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PALbociclib CoLlaborative Adjuvant Study (PALLAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02513394
Recruitment Status : Active, not recruiting
First Posted : July 31, 2015
Results First Posted : April 13, 2022
Last Update Posted : April 13, 2022
Sponsor:
Collaborators:
Austrian Breast & Colorectal Cancer Study Group
NSABP Foundation Inc
PrECOG, LLC.
Breast International Group
Pfizer
Information provided by (Responsible Party):
Alliance Foundation Trials, LLC.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: Palbociclib
Drug: Standard Adjuvant Endocrine Therapy
Enrollment 5796
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years. Standard adjuvant endocrine therapy for a duration of at least 5 years.
Period Title: Overall Study
Started 2896 2900
Completed 2884 2877
Not Completed 12 23
Reason Not Completed
Withdrawal by Subject             11             23
Ineligible             1             0
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B) Total
Hide Arm/Group Description Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years. Standard adjuvant endocrine therapy for a duration of at least 5 years. Total of all reporting groups
Overall Number of Baseline Participants 2884 2877 5761
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 2884 participants 2877 participants 5761 participants
52
(25 to 90)
52
(22 to 85)
52
(22 to 90)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2884 participants 2877 participants 5761 participants
Female
2867
  99.4%
2858
  99.3%
5725
  99.4%
Male
17
   0.6%
19
   0.7%
36
   0.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2884 participants 2877 participants 5761 participants
Hispanic or Latino
138
   4.8%
127
   4.4%
265
   4.6%
Not Hispanic or Latino
2504
  86.8%
2532
  88.0%
5036
  87.4%
Unknown or Not Reported
242
   8.4%
218
   7.6%
460
   8.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 2884 participants 2877 participants 5761 participants
Asain
138
   4.8%
141
   4.9%
279
   4.8%
Black or African American/African Heritage
74
   2.6%
75
   2.6%
149
   2.6%
White
2521
  87.4%
2498
  86.8%
5019
  87.1%
Native Hawaiian or other Pacific Islander
4
   0.1%
8
   0.3%
12
   0.2%
American Indian or Alaska Native
14
   0.5%
22
   0.8%
36
   0.6%
Other
37
   1.3%
36
   1.3%
73
   1.3%
Unknown
96
   3.3%
97
   3.4%
193
   3.4%
1.Primary Outcome
Title Invasive Disease Free Survival (iDFS)
Hide Description Invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC) at 4 years. iDFS is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant recurrence, second primary invasive cancer of non-breast origin or death from any cause. Direct comparison between arms used time to iDFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered iDFS at 4 years is reported.
Time Frame 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description:
Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years.
Standard adjuvant endocrine therapy for a duration of at least 5 years.
Overall Number of Participants Analyzed 2884 2877
Measure Type: Number
Unit of Measure: percentage of participants
84.2 84.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Palbociclib Plus Endocrine Therapy (Arm A), Endocrine Therapy Alone (Arm B)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.65
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.81 to 1.14
Estimation Comments This two sided p value was stratified by (neo)adjuvant chemotherapy (yes vs no) and age (<=50 vs >50).
2.Secondary Outcome
Title Invasive Disease Free Survival (iDFS) Excluding Second Primary Invasive Cancers of Non-breast Origin.
Hide Description Invasive disease-free survival (iDFS, excluding second primary invasive cancers of non-breast origin) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC) at 4 years. iDFS excluding second primary invasive cancers of non-breast origin is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause. Second primary invasive cancers of non-breast origin will not be considered as events for this endpoint. Direct comparison between arms used time to iDFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered iDFS at 4 years is reported.
Time Frame 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description:
Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years.
Standard adjuvant endocrine therapy for a duration of at least 5 years.
Overall Number of Participants Analyzed 2884 2877
Measure Type: Number
Unit of Measure: percentage of patients
85.4 86.0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Palbociclib Plus Endocrine Therapy (Arm A), Endocrine Therapy Alone (Arm B)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.82 to 1.19
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Distant Recurrence-free Survival (DRFS)
Hide Description Compare time to distant recurrence-free survival (DRFS). Distant recurrence is defined according to STEEP criteria as the time from randomization to the date of the first event: distant recurrence or death from any cause. Patients with a locoregional recurrence will continue to be followed for DRFS. Surviving patients who are event-free will be censored at: the date of last disease assessment, or withdrawal of consent to be followed, or death whichever came first. Direct comparison between arms used time to DRFS events and Kaplan-Meier Log-rank analysis. Due to the medians not yet achieved, the percentage of patients considered DRFS at 4 years is reported.
Time Frame 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description:
Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years.
Standard adjuvant endocrine therapy for a duration of at least 5 years.
Overall Number of Participants Analyzed 2884 2877
Measure Type: Number
Unit of Measure: percentage of patients
86.2 87.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Palbociclib Plus Endocrine Therapy (Arm A), Endocrine Therapy Alone (Arm B)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.87 to 1.28
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Overall Survival (OS)
Hide Description Compare overall survival (OS). Overall survival is defined as the time period between randomization and death. Surviving patients classified as lost-to-follow up or having withdrawn consent to be followed will be censored at their date of last contact or withdrawal of consent to be followed, whichever occurs first.
Time Frame 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description:
Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years.
Standard adjuvant endocrine therapy for a duration of at least 5 years.
Overall Number of Participants Analyzed 2884 2877
Measure Type: Number
Unit of Measure: percentage of patients
93.8 95.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Palbociclib Plus Endocrine Therapy (Arm A), Endocrine Therapy Alone (Arm B)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.32
Confidence Interval (2-Sided) 95%
0.98 to 1.78
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Locoregional Recurrences-free Survival (LRRFS)
Hide Description Compare locoregional recurrence-free survival (LRRFS). LRRFS is defined as the time from randomization to the date of the first event: local/regional invasive ipsilateral recurrence, contralateral invasive breast cancer, or death from any cause. Patients with second primary invasive cancers of non-breast origin or distant recurrence will be censored at the date of diagnosis. Surviving patients who are event-free will be censored at: the date of last disease assessment, or withdrawal of consent to be followed, whichever occurs first.
Time Frame 4 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description:
Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years.
Standard adjuvant endocrine therapy for a duration of at least 5 years.
Overall Number of Participants Analyzed 2884 2877
Measure Type: Number
Unit of Measure: percentage of patients
96.8 95.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Palbociclib Plus Endocrine Therapy (Arm A), Endocrine Therapy Alone (Arm B)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.57 to 1.23
Estimation Comments [Not Specified]
Time Frame 4 years
Adverse Event Reporting Description The safety analysis is conducted in the "as-treated" population. Patients randomly assigned to the Arm A who never received Palbociclib but received endocrine therapy (N=36) were included in Arm B for the safety analyses. Thus, the safety analysis included 2841 patients who received at least one dose of Palbociclib plus endocrine therapy and 2902 patients who received endocrine therapy (which included 36 patients from Arm A who received endocrine therapy only).
 
Arm/Group Title Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Hide Arm/Group Description Palbociclib at a dose of 125 mg orally once daily, Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle for a total duration of 2 years, in addition to standard adjuvant endocrine therapy for a duration of at least 5 years. Standard adjuvant endocrine therapy for a duration of at least 5 years.
All-Cause Mortality
Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Affected / at Risk (%) Affected / at Risk (%)
Total   99/2841 (3.48%)      76/2902 (2.62%)    
Hide Serious Adverse Events
Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   369/2841 (12.99%)      229/2902 (7.89%)    
Blood and lymphatic system disorders     
Anaemia  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Anaemia macrocytic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Febrile neutropenia  1  13/2841 (0.46%)  13 0/2902 (0.00%)  0
Leukocytosis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Lymphadenitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Neutropenia  1  4/2841 (0.14%)  5 0/2902 (0.00%)  0
Pancytopenia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Splenic infarction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cardiac disorders     
Acute coronary syndrome  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Acute myocardial infarction  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Angina pectoris  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Arteriospasm coronary  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Atrial fibrillation  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Atrioventricular block  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Atrioventricular block complete  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cardiac arrest  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cardiac failure  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Cardiac failure acute  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cardiac failure congestive  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Cardiac ventricular thrombosis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cardiomyopathy  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Coronary artery disease  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Extrasystoles  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Left ventricular failure  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Myocardial ischaemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Palpitations  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Sinus bradycardia  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Stress cardiomyopathy  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Supraventricular tachycardia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Congenital, familial and genetic disorders     
Atrial septal defect  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Gene mutation  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Ear and labyrinth disorders     
Deafness unilateral  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vertigo  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Vertigo positional  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Endocrine disorders     
Goitre  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Hyperparathyroidism  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hypothyroidism  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Eye disorders     
Cataract  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Diplopia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Eyelid function disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Maculopathy  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrointestinal disorders     
Abdominal hernia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Abdominal pain  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Abdominal pain upper  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Colitis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Colitis ischaemic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Diarrhoea  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Duodenal ulcer  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Duodenitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Enteritis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrooesophageal reflux disease  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Ileus  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Intestinal obstruction  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Intestinal perforation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Intussusception  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Large intestine perforation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Large intestine polyp  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Nausea  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Neutropenic colitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oedematous pancreatitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophagitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pancreatitis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Peritoneal perforation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Small intestinal obstruction  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Volvulus of small bowel  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vomiting  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
General disorders     
Capsular contracture associated with breast implant  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Chest discomfort  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Chest pain  1  3/2841 (0.11%)  5 1/2902 (0.03%)  1
Death  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Disease progression  1  1/2841 (0.04%)  1 2/2902 (0.07%)  4
Disease recurrence  1  1/2841 (0.04%)  2 1/2902 (0.03%)  1
Dysplasia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Fatigue  1  2/2841 (0.07%)  3 0/2902 (0.00%)  0
Hypothermia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Impaired healing  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Implant site fibrosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Influenza like illness  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Infusion site extravasation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Non-cardiac chest pain  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Pyrexia  1  3/2841 (0.11%)  4 1/2902 (0.03%)  1
Hepatobiliary disorders     
Acute hepatic failure  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bile duct stone  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cholangitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cholecystitis  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Cholecystitis acute  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cholelithiasis  1  4/2841 (0.14%)  4 2/2902 (0.07%)  2
Drug-induced liver injury  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hepatic failure  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hepatitis acute  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Immune system disorders     
Anaphylactic reaction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Infections and infestations     
Anal abscess  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Anorectal infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Appendiceal abscess  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Appendicitis  1  3/2841 (0.11%)  3 5/2902 (0.17%)  5
Appendicitis perforated  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Bacterial infection  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Breast abscess  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Breast cellulitis  1  16/2841 (0.56%)  17 10/2902 (0.34%)  10
Bronchitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
COVID-19 pneumonia  1  1/2841 (0.04%)  1 1/2902 (0.03%)  2
Campylobacter infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cellulitis  1  24/2841 (0.84%)  26 9/2902 (0.31%)  10
Cystitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Device related infection  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Disseminated varicella zoster virus infection  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Diverticulitis  1  0/2841 (0.00%)  0 3/2902 (0.10%)  3
Erysipelas  1  5/2841 (0.18%)  5 0/2902 (0.00%)  0
Erysipelothrix sepsis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Escherichia pyelonephritis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Escherichia sepsis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastroenteritis  1  4/2841 (0.14%)  4 3/2902 (0.10%)  3
Gastroenteritis norovirus  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Gastroenteritis viral  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Herpes zoster  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Infected seroma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Infection  1  2/2841 (0.07%)  2 3/2902 (0.10%)  4
Influenza  1  16/2841 (0.56%)  16 2/2902 (0.07%)  2
Laryngitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Listeria sepsis  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Localised infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lower respiratory tract infection  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Mastitis  1  13/2841 (0.46%)  14 10/2902 (0.34%)  11
Paronychia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pelvic inflammatory disease  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Peritonitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pneumonia  1  16/2841 (0.56%)  18 7/2902 (0.24%)  8
Postoperative wound infection  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Pyelonephritis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Pyelonephritis acute  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Respiratory tract infection  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Sepsis  1  8/2841 (0.28%)  9 3/2902 (0.10%)  3
Septic shock  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Sinusitis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Skin infection  1  8/2841 (0.28%)  8 0/2902 (0.00%)  0
Soft tissue infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Staphylococcal bacteraemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Staphylococcal infection  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Upper respiratory tract infection  1  2/2841 (0.07%)  2 1/2902 (0.03%)  3
Urinary tract infection  1  8/2841 (0.28%)  8 3/2902 (0.10%)  3
Urosepsis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vascular device infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vestibular neuronitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Viral infection  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Viral labyrinthitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Viral pericarditis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vulvovaginal candidiasis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Wound abscess  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Wound infection  1  3/2841 (0.11%)  4 4/2902 (0.14%)  4
Injury, poisoning and procedural complications     
Abdominal wound dehiscence  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Alcohol poisoning  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Animal bite  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ankle fracture  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Brain contusion  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast procedural complication  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Clavicle fracture  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Concussion  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Craniocerebral injury  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Fall  1  3/2841 (0.11%)  3 3/2902 (0.10%)  4
Head injury  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hip fracture  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Humerus fracture  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Limb injury  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lower limb fracture  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Meniscus injury  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Open fracture  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Post procedural haematoma  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Postoperative wound complication  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Procedural complication  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Radiation pneumonitis  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Radius fracture  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Rib fracture  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Seroma  1  3/2841 (0.11%)  4 4/2902 (0.14%)  4
Skin flap necrosis  1  1/2841 (0.04%)  3 0/2902 (0.00%)  0
Spinal fracture  1  0/2841 (0.00%)  0 1/2902 (0.03%)  3
Sternal fracture  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Subdural haematoma  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Thermal burn  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Thoracic vertebral fracture  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Upper limb fracture  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vaginal cuff dehiscence  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Vascular access site thrombosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Wound complication  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Wound dehiscence  1  9/2841 (0.32%)  9 5/2902 (0.17%)  5
Wrist fracture  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Investigations     
Alanine aminotransferase increased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Blood bilirubin increased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Liver function test increased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Neutrophil count decreased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Troponin increased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
White blood cell count decreased  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hypercalcaemia  1  1/2841 (0.04%)  2 1/2902 (0.03%)  1
Hypoglycaemia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hypokalaemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hyponatraemia  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/2841 (0.04%)  1 4/2902 (0.14%)  5
Arthritis  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Back pain  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Flank pain  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Foot deformity  1  0/2841 (0.00%)  0 2/2902 (0.07%)  3
Haemarthrosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Intervertebral disc protrusion  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Joint range of motion decreased  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Osteoarthritis  1  1/2841 (0.04%)  1 3/2902 (0.10%)  4
Pain in extremity  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Rotator cuff syndrome  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Soft tissue necrosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Spinal synovial cyst  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Tendonitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute myeloid leukaemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Acute promyelocytic leukaemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Adenocarcinoma pancreas  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
B-cell small lymphocytic lymphoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Basal cell carcinoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Benign breast neoplasm  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bladder neoplasm  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast cancer metastatic  1  2/2841 (0.07%)  3 1/2902 (0.03%)  1
Breast cancer recurrent  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cervix carcinoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cervix carcinoma stage 0  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Colon cancer  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Endometrial adenocarcinoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Intraductal papillary-mucinous carcinoma of pancreas  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lung neoplasm malignant  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Lymphoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lymphoplasmacytoid lymphoma/immunocytoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Malignant melanoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Malignant melanoma in situ  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Metastatic malignant melanoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ovarian adenoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Renal cell carcinoma  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Salivary gland adenoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Second primary malignancy  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Small cell carcinoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Squamous cell carcinoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Squamous cell carcinoma of the tongue  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Thyroid adenoma  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Uterine leiomyoma  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Uterine leiomyosarcoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Uveal melanoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Nervous system disorders     
Ageusia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Aphasia  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Carotid artery stenosis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Carpal tunnel syndrome  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cerebral infarction  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cerebral ischaemia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cerebrovascular accident  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Dizziness  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Encephalopathy  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Epilepsy  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Facial paralysis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Haemorrhage intracranial  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Headache  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
IIIrd nerve disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Intercostal neuralgia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ischaemic stroke  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Myasthenia gravis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Paraesthesia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Presyncope  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Ruptured cerebral aneurysm  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Subarachnoid haemorrhage  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Syncope  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Transient ischaemic attack  1  2/2841 (0.07%)  2 3/2902 (0.10%)  3
VIth nerve paralysis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Vertigo CNS origin  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Product Issues     
Device breakage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Device dislocation  1  1/2841 (0.04%)  1 1/2902 (0.03%)  3
Device leakage  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Psychiatric disorders     
Alcohol abuse  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Alcohol use disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Alcohol withdrawal syndrome  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Anxiety  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Confusional state  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Delusion  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Depression  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Drug abuse  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Mania  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mental disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Mental status changes  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Panic attack  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Paranoia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Psychotic disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Suicidal ideation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Suicide attempt  1  0/2841 (0.00%)  0 3/2902 (0.10%)  4
Renal and urinary disorders     
Acute kidney injury  1  4/2841 (0.14%)  5 1/2902 (0.03%)  1
Chronic kidney disease  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Nephrolithiasis  1  1/2841 (0.04%)  1 4/2902 (0.14%)  4
Renal colic  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Subcapsular renal haematoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ureteric obstruction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Ureteric stenosis  1  1/2841 (0.04%)  4 0/2902 (0.00%)  0
Ureterolithiasis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Reproductive system and breast disorders     
Adnexa uteri cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast calcifications  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Breast cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast haematoma  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast necrosis  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Breast swelling  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cervical cyst  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Endometrial disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Endometrial hyperplasia  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Endometrial hypertrophy  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Endometrial thickening  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Endometriosis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Ovarian cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Uterine polyp  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Uterine prolapse  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Vaginal haematoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Vaginal prolapse  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Acute respiratory failure  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Asthma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Asthma-chronic obstructive pulmonary disease overlap syndrome  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bronchospasm  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Chronic obstructive pulmonary disease  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Dyspnoea  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Hypoxia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Laryngeal stenosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pleural effusion  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Pleurisy  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Pneumonitis  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Pulmonary embolism  1  13/2841 (0.46%)  13 5/2902 (0.17%)  5
Pulmonary fibrosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pulmonary haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pulmonary oedema  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pulmonary sarcoidosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Respiratory disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Respiratory failure  1  1/2841 (0.04%)  2 1/2902 (0.03%)  2
Vocal cord dysfunction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Vocal cord polyp  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Skin and subcutaneous tissue disorders     
Keloid scar  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Skin necrosis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Urticaria  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vascular disorders     
Axillary vein thrombosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Deep vein thrombosis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Embolism  1  4/2841 (0.14%)  4 2/2902 (0.07%)  2
Hypertensive crisis  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Hypotension  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Lymphoedema  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Peripheral ischaemia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
1
Term from vocabulary, MedDRA 23.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Palbociclib Plus Endocrine Therapy (Arm A) Endocrine Therapy Alone (Arm B)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2824/2841 (99.40%)      2600/2902 (89.59%)    
Blood and lymphatic system disorders     
Agranulocytosis  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Anaemia  1  634/2841 (22.32%)  1161 147/2902 (5.07%)  211
Anaemia macrocytic  1  4/2841 (0.14%)  6 0/2902 (0.00%)  0
Anaemia vitamin B12 deficiency  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Blood disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Bone marrow oedema  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Eosinophilia  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Febrile neutropenia  1  16/2841 (0.56%)  16 0/2902 (0.00%)  0
Haematotoxicity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Haemorrhagic diathesis  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Increased tendency to bruise  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Iron deficiency anaemia  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Leukocytosis  1  2/2841 (0.07%)  6 1/2902 (0.03%)  1
Leukopenia  1  397/2841 (13.97%)  1798 64/2902 (2.21%)  98
Lymph node pain  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Lymphadenitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lymphadenopathy  1  6/2841 (0.21%)  6 10/2902 (0.34%)  12
Lymphadenopathy mediastinal  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lymphatic disorder  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Lymphopenia  1  58/2841 (2.04%)  184 24/2902 (0.83%)  40
Macrocytosis  1  7/2841 (0.25%)  7 0/2902 (0.00%)  0
Microcytosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Monocytopenia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Myelosuppression  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Neutropenia  1  1125/2841 (39.60%)  5381 76/2902 (2.62%)  112
Pancytopenia  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Polycythaemia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Thrombocytopenia  1  195/2841 (6.86%)  403 15/2902 (0.52%)  18
Thrombocytosis  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
White blood cell disorder  1  2/2841 (0.07%)  4 0/2902 (0.00%)  0
Cardiac disorders     
Acute left ventricular failure  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Angina pectoris  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Arrhythmia  1  2/2841 (0.07%)  4 2/2902 (0.07%)  2
Atrial fibrillation  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Atrial thrombosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Bradycardia  1  2/2841 (0.07%)  2 5/2902 (0.17%)  5
Bundle branch block right  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Cardiac failure  1  3/2841 (0.11%)  3 3/2902 (0.10%)  3
Cardiac failure chronic  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cardiac failure congestive  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Cardiac flutter  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cardiac ventricular thrombosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cardiomyopathy  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Cardiovascular disorder  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Chronic left ventricular failure  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Coronary artery disease  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Extrasystoles  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Left ventricular dysfunction  1  0/2841 (0.00%)  0 3/2902 (0.10%)  3
Left ventricular failure  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mitral valve disease  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Palpitations  1  46/2841 (1.62%)  52 38/2902 (1.31%)  39
Pericarditis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Sinus arrhythmia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Sinus bradycardia  1  4/2841 (0.14%)  4 4/2902 (0.14%)  5
Sinus tachycardia  1  13/2841 (0.46%)  14 12/2902 (0.41%)  17
Supraventricular tachycardia  1  5/2841 (0.18%)  5 1/2902 (0.03%)  1
Systolic dysfunction  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Tachyarrhythmia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Tachycardia  1  17/2841 (0.60%)  19 29/2902 (1.00%)  31
Tachycardia induced cardiomyopathy  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Ventricular arrhythmia  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Ventricular extrasystoles  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Congenital, familial and genetic disorders     
Developmental hip dysplasia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Gilbert's syndrome  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hereditary haemochromatosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hyper IgM syndrome  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Ear and labyrinth disorders     
Veritgo  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cerumen impaction  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Deafness  1  4/2841 (0.14%)  4 7/2902 (0.24%)  8
Deafness unilateral  1  2/2841 (0.07%)  3 2/2902 (0.07%)  2
Ear congestion  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ear discomfort  1  5/2841 (0.18%)  5 4/2902 (0.14%)  4
Ear disorder  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Ear pain  1  40/2841 (1.41%)  43 11/2902 (0.38%)  11
Ear pruritus  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Eustachian tube patulous  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Excessive cerumen production  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
External ear inflammation  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
External ear pain  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hyperacusis  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Hypoacusis  1  9/2841 (0.32%)  10 1/2902 (0.03%)  1
Middle ear inflammation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Motion sickness  1  1/2841 (0.04%)  2 2/2902 (0.07%)  2
Otorrhoea  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Tinnitus  1  23/2841 (0.81%)  24 20/2902 (0.69%)  20
Tympanic membrane perforation  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Vertigo  1  74/2841 (2.60%)  84 38/2902 (1.31%)  40
Vertigo positional  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Vestibular disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Endocrine disorders     
Autoimmune thyroiditis  1  2/2841 (0.07%)  2 4/2902 (0.14%)  5
Goitre  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Hyperparathyroidism  1  0/2841 (0.00%)  0 3/2902 (0.10%)  3
Hyperthyroidism  1  5/2841 (0.18%)  5 3/2902 (0.10%)  3
Hypothyroidism  1  21/2841 (0.74%)  22 41/2902 (1.41%)  44
Thyroid mass  1  4/2841 (0.14%)  4 7/2902 (0.24%)  7
Thyroid pain  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Eye disorders     
Asthenopia  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Blepharitis  1  5/2841 (0.18%)  5 2/2902 (0.07%)  2
Blepharospasm  1  3/2841 (0.11%)  3 1/2902 (0.03%)  1
Blindness  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Blindness transient  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Cataract  1  16/2841 (0.56%)  20 19/2902 (0.65%)  22
Cataract nuclear  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Chalazion  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Choroidal effusion  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Conjunctival disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Conjunctival haemorrhage  1  6/2841 (0.21%)  6 4/2902 (0.14%)  4
Conjunctivitis allergic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Corneal thickening  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Dacryostenosis acquired  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Diplopia  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Dry eye  1  68/2841 (2.39%)  75 42/2902 (1.45%)  48
Eye disorder  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Eye haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Eye inflammation  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Eye irritation  1  5/2841 (0.18%)  5 2/2902 (0.07%)  2
Eye oedema  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Eye pain  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Eye pruritus  1  10/2841 (0.35%)  11 5/2902 (0.17%)  6
Eye swelling  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Eyelid cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Eyelid disorder  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Eyelid function disorder  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Eyelid oedema  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Eyelid ptosis  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Eyelids pruritus  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Glaucoma  1  3/2841 (0.11%)  3 3/2902 (0.10%)  3
Iritis  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Keratitis  1  4/2841 (0.14%)  8 0/2902 (0.00%)  0
Keratopathy  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Lacrimal cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lacrimation increased  1  96/2841 (3.38%)  105 6/2902 (0.21%)  6
Macular degeneration  1  3/2841 (0.11%)  4 3/2902 (0.10%)  3
Macular fibrosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mydriasis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Neovascular age-related macular degeneration  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ocular hyperaemia  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Orbital haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Orbital oedema  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Pars plana cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Periorbital oedema  1  2/2841 (0.07%)  4 0/2902 (0.00%)  0
Periorbital swelling  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Photophobia  1  4/2841 (0.14%)  4 3/2902 (0.10%)  3
Photopsia  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Presbyopia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Punctate keratitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Retinal detachment  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Retinal dystrophy  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Retinal haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Retinal tear  1  1/2841 (0.04%)  1 2/2902 (0.07%)  3
Retinoschisis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Scleral cyst  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Swelling of eyelid  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Ulcerative keratitis  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Uveitis  1  3/2841 (0.11%)  3 1/2902 (0.03%)  2
Vision blurred  1  69/2841 (2.43%)  75 36/2902 (1.24%)  40
Visual acuity reduced  1  6/2841 (0.21%)  6 4/2902 (0.14%)  4
Visual impairment  1  19/2841 (0.67%)  19 11/2902 (0.38%)  11
Visual snow syndrome  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vitreous detachment  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Vitreous floaters  1  6/2841 (0.21%)  6 10/2902 (0.34%)  10
Xerophthalmia  1  3/2841 (0.11%)  3 1/2902 (0.03%)  2
Gastrointestinal disorders     
Abdominal discomfort  1  22/2841 (0.77%)  27 16/2902 (0.55%)  16
Abdominal distension  1  30/2841 (1.06%)  36 33/2902 (1.14%)  35
Abdominal mass  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Abdominal pain  1  153/2841 (5.39%)  190 110/2902 (3.79%)  134
Abdominal pain lower  1  14/2841 (0.49%)  14 16/2902 (0.55%)  17
Abdominal pain upper  1  84/2841 (2.96%)  103 53/2902 (1.83%)  61
Abdominal rigidity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Abdominal tenderness  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Abdominal wall haematoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Anal fissure  1  12/2841 (0.42%)  16 3/2902 (0.10%)  3
Anal fistula  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Anal haemorrhage  1  11/2841 (0.39%)  12 1/2902 (0.03%)  1
Anal incontinence  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Anal inflammation  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Anal pruritus  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Anal skin tags  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Angular cheilitis  1  4/2841 (0.14%)  6 2/2902 (0.07%)  2
Aphthous ulcer  1  16/2841 (0.56%)  17 3/2902 (0.10%)  3
Apical granuloma  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Ascites  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Barrett's oesophagus  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Bowel movement irregularity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Change of bowel habit  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Cheilitis  1  4/2841 (0.14%)  4 1/2902 (0.03%)  1
Chronic gastritis  1  2/2841 (0.07%)  3 2/2902 (0.07%)  2
Colitis  1  5/2841 (0.18%)  5 3/2902 (0.10%)  3
Colitis ischaemic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Colitis ulcerative  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Constipation  1  395/2841 (13.90%)  485 172/2902 (5.93%)  190
Crohn's disease  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Dental caries  1  16/2841 (0.56%)  17 5/2902 (0.17%)  7
Diarrhoea  1  475/2841 (16.72%)  682 150/2902 (5.17%)  194
Diarrhoea haemorrhagic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Diverticulum  1  5/2841 (0.18%)  5 1/2902 (0.03%)  1
Diverticulum intestinal  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Dry mouth  1  81/2841 (2.85%)  92 46/2902 (1.59%)  49
Duodenitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Dyschezia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Dyspepsia  1  137/2841 (4.82%)  162 64/2902 (2.21%)  67
Dysphagia  1  28/2841 (0.99%)  34 15/2902 (0.52%)  16
Enteritis  1  3/2841 (0.11%)  4 0/2902 (0.00%)  0
Enterocolitis  1  3/2841 (0.11%)  3 2/2902 (0.07%)  3
Epigastric discomfort  1  4/2841 (0.14%)  4 1/2902 (0.03%)  1
Epiploic appendagitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Erosive oesophagitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Eructation  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Faeces discoloured  1  4/2841 (0.14%)  4 0/2902 (0.00%)  0
Faeces hard  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Faeces soft  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Flatulence  1  27/2841 (0.95%)  31 14/2902 (0.48%)  15
Food poisoning  1  3/2841 (0.11%)  4 1/2902 (0.03%)  1
Frequent bowel movements  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastric disorder  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Gastric polyps  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Gastric ulcer  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Gastritis  1  29/2841 (1.02%)  32 9/2902 (0.31%)  9
Gastritis erosive  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Gastrointestinal disorder  1  6/2841 (0.21%)  7 3/2902 (0.10%)  3
Gastrointestinal haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrointestinal inflammation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrointestinal pain  1  6/2841 (0.21%)  7 3/2902 (0.10%)  3
Gastrointestinal sounds abnormal  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrointestinal wall thickening  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gastrooesophageal reflux disease  1  90/2841 (3.17%)  106 55/2902 (1.90%)  59
Gingival bleeding  1  10/2841 (0.35%)  12 1/2902 (0.03%)  1
Gingival discomfort  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Gingival oedema  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Gingival pain  1  11/2841 (0.39%)  15 3/2902 (0.10%)  3
Gingival recession  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Gingival swelling  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Glossitis  1  3/2841 (0.11%)  4 2/2902 (0.07%)  2
Glossodynia  1  6/2841 (0.21%)  6 1/2902 (0.03%)  1
Haematemesis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Haematochezia  1  10/2841 (0.35%)  11 3/2902 (0.10%)  3
Haemorrhoidal haemorrhage  1  7/2841 (0.25%)  9 7/2902 (0.24%)  12
Haemorrhoids  1  43/2841 (1.51%)  44 25/2902 (0.86%)  26
Hiatus hernia  1  4/2841 (0.14%)  4 2/2902 (0.07%)  2
Hyperaesthesia teeth  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Hypertrophic anal papilla  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hypoaesthesia oral  1  3/2841 (0.11%)  4 1/2902 (0.03%)  1
Ileus  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Impaired gastric emptying  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Inguinal hernia  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Intestinal obstruction  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Intestinal polyp  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Intra-abdominal haematoma  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Intussusception  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Irritable bowel syndrome  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Large intestinal ulcer  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Large intestine polyp  1  4/2841 (0.14%)  4 4/2902 (0.14%)  5
Lip blister  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lip discolouration  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lip disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Lip dry  1  4/2841 (0.14%)  4 1/2902 (0.03%)  1
Lip erythema  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lip pain  1  3/2841 (0.11%)  3 0/2902 (0.00%)  0
Lip pruritus  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lip swelling  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Lip ulceration  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Loose tooth  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Lower gastrointestinal haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Melaena  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mouth haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mouth ulceration  1  51/2841 (1.80%)  67 6/2902 (0.21%)  6
Nausea  1  552/2841 (19.43%)  735 241/2902 (8.30%)  294
Noninfective gingivitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Noninfective sialoadenitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Odynophagia  1  13/2841 (0.46%)  14 4/2902 (0.14%)  5
Oedematous pancreatitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophageal achalasia  1  0/2841 (0.00%)  0 1/2902 (0.03%)  2
Oesophageal discomfort  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophageal disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophageal pain  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophageal spasm  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophageal ulcer  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oesophagitis  1  6/2841 (0.21%)  8 3/2902 (0.10%)  3
Oral discomfort  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oral disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Oral dysaesthesia  1  5/2841 (0.18%)  5 0/2902 (0.00%)  0
Oral mucosal blistering  1  1/2841 (0.04%)  3 0/2902 (0.00%)  0
Oral pain  1  49/2841 (1.72%)  61 6/2902 (0.21%)  6
Pancreatitis  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Paraesthesia oral  1  4/2841 (0.14%)  5 0/2902 (0.00%)  0
Peptic ulcer  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Periodontal disease  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Proctalgia  1  6/2841 (0.21%)  6 1/2902 (0.03%)  1
Proctitis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Ranula  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Rectal haemorrhage  1  20/2841 (0.70%)  21 12/2902 (0.41%)  13
Rectal lesion  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Rectal polyp  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Rectal tenesmus  1  1/2841 (0.04%)  2 2/2902 (0.07%)  2
Rectal ulcer  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Reflux gastritis  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Salivary duct inflammation  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Salivary gland calculus  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Salivary hypersecretion  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Small intestinal obstruction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Stomatitis  1  280/2841 (9.86%)  428 21/2902 (0.72%)  23
Swollen tongue  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Teeth brittle  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Tongue coated  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Tongue geographic  1  1/2841 (0.04%)  2 0/2902 (0.00%)  0
Tongue ulceration  1  7/2841 (0.25%)  7 0/2902 (0.00%)  0
Tooth disorder  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Tooth loss  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Toothache  1  35/2841 (1.23%)  39 17/2902 (0.59%)  18
Umbilical hernia  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Volvulus  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Vomiting  1  219/2841 (7.71%)  278 91/2902 (3.14%)  120
General disorders     
Acute phase reaction  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Adverse drug reaction  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Application site coldness  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Asthenia  1  274/2841 (9.64%)  468 153/2902 (5.27%)  193
Axillary pain  1  43/2841 (1.51%)  44 48/2902 (1.65%)  55
Capsular contracture associated with breast implant  1  2/2841 (0.07%)  2 2/2902 (0.07%)  2
Capsular contracture associated with implant  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Catheter site inflammation  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Catheter site pain  1  0/2841 (0.00%)  0 6/2902 (0.21%)  7
Catheter site pruritus  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Catheter site scab  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Catheter site thrombosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Chest discomfort  1  37/2841 (1.30%)  42 22/2902 (0.76%)  24
Chest pain  1  56/2841 (1.97%)  64 51/2902 (1.76%)  54
Chills  1  70/2841 (2.46%)  78 17/2902 (0.59%)  17
Complication associated with device  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Cyst  1  7/2841 (0.25%)  7 7/2902 (0.24%)  7
Decreased activity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Discomfort  1  7/2841 (0.25%)  7 7/2902 (0.24%)  7
Early satiety  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Exercise tolerance decreased  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Face oedema  1  5/2841 (0.18%)  5 4/2902 (0.14%)  4
Facial pain  1  4/2841 (0.14%)  4 4/2902 (0.14%)  4
Fat necrosis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Fatigue  1  1163/2841 (40.94%)  1869 560/2902 (19.30%)  714
Feeling abnormal  1  3/2841 (0.11%)  3 3/2902 (0.10%)  3
Feeling cold  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Feeling hot  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Feeling jittery  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Fibrosis  1  1/2841 (0.04%)  1 3/2902 (0.10%)  3
Gait disturbance  1  6/2841 (0.21%)  6 6/2902 (0.21%)  6
General physical health deterioration  1  6/2841 (0.21%)  7 2/2902 (0.07%)  2
Granuloma  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Hernia pain  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Hyperthermia  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hypertrophy  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Hypothermia  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Illness  1  4/2841 (0.14%)  5 2/2902 (0.07%)  2
Impaired healing  1  14/2841 (0.49%)  14 5/2902 (0.17%)  6
Implant site pain  1  1/2841 (0.04%)  2 3/2902 (0.10%)  3
Induration  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Inflammation  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Influenza like illness  1  166/2841 (5.84%)  205 90/2902 (3.10%)  108
Injection site pain  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Injection site phlebitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Injection site reaction  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Localised oedema  1  16/2841 (0.56%)  16 10/2902 (0.34%)  11
Malaise  1  32/2841 (1.13%)  34 11/2902 (0.38%)  16
Mass  1  5/2841 (0.18%)  5 3/2902 (0.10%)  3
Mucosal disorder  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mucosal dryness  1  11/2841 (0.39%)  12 14/2902 (0.48%)  15
Mucosal haemorrhage  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mucosal inflammation  1  206/2841 (7.25%)  362 10/2902 (0.34%)  10
Mucosal pain  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Mucosal toxicity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Necrosis  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Nodule  1  4/2841 (0.14%)  6 5/2902 (0.17%)  6
Non-cardiac chest pain  1  24/2841 (0.84%)  29 29/2902 (1.00%)  33
Oedema  1  27/2841 (0.95%)  35 25/2902 (0.86%)  29
Oedema peripheral  1  178/2841 (6.27%)  218 121/2902 (4.17%)  137
Pain  1  107/2841 (3.77%)  122 94/2902 (3.24%)  102
Pelvic mass  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Peripheral swelling  1  55/2841 (1.94%)  61 33/2902 (1.14%)  36
Polyp  1  2/2841 (0.07%)  2 1/2902 (0.03%)  2
Pyrexia  1  205/2841 (7.22%)  251 83/2902 (2.86%)  92
Sensitivity to weather change  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Suprapubic pain  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Swelling  1  13/2841 (0.46%)  17 9/2902 (0.31%)  10
Swelling face  1  3/2841 (0.11%)  3 2/2902 (0.07%)  2
Temperature intolerance  1  6/2841 (0.21%)  6 1/2902 (0.03%)  1
Temperature regulation disorder  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Tenderness  1  10/2841 (0.35%)  10 3/2902 (0.10%)  3
Thirst  1  1/2841 (0.04%)  1 3/2902 (0.10%)  3
Unevaluable event  1  9/2841 (0.32%)  9 4/2902 (0.14%)  4
Vessel puncture site pain  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Xerosis  1  6/2841 (0.21%)  7 2/2902 (0.07%)  2
Hepatobiliary disorders     
Biliary colic  1  2/2841 (0.07%)  2 1/2902 (0.03%)  1
Cholecystitis  1  8/2841 (0.28%)  8 4/2902 (0.14%)  4
Cholecystitis chronic  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Cholelithiasis  1  7/2841 (0.25%)  7 8/2902 (0.28%)  9
Gallbladder polyp  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Hepatic cyst  1  1/2841 (0.04%)  1 2/2902 (0.07%)  2
Hepatic lesion  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hepatic pain  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Hepatic steatosis  1  9/2841 (0.32%)  9 9/2902 (0.31%)  9
Hepatitis toxic  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hepatocellular injury  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hepatomegaly  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Hepatotoxicity  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hyperbilirubinaemia  1  2/2841 (0.07%)  3 5/2902 (0.17%)  12
Hypertransaminasaemia  1  2/2841 (0.07%)  3 0/2902 (0.00%)  0
Jaundice  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Liver disorder  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Liver tenderness  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Porcelain gallbladder  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Steatohepatitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Immune system disorders     
Allergy to arthropod bite  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Allergy to vaccine  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Anaphylactic reaction  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Anaphylactic shock  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Drug hypersensitivity  1  5/2841 (0.18%)  6 2/2902 (0.07%)  2
Food allergy  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Hypersensitivity  1  16/2841 (0.56%)  18 4/2902 (0.14%)  4
Immune system disorder  1  0/2841 (0.00%)  0 2/2902 (0.07%)  3
Mite allergy  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Multiple allergies  1  2/2841 (0.07%)  2 3/2902 (0.10%)  3
Perfume sensitivity  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Sarcoidosis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Seasonal allergy  1  19/2841 (0.67%)  20 10/2902 (0.34%)  11
Infections and infestations     
Abdominal infection  1  1/2841 (0.04%)  1 1/2902 (0.03%)  1
Abscess  1  3/2841 (0.11%)  4 2/2902 (0.07%)  2
Abscess limb  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Abscess neck  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Abscess oral  1  4/2841 (0.14%)  4 1/2902 (0.03%)  1
Acarodermatitis  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Acute sinusitis  1  2/2841 (0.07%)  2 3/2902 (0.10%)  4
Anal abscess  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Appendicitis  1  0/2841 (0.00%)  0 2/2902 (0.07%)  2
Arthritis infective  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Babesiosis  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Bacterial infection  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bacterial vaginosis  1  2/2841 (0.07%)  2 4/2902 (0.14%)  4
Bacterial vulvovaginitis  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bacteriuria  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Bartholin's abscess  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Beta haemolytic streptococcal infection  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Blastocystis infection  1  0/2841 (0.00%)  0 1/2902 (0.03%)  1
Blister infected  1  1/2841 (0.04%)  1 0/2902 (0.00%)  0
Breast abscess  1  2/2841 (0.07%)  2 0/2902 (0.00%)  0
Breast cellulitis  1  17/2841 (0.60%)  22 15/2902 (0.52%)  15
Bronchitis  1  68/2841 (2.39%)  85