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

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ClinicalTrials.gov Identifier: NCT01077154
Recruitment Status : Terminated (Terminated: Amgen decision following Primary Analysis. Not due to safety reason)
First Posted : February 26, 2010
Results First Posted : October 3, 2018
Last Update Posted : April 5, 2019
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
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
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
Hide 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
Arm/Group Title Placebo Denosumab Total
Hide 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
Hide 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:

  1. neo-adjuvant therapy / any LN status;
  2. adjuvant therapy / LN negative (based on axillary LN dissection, or based on sentinel node [SN] status);
  3. 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

  1. ER and/or PR positive
  2. 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.
1.Primary Outcome
Title Bone Metastasis-free Survival (BMFS)
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Placebo Denosumab
Hide 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)
Show Statistical Analysis 1 Hide 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)
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Placebo Denosumab
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Placebo Denosumab
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Placebo Denosumab
Hide 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)
Show Statistical Analysis 1 Hide 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.
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
Hide 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%) 
Show Serious Adverse Events Hide 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
Show Other (Not Including Serious) Adverse Events Hide 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
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
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Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
EMail: medinfo@amgen.com
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01077154     History of Changes
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: April 5, 2019