: Non-steroidal aromatase inhibitor therapy; Drug: Zoledronic Acid; Other: Standard of Care
• Enrollment: 3420

Participant Flow

Recruitment Details

Participants were enrolled at 58 centers in Austria and Sweden from December 2006 to August 2020. Data collected during the exploratory ZA substudy were not used for the final analysis of the main study.

Pre-assignment Details

Participants were randomized in a 1:1 ratio to receive either denosumab or placebo in the double-blind phase. Randomization was stratified by type of hospital (major academic centers or other centers), prior aromatase inhibitor usage (Yes/No) and total lumbar spine bone mineral density (BMD) score at baseline (T-score < -1.0 or ≥ -1.0). Willing and eligible participants continued into the open-label phase and receive denosumab for a maximum of 7 doses once Q6M.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Period Title: Overall Study
Started	1709	1711
Received Study Drug in the Double-blind Phase	1699	1700
Continued Into the Open-Label Phase	268	3
Safety Analysis Set	1690 [1]	1709 [1]
Completed	1242	1362
Not Completed	467	349
Reason Not Completed
Withdrawal by Subject	235	205
Death	158	127
Lost to Follow-up	24	17
Continuing into Zoledronic Acid Substudy	50	0
[1] The safety analysis set was summarized based on the actual treatment received in the double-blind phase. Participants who received at least 1 dose of denosumab in the double-blind phase were summarized in the denosumab group regardless of the randomized treatment.

Baseline Characteristics

Arm/Group Title		Placebo	Denosumab	Total
Arm/Group Description		Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Total of all reporting groups
Overall Number of Baseline Participants		1709	1711	3420
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1709 participants	1711 participants	3420 participants
		64.6 (8.0)	64.0 (7.9)	64.3 (8.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1709 participants	1711 participants	3420 participants
	Female	1709 100.0%	1711 100.0%	3420 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1709 participants	1711 participants	3420 participants
	White/Caucasian	1700 99.5%	1702 99.5%	3402 99.5%
	Asian	7 0.4%	5 0.3%	12 0.4%
	Hispanic/Latino	1 0.1%	3 0.2%	4 0.1%
	Black/Afro-Caribbean	0 0.0%	1 0.1%	1 0.0%
	Missing	1 0.1%	0 0.0%	1 0.0%
Stratification Factor: Type of Hospital; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1709 participants	1711 participants	3420 participants
Major Academic Center		632	633	1265
Other Center		1077	1078	2155
Stratification Factor: Prior Aromatase inhibitor Use; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1709 participants	1711 participants	3420 participants
	No	269 15.7%	270 15.8%	539 15.8%
	Yes	1440 84.3%	1441 84.2%	2881 84.2%
Stratification Factor: Total Lumbar Spine BMD T-score [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1709 participants	1711 participants	3420 participants
	T-score < -1.0	775 45.3%	773 45.2%	1548 45.3%
	T-score ≥ -1.0	934 54.7%	938 54.8%	1872 54.7%
		[1] Measure Description: T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. T-score ≥ -1.0: BMD is considered normal. T-score < -1.0: Low BMD.

Outcome Measures

1. Primary Outcome

Title	Time to First Clinical Fracture
Description	The time to first on-study clinical fracture was defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.
Time Frame	From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on main study at the cut-off was 87 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	1709	1711
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not reached due to the low number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	The efficacy clinical hypothesis is that denosumab, when administered subcutaneously at a dose of 60 mg every 6 months, will be considered efficacious in patients with non-metastatic breast cancer receiving AIT if the rate of first clinical fracture in denosumab-treated patients is lower than that in placebo-treated patients. It is anticipated that denosumab will reduce the rate by 30% compared with placebo (ie, the true hazard ratio of denosumab compared with placebo is 0.70).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	Stratification factors are hospital type, prior use of aromatase inhibitor, and baseline lumbar spine BMD.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.504
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.65
	Estimation Comments	From the Cox proportional hazard model with treatment as the independent variable and stratified by randomization strata. A hazard ratio < 1.0 indicates a lower average event rate and a longer fracture-free time for denosumab relative to placebo.

2. Secondary Outcome

Title	Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD Analysis Set: all participants with evaluable lumbar spine BMD values at Baseline and Month 36

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	245	230
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percent Change in BMD
	-2.75; (-3.44 to -2.07)	7.27; (6.56 to 7.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	10.02
	Confidence Interval	(2-Sided) 95%; 9.04 to 11.01
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD Analysis Set: all participants with total hip BMD evaluable values at Baseline and Month 36

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	237	231
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percent Change in BMD
	-3.32; (-4.06 to -2.58)	4.60; (3.85 to 5.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	7.92
	Confidence Interval	(2-Sided) 95%; 6.87 to 8.97
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites
Description	Bone mineral density was assessed by dual x-ray absorptiometry.
Time Frame	Baseline and Month 36

Outcome Measure Data

Analysis Population Description

BMD Analysis Set: all participants with evaluable femoral neck BMD values at Baseline and Month 36

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	238	231
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percent Change in BMD
	-3.10; (-3.72 to -2.48)	3.41; (2.78 to 4.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Hochberg procedure was used to control for multiplicity.
	Method	ANCOVA
	Comments	Model includes treatment group as the independent variable and adjusted for baseline value and the randomization stratification factors.
Method of Estimation	Estimation Parameter	Difference from Placebo
	Estimated Value	6.51
	Confidence Interval	(2-Sided) 95%; 5.62 to 7.39
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Number of Participants With New Vertebral Fractures
Description	Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture was defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Vertebral Fracture Analysis Set: all participants with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	809	835
Measure Type: Count of Participants; Unit of Measure: Participants
	49 6.1%	27 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0088
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model includes treatment groups as the independent variable and stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.85
	Estimation Comments	Values < 1 for odds ratio favor denosumab.

6. Secondary Outcome

Title	Number of Participants With New or Worsening Vertebral Fractures
Description	Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture was defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures was defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Vertebral Fracture Analysis Set: all participants with a Baseline and at least one post-baseline vertebral x-ray prior to or at Month 36

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	809	835
Measure Type: Count of Participants; Unit of Measure: Participants
	55 6.8%	31 3.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0070
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model includes treatment groups as the independent variable and stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.84
	Estimation Comments	Values < 1 for odds ratio favor denosumab.

7. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	DFS was defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first.
Time Frame	From randomization until the DFS data cut-off date of 15 September 2015; maximum time on main study at the cut-off was 102 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	1709	1711
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not reached due to the low number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0515
	Comments	[Not Specified]
	Method	Cox Proportional Hazards Model
	Comments	Stratified by randomization strata (hospital type, use of aromatase inhibitor, baseline lumbar spine BMD).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.816
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.00
	Estimation Comments	From the Cox Proportional hazards model with treatment fitted as a covariate and stratified by randomization strata. A hazard ratio < 1.0 indicates a lower average event rate and a longer disease-free time for denosumab relative to placebo.

8. Secondary Outcome

Title	Bone Metastases-free Survival (BMFS)
Description	BMFS was defined as the time interval from randomization to first occurrence of bone metastasis or death from any cause, whichever comes first. Participants last known to be alive, who did not experience bone metastasis, were censored at their last assessment (i.e., bone scan) date or at the last contact date, whichever comes first.
Time Frame	From randomization until end of main study, maximum time on main study was 152 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	1709	1711
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not reached due to the low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Analysis of BMFS was conditional on the outcome of DFS due to hierarchical testing strategy, therefore p-value not reported.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.808
	Confidence Interval	(2-Sided) 95%; 0.654 to 0.997
	Estimation Comments	A hazard ratio < 1.0 indicates a lower average event rate and a longer bone metastases-free time for denosumab relative to placebo.

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death from any cause.
Time Frame	Randomization until end of main study, maximum duration of main study was 152 months

Outcome Measure Data

Analysis Population Description

Full analysis set: all randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants randomized to receive the matching placebo subcutaneously (SC) once every 6 months (Q6M) in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants randomized to receive 60 mg denosumab SC once Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Overall Number of Participants Analyzed	1709	1711
Median (95% Confidence Interval); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not reached due to the low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Denosumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Analysis of OS was conditional on the outcome of DFS due to hierarchical testing strategy, therefore p-value not reported.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.802
	Confidence Interval	(2-Sided) 95%; 0.635 to 1.013
	Estimation Comments	A hazard ratio < 1.0 indicates a lower average event rate and a longer overall survival time for denosumab relative to placebo.

Adverse Events

Time Frame	Double-blind (DB) phase: from 1st dose of study drug to 30 days after last dose; Open-label (OL) phase: from 1st dose of OL study drug to 30 days after last dose. Median duration of treatment in DB phase: Placebo 35.4 months and denosumab 35.5 months. Median duration of treatment in OL phase: 37 months
Adverse Event Reporting Description	All randomized participants who received >1 dose of treatment; participants were analyzed according to the actual treatment received in double-blind phase. 9 participants randomized to the placebo in the DB phase incorrectly received denosumab. Per protocol, only AEs of special interest and SAEs were collected in the open-label phase. MedDRA 17.1 used in double-blind phase and 24.0 in the open-label phase.
Arm/Group Title	Double-blind Phase: Placebo	Double-blind Phase: Denosumab	Open-label Phase: Placebo/Denosumab	Open-label Phase: Denosumab/Denosumab
Arm/Group Description	Participants received the matching placebo SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants received 60 mg denosumab SC Q6M in the double-blind phase. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.	Participants who received the matching placebo during the double-blind phase, who continued into the open-label phase where they received denosumab 60 mg SC Q6M for up to a maximum of 7 additional doses.	Participants who received denosumab during the double-blind phase, who continued into the open-label phase where they received denosumab 60 mg SC Q6M for up to a maximum of 7 additional doses.
All-Cause Mortality
	Double-blind Phase: Placebo	Double-blind Phase: Denosumab	Open-label Phase: Placebo/Denosumab	Open-label Phase: Denosumab/Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Double-blind Phase: Placebo	Double-blind Phase: Denosumab	Open-label Phase: Placebo/Denosumab	Open-label Phase: Denosumab/Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	515/1690 (30.47%)	521/1709 (30.49%)	40/245 (16.33%)	0/1 (0.00%)
Blood and lymphatic system disorders
Agranulocytosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Anaemia † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Iron deficiency anaemia † 1	3/1690 (0.18%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Leukopenia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Lymphadenitis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Lymphadenopathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pancytopenia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Blood loss anaemia † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Acute left ventricular failure † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Acute myocardial infarction † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Angina pectoris † 1	4/1690 (0.24%)	5/1709 (0.29%)	0/245 (0.00%)	0/1 (0.00%)
Aortic valve incompetence † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Aortic valve stenosis † 1	2/1690 (0.12%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Arrhythmia † 1	1/1690 (0.06%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Arteriosclerosis coronary artery † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Atrial fibrillation † 1	11/1690 (0.65%)	14/1709 (0.82%)	3/245 (1.22%)	0/1 (0.00%)
Atrial flutter † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Atrial tachycardia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Atrioventricular block second degree † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Bradycardia † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Cardiac arrest † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cardiac failure † 1	1/1690 (0.06%)	8/1709 (0.47%)	0/245 (0.00%)	0/1 (0.00%)
Cardio-respiratory arrest † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cardiomyopathy † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Congestive cardiomyopathy † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Coronary artery disease † 1	11/1690 (0.65%)	10/1709 (0.59%)	0/245 (0.00%)	0/1 (0.00%)
Coronary artery stenosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Ischaemic cardiomyopathy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Mitral valve incompetence † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Myocardial infarction † 1	5/1690 (0.30%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Palpitations † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Sick sinus syndrome † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Sinus tachycardia † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Stress cardiomyopathy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Supraventricular extrasystoles † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Supraventricular tachycardia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Tachycardia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Congenital, familial and genetic disorders
Developmental hip dysplasia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Gene mutation † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Ear and labyrinth disorders
Deafness † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Deafness unilateral † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Ear canal stenosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Meniere's disease † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Sudden hearing loss † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Tinnitus † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Vertigo † 1	10/1690 (0.59%)	9/1709 (0.53%)	0/245 (0.00%)	0/1 (0.00%)
Vertigo positional † 1	0/1690 (0.00%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Vestibular disorder † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Endocrine disorders
Basedow's disease † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Goitre † 1	12/1690 (0.71%)	21/1709 (1.23%)	1/245 (0.41%)	0/1 (0.00%)
Hyperparathyroidism † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Hyperthyroidism † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Eye disorders
Blepharochalasis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cataract † 1	28/1690 (1.66%)	16/1709 (0.94%)	2/245 (0.82%)	0/1 (0.00%)
Cataract cortical † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cataract nuclear † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Diabetic retinopathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Exfoliation glaucoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Macular degeneration † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Macular fibrosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Open angle glaucoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Retinal degeneration † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Retinal detachment † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Retinal tear † 1	0/1690 (0.00%)	2/1709 (0.12%)	1/245 (0.41%)	0/1 (0.00%)
Vitreous haemorrhage † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Vitreous opacities † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Glaucoma † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Gastrointestinal disorders
Abdominal adhesions † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Abdominal discomfort † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Abdominal hernia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Abdominal pain † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Abdominal pain upper † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Abdominal wall haematoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Abnormal faeces † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Anal fissure † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Chronic gastritis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Colitis † 1	3/1690 (0.18%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Colitis ischaemic † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Colon dysplasia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Constipation † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Crohn's disease † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Dental caries † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Diaphragmatic hernia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Diarrhoea † 1	4/1690 (0.24%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Diverticular perforation † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Diverticulum † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Diverticulum intestinal † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Duodenitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Dysphagia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Enteritis † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Gastric antral vascular ectasia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastric haemorrhage † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Gastritis † 1	7/1690 (0.41%)	7/1709 (0.41%)	1/245 (0.41%)	0/1 (0.00%)
Gastritis erosive † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Gastritis haemorrhagic † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal angiodysplasia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal haemorrhage † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal motility disorder † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal necrosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastrooesophageal reflux disease † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Haematochezia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Haemorrhoids † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Hiatus hernia † 1	4/1690 (0.24%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Ileus † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Incarcerated umbilical hernia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Inguinal hernia † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Intestinal obstruction † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intestinal perforation † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intestinal polyp † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Large intestinal stenosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Large intestine perforation † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Large intestine polyp † 1	4/1690 (0.24%)	8/1709 (0.47%)	0/245 (0.00%)	0/1 (0.00%)
Mallory-Weiss syndrome † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Nausea † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Oesophageal motility disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Painful defaecation † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pancreatic pseudocyst † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pancreatitis † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Pancreatitis acute † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Peritoneal necrosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Rectal polyp † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Subileus † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Swollen tongue † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Umbilical hernia † 1	2/1690 (0.12%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Vomiting † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
General disorders
Chest discomfort † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Chest pain † 1	7/1690 (0.41%)	4/1709 (0.23%)	1/245 (0.41%)	0/1 (0.00%)
Cyst † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Device connection issue † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Device dislocation † 1	4/1690 (0.24%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Face oedema † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Fat necrosis † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Fibrosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
General physical health deterioration † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Granuloma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Hyperplasia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Impaired healing † 1	0/1690 (0.00%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Incarcerated hernia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Local swelling † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Medical device complication † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Multi-organ failure † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Non-cardiac chest pain † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Oedema peripheral † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Pain † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Pyrexia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hepatobiliary disorders
Bile duct stone † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Biliary cirrhosis primary † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Biliary colic † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cholangitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cholecystitis † 1	2/1690 (0.12%)	8/1709 (0.47%)	0/245 (0.00%)	0/1 (0.00%)
Cholecystitis acute † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cholecystitis chronic † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Cholelithiasis † 1	9/1690 (0.53%)	14/1709 (0.82%)	0/245 (0.00%)	0/1 (0.00%)
Drug-induced liver injury † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Gallbladder polyp † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hepatic cirrhosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Jaundice † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Immune system disorders
Allergy to arthropod sting † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Anaphylactic reaction † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Drug hypersensitivity † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hypersensitivity † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Sarcoidosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Infections and infestations
Abscess † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Abscess jaw † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Abscess limb † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Anal abscess † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Appendicitis † 1	2/1690 (0.12%)	5/1709 (0.29%)	0/245 (0.00%)	0/1 (0.00%)
Arthritis infective † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Bacterial infection † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Borrelia infection † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Breast abscess † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Bronchitis † 1	1/1690 (0.06%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Bronchopneumonia † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Campylobacter gastroenteritis † 1	0/1690 (0.00%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Cellulitis † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cholecystitis infective † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Chronic sinusitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Clostridium difficile colitis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cystitis † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Device related infection † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Diverticulitis † 1	9/1690 (0.53%)	9/1709 (0.53%)	3/245 (1.22%)	0/1 (0.00%)
Encephalitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Erysipelas † 1	10/1690 (0.59%)	15/1709 (0.88%)	1/245 (0.41%)	0/1 (0.00%)
Escherichia sepsis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Escherichia urinary tract infection † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Eye infection bacterial † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Febrile infection † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastroenteritis † 1	1/1690 (0.06%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal infection † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Haematoma infection † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Helicobacter gastritis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Herpes zoster † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Implant site infection † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Incision site abscess † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Infected seroma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Infection † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Infective exacerbation of chronic obstructive airways disease † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Influenza † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Joint abscess † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Localised infection † 1	0/1690 (0.00%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Mastitis † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Nasopharyngitis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Oesophageal candidiasis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Ophthalmic herpes zoster † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Otitis media † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Paronychia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Peritoneal abscess † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pharyngitis † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Pneumonia † 1	7/1690 (0.41%)	9/1709 (0.53%)	1/245 (0.41%)	0/1 (0.00%)
Pneumonia bacterial † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural infection † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Postoperative wound infection † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Psoas abscess † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pyelonephritis † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Respiratory tract infection † 1	1/1690 (0.06%)	4/1709 (0.23%)	1/245 (0.41%)	0/1 (0.00%)
Rhinitis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Salpingitis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Sepsis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Sinusitis † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Skin infection † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Soft tissue infection † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Subcutaneous abscess † 1	3/1690 (0.18%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Tonsillitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Tracheobronchitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Urinary tract infection † 1	9/1690 (0.53%)	7/1709 (0.41%)	0/245 (0.00%)	0/1 (0.00%)
Vestibular neuronitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Meningitis aseptic † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Otitis media chronic † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Pneumonia legionella † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Tooth abscess † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Viral infection † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Injury, poisoning and procedural complications
Alcohol poisoning † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Anastomotic stenosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Animal bite † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Bone contusion † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Brain contusion † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bursa injury † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Concussion † 1	5/1690 (0.30%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Contusion † 1	6/1690 (0.36%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Extradural haematoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Fall † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Haemodilution † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Head injury † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Incisional hernia † 1	3/1690 (0.18%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Joint dislocation † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Joint injury † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Ligament rupture † 1	3/1690 (0.18%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Ligament sprain † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Meniscus injury † 1	24/1690 (1.42%)	23/1709 (1.35%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural bile leak † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural complication † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural haematoma † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural inflammation † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Post-traumatic neck syndrome † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Postoperative hernia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Postoperative thrombosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Procedural intestinal perforation † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Procedural pain † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Radiation alveolitis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Radiation pneumonitis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Radiation skin injury † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Road traffic accident † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Scar † 1	5/1690 (0.30%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Seroma † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Skin abrasion † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Spinal column injury † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Splenic haematoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Subdural haematoma † 1	4/1690 (0.24%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Suture rupture † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Tendon rupture † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Toxicity to various agents † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Traumatic arthrosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Vascular bypass dysfunction † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Wound † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Wound dehiscence † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Post procedural haemorrhage † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Investigations
Blood creatinine increased † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Blood pressure abnormal † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Colonoscopy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Glycosylated haemoglobin increased † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Mammogram abnormal † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary arterial pressure increased † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Smear cervix abnormal † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Weight decreased † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Diabetes mellitus † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Electrolyte imbalance † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Hyperglycaemia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hypocalcaemia † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Hyponatraemia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Insulin resistance † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Obesity † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Type 2 diabetes mellitus † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Metabolic acidosis † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Musculoskeletal and connective tissue disorders
Acquired claw toe † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Arthralgia † 1	2/1690 (0.12%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Arthritis † 1	4/1690 (0.24%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Back pain † 1	8/1690 (0.47%)	10/1709 (0.59%)	0/245 (0.00%)	0/1 (0.00%)
Bone cyst † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bone pain † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bursitis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cervical spinal stenosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Chondromalacia † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Chondropathy † 1	1/1690 (0.06%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Dupuytren's contracture † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Exostosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Fistula † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Foot deformity † 1	12/1690 (0.71%)	13/1709 (0.76%)	0/245 (0.00%)	0/1 (0.00%)
Haemarthrosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intervertebral disc degeneration † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intervertebral disc disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Intervertebral disc protrusion † 1	15/1690 (0.89%)	14/1709 (0.82%)	5/245 (2.04%)	0/1 (0.00%)
Joint effusion † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Joint instability † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Ligament disorder † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Lumbar spinal stenosis † 1	6/1690 (0.36%)	8/1709 (0.47%)	1/245 (0.41%)	0/1 (0.00%)
Meniscal degeneration † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Mobility decreased † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Musculoskeletal chest pain † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Musculoskeletal pain † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Osteoarthritis † 1	59/1690 (3.49%)	62/1709 (3.63%)	2/245 (0.82%)	0/1 (0.00%)
Osteochondrosis † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Osteonecrosis † 1	3/1690 (0.18%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pain in extremity † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Polyarthritis † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Polymyalgia rheumatica † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pseudarthrosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Rheumatoid arthritis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Rotator cuff syndrome † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Scoliosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Spinal column stenosis † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Spinal osteoarthritis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Spinal pain † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Spondyloarthropathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Spondylolisthesis † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Synovitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Tendon disorder † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Tenosynovitis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Tenosynovitis stenosans † 1	4/1690 (0.24%)	9/1709 (0.53%)	0/245 (0.00%)	0/1 (0.00%)
Torticollis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Trigger finger † 1	6/1690 (0.36%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Vertebral foraminal stenosis † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Spinal stenosis † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Spinal synovial cyst † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Synovial cyst † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Basal cell carcinoma † 1	5/1690 (0.30%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Benign breast neoplasm † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Benign lymph node neoplasm † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Benign salivary gland neoplasm † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bladder papilloma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Bladder transitional cell carcinoma recurrent † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Bowen's disease † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Breast adenoma † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Breast cancer † 1	0/1690 (0.00%)	1/1709 (0.06%)	3/245 (1.22%)	0/1 (0.00%)
Breast cancer metastatic † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Breast cancer recurrent † 1	4/1690 (0.24%)	3/1709 (0.18%)	1/245 (0.41%)	0/1 (0.00%)
Breast cancer stage III † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bronchial carcinoma † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Cervix carcinoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Chronic lymphocytic leukaemia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Colon adenoma † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Colon cancer † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Colon neoplasm † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Contralateral breast cancer † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Endometrial adenocarcinoma † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Fibroadenoma of breast † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Gastric cancer † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Gastrointestinal tract adenoma † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Haemangioma of liver † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hepatic neoplasm † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Inflammatory myofibroblastic tumour † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Intestinal adenocarcinoma † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intraductal papilloma of breast † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Intraductal proliferative breast lesion † 1	4/1690 (0.24%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Invasive ductal breast carcinoma † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Lentigo maligna † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Lip and/or oral cavity cancer † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Lipoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Lobular breast carcinoma in situ † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Lung adenocarcinoma † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Lung neoplasm malignant † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Malignant melanoma † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Malignant melanoma in situ † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Malignant pleural effusion † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Mediastinum neoplasm † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Melanocytic naevus † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Meningioma † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Meningioma benign † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to bone † 1	5/1690 (0.30%)	5/1709 (0.29%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to liver † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to lung † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to lymph nodes † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to peritoneum † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to pleura † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Metastases to skin † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Neuroma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Oral fibroma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Ovarian adenoma † 1	0/1690 (0.00%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Ovarian epithelial cancer † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Ovarian fibroma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pancreatic carcinoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Papillary thyroid cancer † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Parathyroid tumour benign † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pituitary tumour benign † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Rectal adenocarcinoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Rectal adenoma † 1	3/1690 (0.18%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Rectal cancer † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Renal cell carcinoma † 1	1/1690 (0.06%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Salivary gland adenoma † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Schwannoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Squamous cell carcinoma † 1	3/1690 (0.18%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Squamous cell carcinoma of lung † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Thyroid adenoma † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Thyroid cancer † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Thyroid neoplasm † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Transitional cell carcinoma † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Transitional cell carcinoma urethra † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Uterine leiomyoma † 1	3/1690 (0.18%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Uterine leiomyosarcoma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cholangiocarcinoma † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Leiomyosarcoma † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Vulval cancer † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Nervous system disorders
Acoustic neuritis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Amnesia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Amnestic disorder † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Carotid artery aneurysm † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Carotid artery disease † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Carotid artery stenosis † 1	2/1690 (0.12%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Carpal tunnel syndrome † 1	13/1690 (0.77%)	14/1709 (0.82%)	0/245 (0.00%)	0/1 (0.00%)
Cerebellar haemorrhage † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cerebral infarction † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cerebral ischaemia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cerebrovascular accident † 1	9/1690 (0.53%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Cerebrovascular disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cervical myelopathy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cervical radiculopathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cervicobrachial syndrome † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Chronic inflammatory demyelinating polyradiculoneuropathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cognitive disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Dementia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Diabetic coma † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Dizziness † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Drop attacks † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Epilepsy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Facial neuralgia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Facial paresis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Generalised tonic-clonic seizure † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Guillain-Barre syndrome † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Headache † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Intercostal neuralgia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intracranial aneurysm † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Loss of consciousness † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Lumbar radiculopathy † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Medication overuse headache † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Meralgia paraesthetica † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Migraine † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Monoplegia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Morton's neuralgia † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Motor neurone disease † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Nerve compression † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Nervous system disorder † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Neuralgia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Paraesthesia † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Peroneal nerve palsy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Polyneuropathy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Radicular syndrome † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Sciatica † 1	4/1690 (0.24%)	7/1709 (0.41%)	1/245 (0.41%)	0/1 (0.00%)
Senile dementia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Small fibre neuropathy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Speech disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Spinal claudication † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Syncope † 1	4/1690 (0.24%)	6/1709 (0.35%)	0/245 (0.00%)	0/1 (0.00%)
Transient global amnesia † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Transient ischaemic attack † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
VIIth nerve paralysis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Vascular encephalopathy † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Paresis † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Psychiatric disorders
Alcohol withdrawal syndrome † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Bipolar disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Burnout syndrome † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Depressed mood † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Depression † 1	8/1690 (0.47%)	8/1709 (0.47%)	0/245 (0.00%)	0/1 (0.00%)
Mental disorder † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Panic attack † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Post-traumatic stress disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Psychosomatic disease † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Stress † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Suicide attempt † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Renal and urinary disorders
Acute prerenal failure † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Calculus ureteric † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Cystitis haemorrhagic † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Diabetic nephropathy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hydronephrosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	1/245 (0.41%)	0/1 (0.00%)
Hypertonic bladder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Incontinence † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Nephrolithiasis † 1	2/1690 (0.12%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Renal artery stenosis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Renal colic † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Renal failure acute † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Stress urinary incontinence † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Urethral disorder † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Urge incontinence † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Urinary incontinence † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Acute kidney injury † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Reproductive system and breast disorders
Adenomyosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Adnexa uteri cyst † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Adnexa uteri mass † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Breast calcifications † 1	4/1690 (0.24%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Breast cyst † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Breast discharge † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Breast disorder † 1	6/1690 (0.36%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Breast enlargement † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Breast fibrosis † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Breast haematoma † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Breast necrosis † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Breast pain † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Cervical dysplasia † 1	1/1690 (0.06%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Cervical polyp † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Cystocele † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Dyspareunia † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Endometrial hyperplasia † 1	2/1690 (0.12%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Fibrocystic breast disease † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Ovarian cyst † 1	1/1690 (0.06%)	7/1709 (0.41%)	0/245 (0.00%)	0/1 (0.00%)
Postmenopausal haemorrhage † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Rectocele † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Uterine adhesions † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Uterine polyp † 1	3/1690 (0.18%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Uterine prolapse † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Uterovaginal prolapse † 1	2/1690 (0.12%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Vaginal prolapse † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Hydrometra † 1	0/1690 (0.00%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Atelectasis † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Cheyne-Stokes respiration † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Chronic obstructive pulmonary disease † 1	0/1690 (0.00%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Cough † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Diaphragmatic paralysis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Dyspnoea † 1	4/1690 (0.24%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Dyspnoea exertional † 1	0/1690 (0.00%)	4/1709 (0.23%)	0/245 (0.00%)	0/1 (0.00%)
Emphysema † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Epistaxis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Hyperventilation † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Lung disorder † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Nasal polyps † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Organising pneumonia † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Oropharyngeal pain † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pharyngeal cyst † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pleural effusion † 1	2/1690 (0.12%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pleurisy † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Pneumonia aspiration † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pneumonitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pneumothorax † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary alveolar haemorrhage † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary embolism † 1	11/1690 (0.65%)	12/1709 (0.70%)	1/245 (0.41%)	0/1 (0.00%)
Pulmonary fibrosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary hypertension † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary mass † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Pulmonary oedema † 1	1/1690 (0.06%)	0/1709 (0.00%)	1/245 (0.41%)	0/1 (0.00%)
Sinus polyp † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Sleep apnoea syndrome † 1	5/1690 (0.30%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Vocal cord polyp † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Skin and subcutaneous tissue disorders
Acquired epidermolysis bullosa † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Angioedema † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Dermal cyst † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Dermatitis allergic † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Diabetic foot † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Drug eruption † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Eczema † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Erythema † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Erythema nodosum † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Hyperkeratosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Keloid scar † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Lichen sclerosus † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Panniculitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Rash † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Rash maculo-papular † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Scar pain † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Skin necrosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Skin ulcer † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Stasis dermatitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Urticaria † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Surgical and medical procedures
Breast reconstruction † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Hysterectomy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hysterosalpingo-oophorectomy † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intraocular lens implant † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Knee arthroplasty † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Mastectomy † 1	3/1690 (0.18%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Oophorectomy † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Prophylaxis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Vascular disorders
Aortic dissection † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Arterial stenosis † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Arteriovenous fistula † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Bleeding varicose vein † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Circulatory collapse † 1	4/1690 (0.24%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Deep vein thrombosis † 1	3/1690 (0.18%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Femoral artery occlusion † 1	1/1690 (0.06%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Haematoma † 1	3/1690 (0.18%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Hypertension † 1	6/1690 (0.36%)	5/1709 (0.29%)	1/245 (0.41%)	0/1 (0.00%)
Hypertensive crisis † 1	14/1690 (0.83%)	10/1709 (0.59%)	1/245 (0.41%)	0/1 (0.00%)
Hypotension † 1	2/1690 (0.12%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Iliac artery occlusion † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Intermittent claudication † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Lymphoedema † 1	2/1690 (0.12%)	5/1709 (0.29%)	0/245 (0.00%)	0/1 (0.00%)
Peripheral arterial occlusive disease † 1	4/1690 (0.24%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Peripheral artery stenosis † 1	1/1690 (0.06%)	3/1709 (0.18%)	0/245 (0.00%)	0/1 (0.00%)
Peripheral venous disease † 1	4/1690 (0.24%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Raynaud's phenomenon † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Subclavian artery stenosis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Subclavian steal syndrome † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Temporal arteritis † 1	0/1690 (0.00%)	2/1709 (0.12%)	0/245 (0.00%)	0/1 (0.00%)
Thrombophlebitis † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Thrombosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Varicose vein † 1	10/1690 (0.59%)	12/1709 (0.70%)	1/245 (0.41%)	0/1 (0.00%)
Vasculitis † 1	1/1690 (0.06%)	0/1709 (0.00%)	0/245 (0.00%)	0/1 (0.00%)
Venous thrombosis † 1	1/1690 (0.06%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
Venous thrombosis limb † 1	0/1690 (0.00%)	1/1709 (0.06%)	0/245 (0.00%)	0/1 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 17.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Double-blind Phase: Placebo	Double-blind Phase: Denosumab	Open-label Phase: Placebo/Denosumab	Open-label Phase: Denosumab/Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	838/1690 (49.59%)	882/1709 (51.61%)	0/245 (0.00%)	0/1 (0.00%)
General disorders
Fatigue † 1	100/1690 (5.92%)	109/1709 (6.38%)	0/245 (0.00%)	0/1 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	446/1690 (26.39%)	441/1709 (25.80%)	0/245 (0.00%)	0/1 (0.00%)
Back pain † 1	146/1690 (8.64%)	151/1709 (8.84%)	0/245 (0.00%)	0/1 (0.00%)
Bone pain † 1	111/1690 (6.57%)	139/1709 (8.13%)	0/245 (0.00%)	0/1 (0.00%)
Osteoarthritis † 1	61/1690 (3.61%)	89/1709 (5.21%)	0/245 (0.00%)	0/1 (0.00%)
Pain in extremity † 1	85/1690 (5.03%)	107/1709 (6.26%)	0/245 (0.00%)	0/1 (0.00%)
Spinal pain † 1	73/1690 (4.32%)	89/1709 (5.21%)	0/245 (0.00%)	0/1 (0.00%)
Skin and subcutaneous tissue disorders
Scar pain † 1	86/1690 (5.09%)	78/1709 (4.56%)	0/245 (0.00%)	0/1 (0.00%)
Vascular disorders
Hot flush † 1	234/1690 (13.85%)	270/1709 (15.80%)	0/245 (0.00%)	0/1 (0.00%)
Hypertension † 1	94/1690 (5.56%)	111/1709 (6.50%)	0/245 (0.00%)	0/1 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 17.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

Results Point of Contact

• Name/Title: Study Director
• Organization: Amgen Inc.
• Phone: 866-572-6436
• EMail: medinfo@amgen.com

Publications:

Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. Epub 2015 May 31.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Minichsdorfer C, Fuereder T, Leutner M, Singer CF, Kacerovsky-Strobl S, Egle D, Greil R, Balic M, Fitzal F, Pfeiler G, Frantal S, Bartsch R, Gnant M. Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18. ESMO Open. 2022 Apr;7(2):100426. doi: 10.1016/j.esmoop.2022.100426. Epub 2022 Mar 22.

Gnant M, Pfeiler G, Steger GG, Egle D, Greil R, Fitzal F, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Jakesz R, Marth C, Sevelda P, Mlineritsch B, Exner R, Fesl C, Frantal S, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):339-351. doi: 10.1016/S1470-2045(18)30862-3. Epub 2019 Feb 19.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00556374
• Other Study ID Numbers: 20050209; ABCSG-18 ( Other Identifier: Austrian Breast and Colorectal Cancer Study Group ); 2005-005275-15 ( EudraCT Number )
• First Submitted: November 8, 2007
• First Posted: November 12, 2007
• Results First Submitted: October 6, 2015
• Results First Posted: November 6, 2015
• Last Update Posted: July 27, 2023