Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)

• ClinicalTrials.gov Identifier: NCT01077154
• Recruitment Status: Terminated
• First Posted: February 26, 2010
• Results First Posted: October 3, 2018
• Last Update Posted: September 28, 2021
• Sponsor: Amgen
• Collaborator: Daiichi Sankyo
• 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: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Placebo; Drug: Denosumab
• Enrollment: 4509

Participant Flow

Recruitment Details	Participants were enrolled at 407 centers in Australia, Western Europe, Eastern Europe, Israel, North America, Asia, South America, South Africa, and Turkey from 02 June 2010 to 24 August 2012.
Pre-assignment Details	Participants were randomized in a 1:1 ratio to 1 of 2 groups. Randomization was stratified based on breast cancer therapy/lymph node (LN) status, hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, age, and geographic region.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Period Title: Overall Study
Started	2253	2256
Received Study Drug	2229	2230
Completed	27	28
Not Completed	2226	2228
Reason Not Completed
Protocol-specified Criteria: Study Ended	1524	1514
Withdrawal by Subject	369	385
Death	215	214
Lost to Follow-up	43	35
Noncompliance	22	20
Disease Progression	18	20
Ineligibility Determined	10	14
Other	14	11
Adverse Event	9	9
Administrative Decision	1	6
Protocol Deviation	1	0

Baseline Characteristics

Arm/Group Title		Placebo	Denosumab	Total
Arm/Group Description		Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.	Total of all reporting groups
Overall Number of Baseline Participants		2253	2256	4509
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	2253 participants	2256 participants	4509 participants
		51.6 (10.6)	51.4 (10.7)	51.5 (10.7)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	18 - 64 years	1960 87.0%	1959 86.8%	3919 86.9%
	65 - 74 years	259 11.5%	260 11.5%	519 11.5%
	75 - 84 years	33 1.5%	36 1.6%	69 1.5%
	≥ 85 years	1 0.0%	1 0.0%	2 0.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	Female	2253 100.0%	2256 100.0%	4509 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	2253 participants	2256 participants	4509 participants
	White	1692 75.1%	1676 74.3%	3368 74.7%
	Asian	222 9.9%	213 9.4%	435 9.6%
	Japanese	134 5.9%	135 6.0%	269 6.0%
	Hispanic/Latino	112 5.0%	135 6.0%	247 5.5%
	Black	70 3.1%	74 3.3%	144 3.2%
	Native Hawaiian or Other Pacific Islander	4 0.2%	3 0.1%	7 0.2%
	American Indian or Alaska Native	1 0.0%	0 0.0%	1 0.0%
	Other	18 0.8%	20 0.9%	38 0.8%
Menopausal Status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	Premenopausal	1165 51.7%	1195 53.0%	2360 52.3%
	Postmenopausal	1088 48.3%	1061 47.0%	2149 47.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	0 (Fully active)	1913 84.9%	1922 85.2%	3835 85.1%
	1 (Restricted but ambulatory)	340 15.1%	329 14.6%	669 14.8%
	2 (Ambulatory, unable to work)	0 0.0%	3 0.1%	3 0.1%
	Missing	0 0.0%	2 0.1%	2 0.0%
		[1] Measure Description: A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
Breast Cancer Therapy / Lymph Node Status (Strata per Randomization) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	Neo-adjuvant therapy / any lymph node status	550 24.4%	552 24.5%	1102 24.4%
	Adjuvant therapy / lymph node negative	68 3.0%	65 2.9%	133 2.9%
	Adjuvant therapy / lymph node positive	1635 72.6%	1639 72.7%	3274 72.6%
		[1] Measure Description: Breast cancer therapy / lymph node (LN) status: neo-adjuvant therapy / any LN status;; adjuvant therapy / LN negative (based on axillary LN dissection, or based on sentinel node [SN] status);; adjuvant therapy / LN positive
Hormone Receptor Status (Strata per Randomization) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	ER and/or PR positive	1740 77.2%	1747 77.4%	3487 77.3%
	ER and PR negative	513 22.8%	509 22.6%	1022 22.7%
		[1] Measure Description: Hormone receptor (estrogen receptor [ER] / progesterone receptor [PR]) status; ER and/or PR positive; ER and PR negative
Human Epidermal Growth Factor Receptor 2 (HER-2) Status (Strata per Randomization); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	HER-2 positive	490 21.7%	492 21.8%	982 21.8%
	HER-2 negative	1763 78.3%	1764 78.2%	3527 78.2%
Age (Strata per Randomization); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	< 50 years	1026 45.5%	1029 45.6%	2055 45.6%
	≥ 50 years	1227 54.5%	1227 54.4%	2454 54.4%
Geographic Region (Strata per Randomization); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	Japan	131 5.8%	131 5.8%	262 5.8%
	Other	2122 94.2%	2125 94.2%	4247 94.2%
Molecular Subtypes of Breast Cancer [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	HR positive and HER-2 positive	288 12.8%	286 12.7%	574 12.7%
	HR positive and HER-2 negative	1460 64.8%	1458 64.6%	2918 64.7%
	HR negative and HER-2 positive	163 7.2%	168 7.4%	331 7.3%
	HR negative and HER-2 negative	341 15.1%	343 15.2%	684 15.2%
	Missing	1 0.0%	1 0.0%	2 0.0%
		[1] Measure Description: Hormone receptor (HR; estrogen receptor [ER] / progesterone receptor [PR]); HR positive = ER and/or PR positive; HR negative = ER and PR negative
Lymph Node Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	N0	130 5.8%	131 5.8%	261 5.8%
	N1	1369 60.8%	1381 61.2%	2750 61.0%
	N2	506 22.5%	505 22.4%	1011 22.4%
	N3	230 10.2%	224 9.9%	454 10.1%
	Nx	18 0.8%	15 0.7%	33 0.7%
		[1] Measure Description: Clinical and pathologic regional lymph node (LN) status (by American Joint Committee on Cancer (AJCC)): N0 = no LN metastasis or pathologic (p) micrometastases <2.0 mm; N1 = Ipsilateral level I, II axillary (Ax) LN or p micrometastases >2.0mm or in internal mammary (IM) LN; N2 = fixed ipsilateral level I, II Ax LNs or clinically detected IM LNs only or pLN metastases in 4-9 Ax LNs; N3 = ipsilateral level III infraclavicular (IC) LNs or clinically detected IM LNs with other level I/II Ax LNs or supraclavicular (SC) LNs or pLN metastases in ≥10 Ax LNs; NX =LNs cannot be assessed.
Breast Cancer Histopathologic Grade [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	2253 participants	2256 participants	4509 participants
	Grade 1 = Low	222 9.9%	209 9.3%	431 9.6%
	Grade 2 = Intermediate	1015 45.1%	1079 47.8%	2094 46.4%
	Grade 3 = High	938 41.6%	906 40.2%	1844 40.9%
	Not Evaluable/Missing	78 3.5%	62 2.7%	140 3.1%
		[1] Measure Description: Tumor grade was determined according to the Nottingham Combined Histological Grading System, based on morphological features (tubule formation, nuclear pleomorphism, and mitotic count), by assigning a value of 1 (favorable) to 3 (unfavorable) for each feature. Scores for the 3 categories were added to give a combined histopathologic grade score: Grade (G)1 (low grade; favorable) = total score of 3, 4, or 5; G2 (intermediate) = total score of 6 or 7; G3 (high; unfavorable) = total score of 8 or 9.

Outcome Measures

1. Primary Outcome

Title	Bone Metastasis-free Survival (BMFS)
Description	BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date. Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis. Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Overall Number of Participants Analyzed	2253	2256
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	13.5; (12.1 to 15.0)	12.9; (11.6 to 14.3)

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	0.70
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.14
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

2. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Overall Number of Participants Analyzed	2253	2256
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	19.2; (17.6 to 20.8)	19.6; (18.0 to 21.2)

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	0.57
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.19
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hzard ratio < 1 favors denosumab.

3. Secondary Outcome

Title	Disease-free Survival (DFS) in the Postmenopausal Subset
Description	DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date. Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence. Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Randomized participants postmenopausal at enrollment, defined as:

• Undergone bilateral oophorectomy
• Age ≥ 60 years
• Age 45 to 59 years with 1 of the criteria, ie, either amenorrhea > 12 months with an intact uterus and ≥ 1 intact ovary; or amenorrhea for ≤ 12 months and follicle-stimulating hormone and estradiol in postmenopausal range.

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Overall Number of Participants Analyzed	1088	1061
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	18.6; (16.3 to 20.9)	20.3; (17.8 to 22.7)

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	0.26
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.36
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date. Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.
Time Frame	From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Overall Number of Participants Analyzed	2253	2256
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.5; (8.3 to 10.8)	9.5; (8.3 to 10.7)

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	0.94
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.22
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

5. Secondary Outcome

Title	Distant Recurrence-free Survival
Description	Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date. Distant disease recurrence includes confirmed bone metastasis and extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence. Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.
Time Frame	From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Placebo	Denosumab
Arm/Group Description:	Participants were randomized to receive placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants were randomized to receive denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
Overall Number of Participants Analyzed	2253	2256
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	18.0; (16.4 to 19.6)	18.7; (17.1 to 20.3)

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	0.41
	Comments	[Not Specified]
	Method	Stratified Log Rank
	Comments	Stratified by breast cancer therapy/LN status, hormone receptor status, HER-2 status, age, and geographic region.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.21
	Estimation Comments	Based on a Cox proportional hazards model stratified by the randomization stratification factors; a hazard ratio < 1 favors denosumab.

Adverse Events

Time Frame	All-cause mortality includes deaths from first dose of study drug to the end of study date; median (min, max) time on study was 72.7 (0, 92) and 72.3 (0, 92) months for Placebo/Denosumab respectively. Adverse Events are from first dose of study drug to 30 days after last dose; median (min, max) time on treatment was 59.4 (0.7, 67) and 59.3 (0.7, 67) months for Placebo/Denosumab respectively.
Adverse Event Reporting Description	Eleven participants randomized to the placebo group received at least 1 dose of denosumab during the study and are counted in the denosumab group for safety analyses. Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo	Denosumab
Arm/Group Description	Participants received placebo subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.	Participants received denosumab 120 mg subcutaneous injections once every 3 or 4 weeks for approximately 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.
All-Cause Mortality
	Placebo	Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	215/2218 (9.69%)	215/2241 (9.59%)
Serious Adverse Events
	Placebo	Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	675/2218 (30.43%)	702/2241 (31.33%)
Blood and lymphatic system disorders
Agranulocytosis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Anaemia † 1	12/2218 (0.54%)	17/2241 (0.76%)
Anaemia megaloblastic † 1	1/2218 (0.05%)	0/2241 (0.00%)
Bone marrow failure † 1	1/2218 (0.05%)	0/2241 (0.00%)
Febrile neutropenia † 1	114/2218 (5.14%)	83/2241 (3.70%)
Immune thrombocytopenic purpura † 1	0/2218 (0.00%)	1/2241 (0.04%)
Leukocytosis † 1	3/2218 (0.14%)	0/2241 (0.00%)
Leukopenia † 1	5/2218 (0.23%)	2/2241 (0.09%)
Neutropenia † 1	36/2218 (1.62%)	35/2241 (1.56%)
Pancytopenia † 1	4/2218 (0.18%)	3/2241 (0.13%)
Thrombocytopenia † 1	5/2218 (0.23%)	6/2241 (0.27%)
Cardiac disorders
Acute myocardial infarction † 1	3/2218 (0.14%)	2/2241 (0.09%)
Angina pectoris † 1	0/2218 (0.00%)	1/2241 (0.04%)
Angina unstable † 1	1/2218 (0.05%)	0/2241 (0.00%)
Arteriospasm coronary † 1	1/2218 (0.05%)	0/2241 (0.00%)
Atrial fibrillation † 1	6/2218 (0.27%)	1/2241 (0.04%)
Atrial flutter † 1	1/2218 (0.05%)	1/2241 (0.04%)
Atrial thrombosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Bradycardia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cardiac aneurysm † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cardiac arrest † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cardiac failure chronic † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cardiac failure congestive † 1	4/2218 (0.18%)	4/2241 (0.18%)
Cardio-respiratory arrest † 1	0/2218 (0.00%)	2/2241 (0.09%)
Cardiogenic shock † 1	1/2218 (0.05%)	1/2241 (0.04%)
Cardiopulmonary failure † 1	1/2218 (0.05%)	0/2241 (0.00%)
Coronary artery disease † 1	0/2218 (0.00%)	2/2241 (0.09%)
Coronary artery occlusion † 1	1/2218 (0.05%)	0/2241 (0.00%)
Coronary artery stenosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Left ventricular dysfunction † 1	1/2218 (0.05%)	1/2241 (0.04%)
Metabolic cardiomyopathy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Myocardial infarction † 1	4/2218 (0.18%)	2/2241 (0.09%)
Palpitations † 1	1/2218 (0.05%)	2/2241 (0.09%)
Pericardial effusion † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pericarditis constrictive † 1	0/2218 (0.00%)	1/2241 (0.04%)
Sinus tachycardia † 1	0/2218 (0.00%)	2/2241 (0.09%)
Supraventricular tachycardia † 1	2/2218 (0.09%)	0/2241 (0.00%)
Tachyarrhythmia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Tachycardia † 1	5/2218 (0.23%)	0/2241 (0.00%)
Ventricular tachycardia † 1	2/2218 (0.09%)	0/2241 (0.00%)
Ear and labyrinth disorders
Deafness † 1	1/2218 (0.05%)	0/2241 (0.00%)
Ear pain † 1	0/2218 (0.00%)	1/2241 (0.04%)
External ear disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Tinnitus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Vertigo † 1	0/2218 (0.00%)	5/2241 (0.22%)
Vertigo positional † 1	1/2218 (0.05%)	0/2241 (0.00%)
Endocrine disorders
Hypothyroidism † 1	0/2218 (0.00%)	1/2241 (0.04%)
Thyroiditis acute † 1	1/2218 (0.05%)	0/2241 (0.00%)
Eye disorders
Angle closure glaucoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Blindness † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cataract † 1	5/2218 (0.23%)	5/2241 (0.22%)
Diplopia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Macular hole † 1	0/2218 (0.00%)	1/2241 (0.04%)
Retinal artery occlusion † 1	0/2218 (0.00%)	1/2241 (0.04%)
Retinal detachment † 1	0/2218 (0.00%)	2/2241 (0.09%)
Retinopathy proliferative † 1	0/2218 (0.00%)	1/2241 (0.04%)
Vision blurred † 1	1/2218 (0.05%)	0/2241 (0.00%)
Vitreous haematoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Vitreous haemorrhage † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gastrointestinal disorders
Abdominal hernia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Abdominal incarcerated hernia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Abdominal pain † 1	2/2218 (0.09%)	6/2241 (0.27%)
Abdominal pain lower † 1	3/2218 (0.14%)	0/2241 (0.00%)
Abdominal pain upper † 1	0/2218 (0.00%)	2/2241 (0.09%)
Anal fissure † 1	1/2218 (0.05%)	1/2241 (0.04%)
Anal fistula † 1	1/2218 (0.05%)	1/2241 (0.04%)
Anal prolapse † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ascites † 1	0/2218 (0.00%)	2/2241 (0.09%)
Chronic gastritis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Colitis † 1	1/2218 (0.05%)	2/2241 (0.09%)
Colitis ischaemic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Colitis ulcerative † 1	1/2218 (0.05%)	0/2241 (0.00%)
Constipation † 1	2/2218 (0.09%)	4/2241 (0.18%)
Crohn's disease † 1	0/2218 (0.00%)	1/2241 (0.04%)
Dental caries † 1	1/2218 (0.05%)	0/2241 (0.00%)
Diarrhoea † 1	24/2218 (1.08%)	15/2241 (0.67%)
Diverticular perforation † 1	1/2218 (0.05%)	0/2241 (0.00%)
Diverticulum intestinal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Duodenal obstruction † 1	1/2218 (0.05%)	0/2241 (0.00%)
Duodenal ulcer † 1	0/2218 (0.00%)	1/2241 (0.04%)
Dyspepsia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Enteritis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Enterocolitis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Enterocolitis haemorrhagic † 1	2/2218 (0.09%)	0/2241 (0.00%)
Femoral hernia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gastric disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Gastric polyps † 1	0/2218 (0.00%)	1/2241 (0.04%)
Gastric ulcer † 1	0/2218 (0.00%)	2/2241 (0.09%)
Gastritis † 1	2/2218 (0.09%)	3/2241 (0.13%)
Gastrointestinal disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Gastrointestinal haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Gastrooesophageal reflux disease † 1	1/2218 (0.05%)	2/2241 (0.09%)
Gingival pain † 1	0/2218 (0.00%)	1/2241 (0.04%)
Haemorrhoidal haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Haemorrhoids thrombosed † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hiatus hernia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Inguinal hernia † 1	1/2218 (0.05%)	1/2241 (0.04%)
Intestinal haemorrhage † 1	1/2218 (0.05%)	1/2241 (0.04%)
Intestinal obstruction † 1	0/2218 (0.00%)	1/2241 (0.04%)
Large intestinal haemorrhage † 1	1/2218 (0.05%)	0/2241 (0.00%)
Large intestine perforation † 1	1/2218 (0.05%)	1/2241 (0.04%)
Large intestine polyp † 1	1/2218 (0.05%)	1/2241 (0.04%)
Lower gastrointestinal haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Mouth ulceration † 1	0/2218 (0.00%)	2/2241 (0.09%)
Nausea † 1	10/2218 (0.45%)	18/2241 (0.80%)
Necrotising colitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Obstructive pancreatitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Oesophageal spasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Oesophageal stenosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Oesophagitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pancreatitis acute † 1	1/2218 (0.05%)	3/2241 (0.13%)
Pancreatitis chronic † 1	1/2218 (0.05%)	0/2241 (0.00%)
Rectal haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Rectal prolapse † 1	1/2218 (0.05%)	0/2241 (0.00%)
Small intestinal obstruction † 1	2/2218 (0.09%)	1/2241 (0.04%)
Stomatitis † 1	1/2218 (0.05%)	2/2241 (0.09%)
Umbilical hernia † 1	1/2218 (0.05%)	1/2241 (0.04%)
Upper gastrointestinal haemorrhage † 1	1/2218 (0.05%)	0/2241 (0.00%)
Vomiting † 1	13/2218 (0.59%)	24/2241 (1.07%)
General disorders
Adverse drug reaction † 1	1/2218 (0.05%)	0/2241 (0.00%)
Application site pain † 1	1/2218 (0.05%)	0/2241 (0.00%)
Asthenia † 1	3/2218 (0.14%)	3/2241 (0.13%)
BRCA2 gene mutation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast complication associated with device † 1	1/2218 (0.05%)	0/2241 (0.00%)
Capsular contracture associated with breast implant † 1	0/2218 (0.00%)	1/2241 (0.04%)
Catheter site haematoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Chest discomfort † 1	1/2218 (0.05%)	2/2241 (0.09%)
Chest pain † 1	6/2218 (0.27%)	5/2241 (0.22%)
Chills † 1	2/2218 (0.09%)	0/2241 (0.00%)
Complication associated with device † 1	1/2218 (0.05%)	1/2241 (0.04%)
Death † 1	1/2218 (0.05%)	0/2241 (0.00%)
Disease progression † 1	1/2218 (0.05%)	0/2241 (0.00%)
Drug intolerance † 1	1/2218 (0.05%)	0/2241 (0.00%)
Extravasation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Fatigue † 1	4/2218 (0.18%)	4/2241 (0.18%)
General physical health deterioration † 1	3/2218 (0.14%)	3/2241 (0.13%)
Generalised oedema † 1	0/2218 (0.00%)	1/2241 (0.04%)
Granuloma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Idiosyncratic drug reaction † 1	0/2218 (0.00%)	1/2241 (0.04%)
Impaired healing † 1	3/2218 (0.14%)	0/2241 (0.00%)
Incarcerated hernia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Inflammation † 1	1/2218 (0.05%)	0/2241 (0.00%)
Influenza like illness † 1	0/2218 (0.00%)	2/2241 (0.09%)
Infusion site extravasation † 1	1/2218 (0.05%)	1/2241 (0.04%)
Malaise † 1	1/2218 (0.05%)	7/2241 (0.31%)
Mucosal inflammation † 1	4/2218 (0.18%)	2/2241 (0.09%)
Non-cardiac chest pain † 1	4/2218 (0.18%)	6/2241 (0.27%)
Oedema peripheral † 1	2/2218 (0.09%)	2/2241 (0.09%)
Pain † 1	1/2218 (0.05%)	2/2241 (0.09%)
Peripheral swelling † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pseudocyst † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pyrexia † 1	33/2218 (1.49%)	37/2241 (1.65%)
Hepatobiliary disorders
Bile duct stone † 1	0/2218 (0.00%)	1/2241 (0.04%)
Biliary colic † 1	2/2218 (0.09%)	2/2241 (0.09%)
Cholangitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cholecystitis † 1	3/2218 (0.14%)	6/2241 (0.27%)
Cholecystitis acute † 1	4/2218 (0.18%)	3/2241 (0.13%)
Cholecystitis chronic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cholelithiasis † 1	4/2218 (0.18%)	5/2241 (0.22%)
Cholestasis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gallbladder non-functioning † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hepatic failure † 1	2/2218 (0.09%)	1/2241 (0.04%)
Hepatic function abnormal † 1	1/2218 (0.05%)	1/2241 (0.04%)
Hepatic steatosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hepatocellular injury † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hepatomegaly † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hyperbilirubinaemia † 1	1/2218 (0.05%)	1/2241 (0.04%)
Hyperplastic cholecystopathy † 1	1/2218 (0.05%)	0/2241 (0.00%)
Jaundice cholestatic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Immune system disorders
Allergy to vaccine † 1	0/2218 (0.00%)	1/2241 (0.04%)
Drug hypersensitivity † 1	3/2218 (0.14%)	2/2241 (0.09%)
Hypersensitivity † 1	2/2218 (0.09%)	3/2241 (0.13%)
Reaction to preservatives † 1	0/2218 (0.00%)	1/2241 (0.04%)
Infections and infestations
Abdominal abscess † 1	1/2218 (0.05%)	0/2241 (0.00%)
Anal abscess † 1	2/2218 (0.09%)	2/2241 (0.09%)
Appendiceal abscess † 1	0/2218 (0.00%)	1/2241 (0.04%)
Appendicitis † 1	3/2218 (0.14%)	7/2241 (0.31%)
Appendicitis perforated † 1	0/2218 (0.00%)	2/2241 (0.09%)
Atypical pneumonia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Bacteraemia † 1	1/2218 (0.05%)	2/2241 (0.09%)
Bacterial sepsis † 1	1/2218 (0.05%)	2/2241 (0.09%)
Bartholinitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast abscess † 1	3/2218 (0.14%)	5/2241 (0.22%)
Breast cellulitis † 1	18/2218 (0.81%)	20/2241 (0.89%)
Bronchitis † 1	3/2218 (0.14%)	4/2241 (0.18%)
Bursitis infective † 1	1/2218 (0.05%)	0/2241 (0.00%)
Campylobacter gastroenteritis † 1	0/2218 (0.00%)	3/2241 (0.13%)
Catheter site infection † 1	2/2218 (0.09%)	0/2241 (0.00%)
Cellulitis † 1	30/2218 (1.35%)	34/2241 (1.52%)
Cellulitis staphylococcal † 1	2/2218 (0.09%)	0/2241 (0.00%)
Cellulitis streptococcal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Chest wall abscess † 1	1/2218 (0.05%)	1/2241 (0.04%)
Clostridial infection † 1	1/2218 (0.05%)	0/2241 (0.00%)
Clostridium colitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Clostridium difficile colitis † 1	2/2218 (0.09%)	3/2241 (0.13%)
Clostridium difficile infection † 1	2/2218 (0.09%)	0/2241 (0.00%)
Colonic abscess † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cystitis † 1	2/2218 (0.09%)	1/2241 (0.04%)
Dengue fever † 1	0/2218 (0.00%)	2/2241 (0.09%)
Device related infection † 1	10/2218 (0.45%)	3/2241 (0.13%)
Device related sepsis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Diverticulitis † 1	8/2218 (0.36%)	1/2241 (0.04%)
Erysipelas † 1	4/2218 (0.18%)	14/2241 (0.62%)
Erysipelothrix infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Escherichia bacteraemia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Escherichia sepsis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Escherichia urinary tract infection † 1	2/2218 (0.09%)	4/2241 (0.18%)
Febrile infection † 1	1/2218 (0.05%)	0/2241 (0.00%)
Fungal skin infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Gastroenteritis † 1	3/2218 (0.14%)	2/2241 (0.09%)
Gastroenteritis salmonella † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gastroenteritis viral † 1	0/2218 (0.00%)	1/2241 (0.04%)
Genital herpes simplex † 1	0/2218 (0.00%)	1/2241 (0.04%)
H1N1 influenza † 1	1/2218 (0.05%)	1/2241 (0.04%)
Haemophilus infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hepatitis B † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hepatitis C † 1	1/2218 (0.05%)	0/2241 (0.00%)
Herpes zoster † 1	2/2218 (0.09%)	4/2241 (0.18%)
Infected fistula † 1	1/2218 (0.05%)	0/2241 (0.00%)
Infected seroma † 1	0/2218 (0.00%)	2/2241 (0.09%)
Infection † 1	2/2218 (0.09%)	1/2241 (0.04%)
Infectious colitis † 1	0/2218 (0.00%)	2/2241 (0.09%)
Influenza † 1	5/2218 (0.23%)	1/2241 (0.04%)
Intervertebral discitis † 1	0/2218 (0.00%)	2/2241 (0.09%)
Labyrinthitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Localised infection † 1	1/2218 (0.05%)	1/2241 (0.04%)
Lower respiratory tract infection † 1	3/2218 (0.14%)	6/2241 (0.27%)
Lower respiratory tract infection bacterial † 1	1/2218 (0.05%)	0/2241 (0.00%)
Lung infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lymphangitis † 1	3/2218 (0.14%)	2/2241 (0.09%)
Mastitis † 1	8/2218 (0.36%)	12/2241 (0.54%)
Mastitis bacterial † 1	1/2218 (0.05%)	0/2241 (0.00%)
Meningitis aseptic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Mycobacterial infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Necrotising fasciitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Neutropenic infection † 1	2/2218 (0.09%)	1/2241 (0.04%)
Neutropenic sepsis † 1	14/2218 (0.63%)	15/2241 (0.67%)
Oesophageal candidiasis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ophthalmic herpes zoster † 1	1/2218 (0.05%)	0/2241 (0.00%)
Oral candidiasis † 1	2/2218 (0.09%)	3/2241 (0.13%)
Osteomyelitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Osteomyelitis chronic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pelvic inflammatory disease † 1	1/2218 (0.05%)	1/2241 (0.04%)
Pericoronitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Perirectal abscess † 1	0/2218 (0.00%)	1/2241 (0.04%)
Peritoneal abscess † 1	1/2218 (0.05%)	0/2241 (0.00%)
Periumbilical abscess † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pharyngeal abscess † 1	1/2218 (0.05%)	1/2241 (0.04%)
Pharyngitis † 1	2/2218 (0.09%)	1/2241 (0.04%)
Pharyngitis streptococcal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pneumonia † 1	30/2218 (1.35%)	27/2241 (1.20%)
Pneumonia bacterial † 1	0/2218 (0.00%)	2/2241 (0.09%)
Pneumonia haemophilus † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pneumonia klebsiella † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pneumonia pneumococcal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pneumonia staphylococcal † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pneumonia streptococcal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Post procedural cellulitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Post procedural infection † 1	1/2218 (0.05%)	2/2241 (0.09%)
Postoperative abscess † 1	0/2218 (0.00%)	1/2241 (0.04%)
Postoperative wound infection † 1	9/2218 (0.41%)	7/2241 (0.31%)
Pseudomonal sepsis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pyelonephritis † 1	0/2218 (0.00%)	5/2241 (0.22%)
Pyelonephritis acute † 1	1/2218 (0.05%)	4/2241 (0.18%)
Respiratory tract infection † 1	1/2218 (0.05%)	3/2241 (0.13%)
Sebaceous gland infection † 1	1/2218 (0.05%)	0/2241 (0.00%)
Sepsis † 1	11/2218 (0.50%)	3/2241 (0.13%)
Septic shock † 1	2/2218 (0.09%)	2/2241 (0.09%)
Sinusitis † 1	1/2218 (0.05%)	3/2241 (0.13%)
Skin infection † 1	2/2218 (0.09%)	1/2241 (0.04%)
Staphylococcal infection † 1	2/2218 (0.09%)	4/2241 (0.18%)
Staphylococcal skin infection † 1	1/2218 (0.05%)	0/2241 (0.00%)
Streptococcal sepsis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Subcutaneous abscess † 1	1/2218 (0.05%)	0/2241 (0.00%)
Tooth abscess † 1	1/2218 (0.05%)	2/2241 (0.09%)
Tooth infection † 1	0/2218 (0.00%)	1/2241 (0.04%)
Tracheobronchitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Upper respiratory tract infection † 1	9/2218 (0.41%)	7/2241 (0.31%)
Upper respiratory tract infection bacterial † 1	1/2218 (0.05%)	0/2241 (0.00%)
Urinary tract infection † 1	13/2218 (0.59%)	6/2241 (0.27%)
Urinary tract infection bacterial † 1	2/2218 (0.09%)	2/2241 (0.09%)
Urinary tract infection pseudomonal † 1	0/2218 (0.00%)	1/2241 (0.04%)
Urosepsis † 1	3/2218 (0.14%)	1/2241 (0.04%)
Vestibular neuronitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Viral infection † 1	2/2218 (0.09%)	0/2241 (0.00%)
Viral upper respiratory tract infection † 1	3/2218 (0.14%)	1/2241 (0.04%)
Vulval abscess † 1	0/2218 (0.00%)	1/2241 (0.04%)
Vulvovaginal candidiasis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Wound infection † 1	2/2218 (0.09%)	1/2241 (0.04%)
Wound infection bacterial † 1	3/2218 (0.14%)	6/2241 (0.27%)
Wound infection staphylococcal † 1	3/2218 (0.14%)	1/2241 (0.04%)
Cystitis escherichia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence † 1	0/2218 (0.00%)	1/2241 (0.04%)
Accidental overdose † 1	1/2218 (0.05%)	0/2241 (0.00%)
Acetabulum fracture † 1	0/2218 (0.00%)	1/2241 (0.04%)
Alcohol poisoning † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ankle fracture † 1	1/2218 (0.05%)	1/2241 (0.04%)
Cartilage injury † 1	1/2218 (0.05%)	0/2241 (0.00%)
Concussion † 1	2/2218 (0.09%)	2/2241 (0.09%)
Craniocerebral injury † 1	0/2218 (0.00%)	1/2241 (0.04%)
Exposure to radiation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Facial bones fracture † 1	1/2218 (0.05%)	0/2241 (0.00%)
Fall † 1	2/2218 (0.09%)	1/2241 (0.04%)
Femoral neck fracture † 1	3/2218 (0.14%)	0/2241 (0.00%)
Femur fracture † 1	0/2218 (0.00%)	3/2241 (0.13%)
Fibula fracture † 1	6/2218 (0.27%)	3/2241 (0.13%)
Foot fracture † 1	0/2218 (0.00%)	3/2241 (0.13%)
Fracture † 1	0/2218 (0.00%)	2/2241 (0.09%)
Graft complication † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hand fracture † 1	1/2218 (0.05%)	0/2241 (0.00%)
Head injury † 1	1/2218 (0.05%)	0/2241 (0.00%)
Humerus fracture † 1	2/2218 (0.09%)	1/2241 (0.04%)
Incision site pain † 1	0/2218 (0.00%)	1/2241 (0.04%)
Incisional hernia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Infusion related reaction † 1	0/2218 (0.00%)	1/2241 (0.04%)
Intentional overdose † 1	0/2218 (0.00%)	1/2241 (0.04%)
Joint dislocation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Laceration † 1	1/2218 (0.05%)	1/2241 (0.04%)
Ligament sprain † 1	2/2218 (0.09%)	0/2241 (0.00%)
Lumbar vertebral fracture † 1	1/2218 (0.05%)	0/2241 (0.00%)
Meniscus injury † 1	0/2218 (0.00%)	1/2241 (0.04%)
Muscle strain † 1	1/2218 (0.05%)	0/2241 (0.00%)
Overdose † 1	1/2218 (0.05%)	1/2241 (0.04%)
Pneumothorax traumatic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Poisoning † 1	0/2218 (0.00%)	1/2241 (0.04%)
Post procedural complication † 1	2/2218 (0.09%)	2/2241 (0.09%)
Post procedural haematoma † 1	0/2218 (0.00%)	3/2241 (0.13%)
Post procedural inflammation † 1	0/2218 (0.00%)	2/2241 (0.09%)
Postmastectomy lymphoedema syndrome † 1	1/2218 (0.05%)	0/2241 (0.00%)
Postoperative renal failure † 1	1/2218 (0.05%)	0/2241 (0.00%)
Postoperative thrombosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Postoperative wound complication † 1	0/2218 (0.00%)	1/2241 (0.04%)
Procedural complication † 1	1/2218 (0.05%)	0/2241 (0.00%)
Procedural pain † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pubis fracture † 1	1/2218 (0.05%)	0/2241 (0.00%)
Radiation injury † 1	0/2218 (0.00%)	1/2241 (0.04%)
Radiation mastitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Radiation pneumonitis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Radius fracture † 1	6/2218 (0.27%)	0/2241 (0.00%)
Rib fracture † 1	0/2218 (0.00%)	1/2241 (0.04%)
Road traffic accident † 1	0/2218 (0.00%)	2/2241 (0.09%)
Scapula fracture † 1	0/2218 (0.00%)	1/2241 (0.04%)
Seroma † 1	6/2218 (0.27%)	5/2241 (0.22%)
Skin flap necrosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Subarachnoid haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Synovial rupture † 1	1/2218 (0.05%)	0/2241 (0.00%)
Thermal burn † 1	0/2218 (0.00%)	1/2241 (0.04%)
Tibia fracture † 1	2/2218 (0.09%)	3/2241 (0.13%)
Ulna fracture † 1	1/2218 (0.05%)	1/2241 (0.04%)
Wound dehiscence † 1	1/2218 (0.05%)	2/2241 (0.09%)
Wrist fracture † 1	4/2218 (0.18%)	1/2241 (0.04%)
Wrong drug administered † 1	0/2218 (0.00%)	1/2241 (0.04%)
Investigations
Alanine aminotransferase increased † 1	1/2218 (0.05%)	1/2241 (0.04%)
Aspartate aminotransferase increased † 1	1/2218 (0.05%)	1/2241 (0.04%)
Body temperature increased † 1	2/2218 (0.09%)	2/2241 (0.09%)
Bone scan abnormal † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cardiac murmur † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ejection fraction decreased † 1	2/2218 (0.09%)	0/2241 (0.00%)
Fibrin D dimer increased † 1	0/2218 (0.00%)	1/2241 (0.04%)
Haemoglobin decreased † 1	2/2218 (0.09%)	0/2241 (0.00%)
International normalised ratio increased † 1	0/2218 (0.00%)	2/2241 (0.09%)
Liver function test abnormal † 1	0/2218 (0.00%)	2/2241 (0.09%)
Neutrophil count abnormal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Neutrophil count decreased † 1	2/2218 (0.09%)	2/2241 (0.09%)
Oestradiol increased † 1	1/2218 (0.05%)	0/2241 (0.00%)
Oxygen saturation decreased † 1	1/2218 (0.05%)	0/2241 (0.00%)
Stroke volume increased † 1	1/2218 (0.05%)	0/2241 (0.00%)
Transaminases increased † 1	0/2218 (0.00%)	1/2241 (0.04%)
White blood cell count decreased † 1	1/2218 (0.05%)	0/2241 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/2218 (0.05%)	3/2241 (0.13%)
Dehydration † 1	8/2218 (0.36%)	16/2241 (0.71%)
Diabetes mellitus † 1	1/2218 (0.05%)	2/2241 (0.09%)
Diabetes mellitus inadequate control † 1	1/2218 (0.05%)	0/2241 (0.00%)
Electrolyte imbalance † 1	0/2218 (0.00%)	1/2241 (0.04%)
Fluid overload † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hypercalcaemia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hyperglycaemia † 1	2/2218 (0.09%)	0/2241 (0.00%)
Hypocalcaemia † 1	3/2218 (0.14%)	5/2241 (0.22%)
Hypoglycaemia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hypokalaemia † 1	1/2218 (0.05%)	6/2241 (0.27%)
Hyponatraemia † 1	1/2218 (0.05%)	1/2241 (0.04%)
Hypophosphataemia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hypovolaemia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Malnutrition † 1	0/2218 (0.00%)	1/2241 (0.04%)
Type 2 diabetes mellitus † 1	2/2218 (0.09%)	0/2241 (0.00%)
Vitamin D deficiency † 1	0/2218 (0.00%)	1/2241 (0.04%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/2218 (0.05%)	6/2241 (0.27%)
Arthritis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Back pain † 1	6/2218 (0.27%)	3/2241 (0.13%)
Bone pain † 1	1/2218 (0.05%)	1/2241 (0.04%)
Flank pain † 1	0/2218 (0.00%)	1/2241 (0.04%)
Foot deformity † 1	1/2218 (0.05%)	1/2241 (0.04%)
Intervertebral disc protrusion † 1	2/2218 (0.09%)	6/2241 (0.27%)
Jaw disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Joint instability † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lumbar spinal stenosis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Muscle haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Muscle spasms † 1	0/2218 (0.00%)	1/2241 (0.04%)
Muscular weakness † 1	1/2218 (0.05%)	3/2241 (0.13%)
Musculoskeletal pain † 1	1/2218 (0.05%)	2/2241 (0.09%)
Myalgia † 1	4/2218 (0.18%)	1/2241 (0.04%)
Neck pain † 1	1/2218 (0.05%)	1/2241 (0.04%)
Osteitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Osteoarthritis † 1	4/2218 (0.18%)	6/2241 (0.27%)
Osteochondritis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Osteochondrosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Osteonecrosis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Osteonecrosis of jaw † 1	0/2218 (0.00%)	30/2241 (1.34%)
Pain in extremity † 1	1/2218 (0.05%)	3/2241 (0.13%)
Pain in jaw † 1	0/2218 (0.00%)	1/2241 (0.04%)
Periarthritis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Periostitis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Soft tissue necrosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Synovial cyst † 1	0/2218 (0.00%)	1/2241 (0.04%)
Synovitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Tendon disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Tenosynovitis stenosans † 1	0/2218 (0.00%)	1/2241 (0.04%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon † 1	1/2218 (0.05%)	0/2241 (0.00%)
Acute leukaemia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Acute myeloid leukaemia † 1	1/2218 (0.05%)	1/2241 (0.04%)
Adenocarcinoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Adenocarcinoma gastric † 1	1/2218 (0.05%)	0/2241 (0.00%)
Adenocarcinoma of colon † 1	2/2218 (0.09%)	0/2241 (0.00%)
Adenolipoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Appendix cancer † 1	0/2218 (0.00%)	1/2241 (0.04%)
B-cell lymphoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
B-cell small lymphocytic lymphoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Basal cell carcinoma † 1	0/2218 (0.00%)	4/2241 (0.18%)
Benign neoplasm of thymus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Benign neoplasm of thyroid gland † 1	0/2218 (0.00%)	1/2241 (0.04%)
Bladder transitional cell carcinoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Bladder transitional cell carcinoma stage III † 1	0/2218 (0.00%)	1/2241 (0.04%)
Bone neoplasm † 1	1/2218 (0.05%)	0/2241 (0.00%)
Bowen's disease † 1	1/2218 (0.05%)	0/2241 (0.00%)
Brain cancer metastatic † 1	1/2218 (0.05%)	1/2241 (0.04%)
Breast cancer † 1	3/2218 (0.14%)	8/2241 (0.36%)
Breast cancer metastatic † 1	3/2218 (0.14%)	4/2241 (0.18%)
Breast cancer recurrent † 1	2/2218 (0.09%)	2/2241 (0.09%)
Cancer pain † 1	0/2218 (0.00%)	2/2241 (0.09%)
Chest wall tumour † 1	1/2218 (0.05%)	0/2241 (0.00%)
Chronic myeloid leukaemia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Colon cancer † 1	5/2218 (0.23%)	1/2241 (0.04%)
Colorectal adenocarcinoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Endometrial adenocarcinoma † 1	1/2218 (0.05%)	1/2241 (0.04%)
Endometrial adenoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Endometrial cancer † 1	1/2218 (0.05%)	1/2241 (0.04%)
Endometrial cancer stage I † 1	0/2218 (0.00%)	1/2241 (0.04%)
Endometrial stromal sarcoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Extranodal marginal zone B-cell lymphoma (MALT type) † 1	0/2218 (0.00%)	1/2241 (0.04%)
Fallopian tube cancer † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gastric cancer † 1	1/2218 (0.05%)	0/2241 (0.00%)
Gastric neoplasm † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hepatic cancer † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hepatocellular carcinoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Intestinal metastasis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Intraductal proliferative breast lesion † 1	1/2218 (0.05%)	1/2241 (0.04%)
Invasive ductal breast carcinoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Large intestine benign neoplasm † 1	1/2218 (0.05%)	0/2241 (0.00%)
Leiomyoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Leiomyosarcoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Leiomyosarcoma metastatic † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lung adenocarcinoma † 1	3/2218 (0.14%)	2/2241 (0.09%)
Lung adenocarcinoma stage IV † 1	1/2218 (0.05%)	0/2241 (0.00%)
Lung cancer metastatic † 1	1/2218 (0.05%)	0/2241 (0.00%)
Lung neoplasm malignant † 1	1/2218 (0.05%)	0/2241 (0.00%)
Lymphangiosis carcinomatosa † 1	2/2218 (0.09%)	1/2241 (0.04%)
Malignant melanoma † 1	2/2218 (0.09%)	0/2241 (0.00%)
Malignant melanoma stage III † 1	1/2218 (0.05%)	0/2241 (0.00%)
Malignant neoplasm of thorax † 1	0/2218 (0.00%)	1/2241 (0.04%)
Malignant neoplasm progression † 1	1/2218 (0.05%)	0/2241 (0.00%)
Malignant pleural effusion † 1	3/2218 (0.14%)	0/2241 (0.00%)
Meningioma † 1	1/2218 (0.05%)	1/2241 (0.04%)
Metastases to bone † 1	0/2218 (0.00%)	1/2241 (0.04%)
Metastases to breast † 1	0/2218 (0.00%)	1/2241 (0.04%)
Metastases to central nervous system † 1	17/2218 (0.77%)	15/2241 (0.67%)
Metastases to liver † 1	4/2218 (0.18%)	3/2241 (0.13%)
Metastases to lung † 1	4/2218 (0.18%)	7/2241 (0.31%)
Metastases to lymph nodes † 1	0/2218 (0.00%)	1/2241 (0.04%)
Metastases to meninges † 1	3/2218 (0.14%)	0/2241 (0.00%)
Metastases to ovary † 1	2/2218 (0.09%)	0/2241 (0.00%)
Metastases to peritoneum † 1	1/2218 (0.05%)	0/2241 (0.00%)
Metastases to skin † 1	1/2218 (0.05%)	0/2241 (0.00%)
Metastatic neoplasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Neuroendocrine carcinoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Non-small cell lung cancer stage I † 1	1/2218 (0.05%)	0/2241 (0.00%)
Oesophageal neoplasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ovarian adenoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Ovarian cancer † 1	1/2218 (0.05%)	1/2241 (0.04%)
Ovarian cancer stage III † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ovarian epithelial cancer † 1	1/2218 (0.05%)	0/2241 (0.00%)
Ovarian neoplasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Paget's disease of the vulva † 1	1/2218 (0.05%)	0/2241 (0.00%)
Papillary thyroid cancer † 1	2/2218 (0.09%)	1/2241 (0.04%)
Paraneoplastic syndrome † 1	1/2218 (0.05%)	0/2241 (0.00%)
Parathyroid tumour benign † 1	0/2218 (0.00%)	1/2241 (0.04%)
Rectal adenocarcinoma † 1	1/2218 (0.05%)	1/2241 (0.04%)
Rectal cancer † 1	1/2218 (0.05%)	3/2241 (0.13%)
Renal cancer † 1	0/2218 (0.00%)	1/2241 (0.04%)
Renal cancer stage I † 1	1/2218 (0.05%)	0/2241 (0.00%)
Renal cell carcinoma † 1	0/2218 (0.00%)	2/2241 (0.09%)
Retro-orbital neoplasm † 1	1/2218 (0.05%)	0/2241 (0.00%)
Small intestine carcinoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Squamous cell carcinoma of the cervix † 1	0/2218 (0.00%)	1/2241 (0.04%)
Thymoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Thyroid cancer † 1	1/2218 (0.05%)	0/2241 (0.00%)
Thyroid neoplasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Uterine leiomyoma † 1	5/2218 (0.23%)	5/2241 (0.22%)
Astrocytoma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Papilloma † 1	0/2218 (0.00%)	1/2241 (0.04%)
Nervous system disorders
Aphasia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ataxia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Brain oedema † 1	1/2218 (0.05%)	3/2241 (0.13%)
Carotid artery stenosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Carpal tunnel syndrome † 1	1/2218 (0.05%)	1/2241 (0.04%)
Cerebellar ataxia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cerebellar infarction † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cerebral disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cerebral haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cerebral infarction † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cerebral ischaemia † 1	3/2218 (0.14%)	1/2241 (0.04%)
Cerebrospinal fistula † 1	0/2218 (0.00%)	1/2241 (0.04%)
Cerebrovascular accident † 1	6/2218 (0.27%)	5/2241 (0.22%)
Cervical radiculopathy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Coma hepatic † 1	1/2218 (0.05%)	0/2241 (0.00%)
Dementia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Dementia with Lewy bodies † 1	1/2218 (0.05%)	0/2241 (0.00%)
Depressed level of consciousness † 1	1/2218 (0.05%)	2/2241 (0.09%)
Dizziness † 1	4/2218 (0.18%)	3/2241 (0.13%)
Dystonia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Encephalopathy † 1	1/2218 (0.05%)	0/2241 (0.00%)
Epilepsy † 1	0/2218 (0.00%)	2/2241 (0.09%)
Facial neuralgia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Facial paralysis † 1	2/2218 (0.09%)	1/2241 (0.04%)
Headache † 1	3/2218 (0.14%)	10/2241 (0.45%)
Hemiparesis † 1	0/2218 (0.00%)	2/2241 (0.09%)
Hydrocephalus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Intracranial aneurysm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ischaemic stroke † 1	0/2218 (0.00%)	3/2241 (0.13%)
Lethargy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Loss of consciousness † 1	0/2218 (0.00%)	1/2241 (0.04%)
Migraine † 1	1/2218 (0.05%)	1/2241 (0.04%)
Myoclonus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Neurological symptom † 1	0/2218 (0.00%)	1/2241 (0.04%)
Neuropathy peripheral † 1	1/2218 (0.05%)	0/2241 (0.00%)
Occipital neuralgia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Peripheral sensory neuropathy † 1	1/2218 (0.05%)	0/2241 (0.00%)
Presyncope † 1	1/2218 (0.05%)	1/2241 (0.04%)
Psychomotor hyperactivity † 1	0/2218 (0.00%)	1/2241 (0.04%)
Ruptured cerebral aneurysm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Sciatica † 1	1/2218 (0.05%)	1/2241 (0.04%)
Seizure † 1	4/2218 (0.18%)	5/2241 (0.22%)
Somnolence † 1	0/2218 (0.00%)	1/2241 (0.04%)
Status epilepticus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Superior sagittal sinus thrombosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Syncope † 1	9/2218 (0.41%)	2/2241 (0.09%)
Thrombotic stroke † 1	1/2218 (0.05%)	0/2241 (0.00%)
Transient ischaemic attack † 1	4/2218 (0.18%)	3/2241 (0.13%)
Trigeminal nerve disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Visual field defect † 1	0/2218 (0.00%)	1/2241 (0.04%)
IIIrd nerve paralysis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Nerve root compression † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pregnancy, puerperium and perinatal conditions
Foetal death † 1	0/2218 (0.00%)	1/2241 (0.04%)
Product Issues
Device expulsion † 1	0/2218 (0.00%)	1/2241 (0.04%)
Device failure † 1	0/2218 (0.00%)	1/2241 (0.04%)
Psychiatric disorders
Alcoholism † 1	1/2218 (0.05%)	0/2241 (0.00%)
Anxiety † 1	0/2218 (0.00%)	7/2241 (0.31%)
Anxiety disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Completed suicide † 1	1/2218 (0.05%)	0/2241 (0.00%)
Confusional state † 1	3/2218 (0.14%)	0/2241 (0.00%)
Delirium † 1	1/2218 (0.05%)	0/2241 (0.00%)
Depressed mood † 1	1/2218 (0.05%)	0/2241 (0.00%)
Depression † 1	2/2218 (0.09%)	8/2241 (0.36%)
Hypomania † 1	1/2218 (0.05%)	0/2241 (0.00%)
Insomnia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Major depression † 1	1/2218 (0.05%)	0/2241 (0.00%)
Mania † 1	0/2218 (0.00%)	1/2241 (0.04%)
Persistent depressive disorder † 1	2/2218 (0.09%)	0/2241 (0.00%)
Psychomotor retardation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Psychotic disorder † 1	1/2218 (0.05%)	1/2241 (0.04%)
Restlessness † 1	0/2218 (0.00%)	1/2241 (0.04%)
Suicidal ideation † 1	1/2218 (0.05%)	2/2241 (0.09%)
Renal and urinary disorders
Acute kidney injury † 1	3/2218 (0.14%)	6/2241 (0.27%)
Bladder perforation † 1	1/2218 (0.05%)	0/2241 (0.00%)
Calculus bladder † 1	1/2218 (0.05%)	0/2241 (0.00%)
Dysuria † 1	0/2218 (0.00%)	1/2241 (0.04%)
Haematuria † 1	0/2218 (0.00%)	2/2241 (0.09%)
Hydronephrosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Nephrocalcinosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Renal failure † 1	3/2218 (0.14%)	2/2241 (0.09%)
Renal impairment † 1	1/2218 (0.05%)	1/2241 (0.04%)
Ureteric stenosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Urinary incontinence † 1	1/2218 (0.05%)	0/2241 (0.00%)
Urinary retention † 1	0/2218 (0.00%)	1/2241 (0.04%)
Reproductive system and breast disorders
Bartholin's cyst † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast haematoma † 1	1/2218 (0.05%)	2/2241 (0.09%)
Breast inflammation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast mass † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast necrosis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Breast pain † 1	2/2218 (0.09%)	1/2241 (0.04%)
Cervical dysplasia † 1	2/2218 (0.09%)	3/2241 (0.13%)
Cystocele † 1	1/2218 (0.05%)	0/2241 (0.00%)
Dysfunctional uterine bleeding † 1	0/2218 (0.00%)	1/2241 (0.04%)
Endometrial disorder † 1	1/2218 (0.05%)	0/2241 (0.00%)
Endometrial hyperplasia † 1	4/2218 (0.18%)	7/2241 (0.31%)
Endometriosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Genital haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Genital prolapse † 1	1/2218 (0.05%)	0/2241 (0.00%)
Haemorrhagic ovarian cyst † 1	0/2218 (0.00%)	1/2241 (0.04%)
Menometrorrhagia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Menopausal symptoms † 1	1/2218 (0.05%)	0/2241 (0.00%)
Menorrhagia † 1	2/2218 (0.09%)	1/2241 (0.04%)
Metrorrhagia † 1	1/2218 (0.05%)	0/2241 (0.00%)
Ovarian cyst † 1	7/2218 (0.32%)	3/2241 (0.13%)
Ovarian enlargement † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pelvic pain † 1	1/2218 (0.05%)	0/2241 (0.00%)
Postmenopausal haemorrhage † 1	1/2218 (0.05%)	0/2241 (0.00%)
Uterine polyp † 1	2/2218 (0.09%)	3/2241 (0.13%)
Uterine prolapse † 1	4/2218 (0.18%)	0/2241 (0.00%)
Vaginal haemorrhage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	0/2218 (0.00%)	1/2241 (0.04%)
Acute respiratory distress syndrome † 1	3/2218 (0.14%)	0/2241 (0.00%)
Asthma † 1	4/2218 (0.18%)	0/2241 (0.00%)
Atelectasis † 1	0/2218 (0.00%)	2/2241 (0.09%)
Chronic obstructive pulmonary disease † 1	0/2218 (0.00%)	3/2241 (0.13%)
Cough † 1	1/2218 (0.05%)	2/2241 (0.09%)
Dyspnoea † 1	10/2218 (0.45%)	13/2241 (0.58%)
Dyspnoea at rest † 1	1/2218 (0.05%)	0/2241 (0.00%)
Dyspnoea exertional † 1	2/2218 (0.09%)	0/2241 (0.00%)
Epistaxis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hyperventilation † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hypoxia † 1	2/2218 (0.09%)	1/2241 (0.04%)
Interstitial lung disease † 1	0/2218 (0.00%)	1/2241 (0.04%)
Laryngospasm † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lung disorder † 1	1/2218 (0.05%)	1/2241 (0.04%)
Lung infiltration † 1	1/2218 (0.05%)	1/2241 (0.04%)
Obstructive airways disorder † 1	1/2218 (0.05%)	0/2241 (0.00%)
Organising pneumonia † 1	0/2218 (0.00%)	1/2241 (0.04%)
Oropharyngeal pain † 1	1/2218 (0.05%)	1/2241 (0.04%)
Pleural effusion † 1	5/2218 (0.23%)	4/2241 (0.18%)
Pleurisy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pneumonia aspiration † 1	0/2218 (0.00%)	1/2241 (0.04%)
Pneumonitis † 1	2/2218 (0.09%)	6/2241 (0.27%)
Pneumothorax † 1	2/2218 (0.09%)	3/2241 (0.13%)
Productive cough † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pulmonary embolism † 1	20/2218 (0.90%)	17/2241 (0.76%)
Pulmonary mass † 1	1/2218 (0.05%)	1/2241 (0.04%)
Respiratory arrest † 1	0/2218 (0.00%)	1/2241 (0.04%)
Respiratory failure † 1	7/2218 (0.32%)	2/2241 (0.09%)
Vocal cord polyp † 1	0/2218 (0.00%)	1/2241 (0.04%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/2218 (0.05%)	0/2241 (0.00%)
Dermatitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Erythema † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lichen sclerosus † 1	1/2218 (0.05%)	0/2241 (0.00%)
Onycholysis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Pain of skin † 1	0/2218 (0.00%)	1/2241 (0.04%)
Rash † 1	1/2218 (0.05%)	1/2241 (0.04%)
Rash papular † 1	0/2218 (0.00%)	1/2241 (0.04%)
Segmented hyalinising vasculitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Skin ulcer † 1	0/2218 (0.00%)	2/2241 (0.09%)
Toxic skin eruption † 1	0/2218 (0.00%)	1/2241 (0.04%)
Urticaria † 1	1/2218 (0.05%)	0/2241 (0.00%)
Surgical and medical procedures
Ankle arthroplasty † 1	0/2218 (0.00%)	1/2241 (0.04%)
Breast conserving surgery † 1	1/2218 (0.05%)	0/2241 (0.00%)
Breast operation † 1	1/2218 (0.05%)	0/2241 (0.00%)
Breast reconstruction † 1	2/2218 (0.09%)	2/2241 (0.09%)
Cancer surgery † 1	0/2218 (0.00%)	1/2241 (0.04%)
Catheter removal † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cervical polypectomy † 1	1/2218 (0.05%)	0/2241 (0.00%)
Cholecystectomy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Hysterectomy † 1	1/2218 (0.05%)	0/2241 (0.00%)
Incisional drainage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Mammoplasty † 1	1/2218 (0.05%)	0/2241 (0.00%)
Oophorectomy bilateral † 1	1/2218 (0.05%)	0/2241 (0.00%)
Salpingo-oophorectomy bilateral † 1	1/2218 (0.05%)	0/2241 (0.00%)
Uterine dilation and curettage † 1	0/2218 (0.00%)	1/2241 (0.04%)
Mastectomy † 1	0/2218 (0.00%)	1/2241 (0.04%)
Vascular disorders
Aortic stenosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Arteritis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Brachiocephalic vein thrombosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Circulatory collapse † 1	0/2218 (0.00%)	1/2241 (0.04%)
Deep vein thrombosis † 1	12/2218 (0.54%)	9/2241 (0.40%)
Embolism † 1	1/2218 (0.05%)	1/2241 (0.04%)
Embolism arterial † 1	0/2218 (0.00%)	1/2241 (0.04%)
Embolism venous † 1	0/2218 (0.00%)	1/2241 (0.04%)
Haematoma † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hypertension † 1	3/2218 (0.14%)	3/2241 (0.13%)
Hypertensive crisis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Hypotension † 1	6/2218 (0.27%)	7/2241 (0.31%)
Intermittent claudication † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lymphocele † 1	0/2218 (0.00%)	1/2241 (0.04%)
Lymphoedema † 1	2/2218 (0.09%)	5/2241 (0.22%)
Peripheral arterial occlusive disease † 1	1/2218 (0.05%)	0/2241 (0.00%)
Peripheral artery stenosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Peripheral artery thrombosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Peripheral vascular disorder † 1	0/2218 (0.00%)	1/2241 (0.04%)
Phlebitis † 1	2/2218 (0.09%)	0/2241 (0.00%)
Shock † 1	1/2218 (0.05%)	0/2241 (0.00%)
Subclavian artery thrombosis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Subclavian vein thrombosis † 1	1/2218 (0.05%)	1/2241 (0.04%)
Superior vena cava syndrome † 1	1/2218 (0.05%)	3/2241 (0.13%)
Thrombophlebitis † 1	1/2218 (0.05%)	0/2241 (0.00%)
Thrombophlebitis superficial † 1	3/2218 (0.14%)	0/2241 (0.00%)
Thrombosis † 1	2/2218 (0.09%)	2/2241 (0.09%)
Varicose vein † 1	1/2218 (0.05%)	2/2241 (0.09%)
Vena cava thrombosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
Venous thrombosis † 1	0/2218 (0.00%)	1/2241 (0.04%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Denosumab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2123/2218 (95.72%)	2149/2241 (95.89%)
Blood and lymphatic system disorders
Anaemia † 1	349/2218 (15.73%)	354/2241 (15.80%)
Leukopenia † 1	154/2218 (6.94%)	145/2241 (6.47%)
Neutropenia † 1	461/2218 (20.78%)	441/2241 (19.68%)
Eye disorders
Lacrimation increased † 1	243/2218 (10.96%)	195/2241 (8.70%)
Gastrointestinal disorders
Abdominal pain † 1	242/2218 (10.91%)	232/2241 (10.35%)
Abdominal pain upper † 1	199/2218 (8.97%)	179/2241 (7.99%)
Constipation † 1	635/2218 (28.63%)	626/2241 (27.93%)
Diarrhoea † 1	638/2218 (28.76%)	660/2241 (29.45%)
Dyspepsia † 1	245/2218 (11.05%)	273/2241 (12.18%)
Nausea † 1	1095/2218 (49.37%)	1145/2241 (51.09%)
Stomatitis † 1	398/2218 (17.94%)	399/2241 (17.80%)
Toothache † 1	159/2218 (7.17%)	198/2241 (8.84%)
Vomiting † 1	536/2218 (24.17%)	536/2241 (23.92%)
General disorders
Asthenia † 1	404/2218 (18.21%)	407/2241 (18.16%)
Fatigue † 1	893/2218 (40.26%)	901/2241 (40.21%)
Influenza like illness † 1	145/2218 (6.54%)	154/2241 (6.87%)
Mucosal inflammation † 1	278/2218 (12.53%)	281/2241 (12.54%)
Oedema † 1	112/2218 (5.05%)	106/2241 (4.73%)
Oedema peripheral † 1	397/2218 (17.90%)	380/2241 (16.96%)
Pain † 1	178/2218 (8.03%)	156/2241 (6.96%)
Pyrexia † 1	342/2218 (15.42%)	338/2241 (15.08%)
Infections and infestations
Bronchitis † 1	112/2218 (5.05%)	86/2241 (3.84%)
Influenza † 1	117/2218 (5.28%)	117/2241 (5.22%)
Nasopharyngitis † 1	290/2218 (13.07%)	292/2241 (13.03%)
Sinusitis † 1	101/2218 (4.55%)	113/2241 (5.04%)
Upper respiratory tract infection † 1	195/2218 (8.79%)	206/2241 (9.19%)
Urinary tract infection † 1	149/2218 (6.72%)	177/2241 (7.90%)
Injury, poisoning and procedural complications
Procedural pain † 1	161/2218 (7.26%)	170/2241 (7.59%)
Radiation skin injury † 1	351/2218 (15.83%)	361/2241 (16.11%)
Investigations
Weight increased † 1	151/2218 (6.81%)	167/2241 (7.45%)
Metabolism and nutrition disorders
Decreased appetite † 1	289/2218 (13.03%)	330/2241 (14.73%)
Hypocalcaemia † 1	73/2218 (3.29%)	135/2241 (6.02%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	974/2218 (43.91%)	973/2241 (43.42%)
Back pain † 1	486/2218 (21.91%)	563/2241 (25.12%)
Bone pain † 1	256/2218 (11.54%)	288/2241 (12.85%)
Muscle spasms † 1	204/2218 (9.20%)	201/2241 (8.97%)
Musculoskeletal chest pain † 1	143/2218 (6.45%)	129/2241 (5.76%)
Musculoskeletal pain † 1	308/2218 (13.89%)	337/2241 (15.04%)
Myalgia † 1	539/2218 (24.30%)	553/2241 (24.68%)
Neck pain † 1	112/2218 (5.05%)	106/2241 (4.73%)
Pain in extremity † 1	545/2218 (24.57%)	570/2241 (25.44%)
Pain in jaw † 1	124/2218 (5.59%)	150/2241 (6.69%)
Nervous system disorders
Dizziness † 1	255/2218 (11.50%)	273/2241 (12.18%)
Dysgeusia † 1	344/2218 (15.51%)	351/2241 (15.66%)
Headache † 1	567/2218 (25.56%)	527/2241 (23.52%)
Hypoaesthesia † 1	112/2218 (5.05%)	112/2241 (5.00%)
Neuropathy peripheral † 1	421/2218 (18.98%)	417/2241 (18.61%)
Paraesthesia † 1	197/2218 (8.88%)	216/2241 (9.64%)
Peripheral sensory neuropathy † 1	177/2218 (7.98%)	198/2241 (8.84%)
Psychiatric disorders
Anxiety † 1	207/2218 (9.33%)	220/2241 (9.82%)
Depression † 1	202/2218 (9.11%)	195/2241 (8.70%)
Insomnia † 1	432/2218 (19.48%)	429/2241 (19.14%)
Reproductive system and breast disorders
Breast pain † 1	189/2218 (8.52%)	178/2241 (7.94%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	426/2218 (19.21%)	410/2241 (18.30%)
Dyspnoea † 1	268/2218 (12.08%)	280/2241 (12.49%)
Epistaxis † 1	151/2218 (6.81%)	168/2241 (7.50%)
Oropharyngeal pain † 1	176/2218 (7.94%)	157/2241 (7.01%)
Skin and subcutaneous tissue disorders
Alopecia † 1	923/2218 (41.61%)	938/2241 (41.86%)
Dermatitis † 1	112/2218 (5.05%)	107/2241 (4.77%)
Dry skin † 1	133/2218 (6.00%)	125/2241 (5.58%)
Erythema † 1	226/2218 (10.19%)	260/2241 (11.60%)
Nail disorder † 1	264/2218 (11.90%)	275/2241 (12.27%)
Palmar-plantar erythrodysaesthesia syndrome † 1	114/2218 (5.14%)	138/2241 (6.16%)
Pruritus † 1	181/2218 (8.16%)	144/2241 (6.43%)
Rash † 1	372/2218 (16.77%)	392/2241 (17.49%)
Vascular disorders
Hot flush † 1	645/2218 (29.08%)	669/2241 (29.85%)
Hypertension † 1	209/2218 (9.42%)	195/2241 (8.70%)
Lymphoedema † 1	350/2218 (15.78%)	392/2241 (17.49%)
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment

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:

Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Perianez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. doi: 10.1016/S1470-2045(19)30687-4. Epub 2019 Dec 2.

Coleman R, Zhou Y, Jandial D, Cadieux B, Chan A. Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer. Adv Ther. 2021 Aug;38(8):4569-4580. doi: 10.1007/s12325-021-01812-9. Epub 2021 Jun 29.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01077154
• Other Study ID Numbers: 20060359; 2009-011299-32 ( EudraCT Number )
• First Submitted: February 4, 2010
• First Posted: February 26, 2010
• Results First Submitted: August 13, 2018
• Results First Posted: October 3, 2018
• Last Update Posted: September 28, 2021