Trial Outcomes & Findings for A Study of Vemurafenib in Participants With Metastatic Melanoma (NCT NCT01307397)
NCT ID: NCT01307397
Last Updated: 2017-12-18
Results Overview
The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the NCI-CTCAE version 4.0, where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: Grade 3 means "Severe"; Inability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall well-being or symptoms; delaying the onset of treatment is not putting the survival of the participant at direct risk. Grade 4 means "Life-threatening, Disabling"; based on extreme limitation in activity; significant medical intervention/therapy required; and hospitalization probable.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
3219 participants
Primary outcome timeframe
Baseline up to 28 days post end of treatment (maximum up to 46 months)
Results posted on
2017-12-18
Participant Flow
Participant milestones
| Measure |
Vemurafenib
Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Overall Study
STARTED
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3219
|
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Overall Study
COMPLETED
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3219
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|
Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
A Study of Vemurafenib in Participants With Metastatic Melanoma
Baseline characteristics by cohort
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Age, Continuous
|
54.5 years
STANDARD_DEVIATION 14.06 • n=5 Participants
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Sex: Female, Male
Female
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1397 Participants
n=5 Participants
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Sex: Female, Male
Male
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1822 Participants
n=5 Participants
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PRIMARY outcome
Timeframe: Baseline up to 28 days post end of treatment (maximum up to 46 months)Population: Safety population. Number of participants analyzed = participants with measurable disease at baseline
The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the NCI-CTCAE version 4.0, where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: Grade 3 means "Severe"; Inability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall well-being or symptoms; delaying the onset of treatment is not putting the survival of the participant at direct risk. Grade 4 means "Life-threatening, Disabling"; based on extreme limitation in activity; significant medical intervention/therapy required; and hospitalization probable.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants Experiencing Any Grade 3 or 4 Adverse Events (AEs) as Determined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.0
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52.8 Percentage of participants
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PRIMARY outcome
Timeframe: Baseline up to 28 days post end of treatment (maximum up to 46 months)Population: Safety population
An AE was considered as any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Pre existing conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Percentage of participants with dose interruption or discontinuation due to AE was presented.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants With at Least 1 AE Leading to Study Drug Interruption or Drug Discontinuation
AE Leading to Drug Discontinuation
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7.0 Percentage of participants
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Percentage of Participants With at Least 1 AE Leading to Study Drug Interruption or Drug Discontinuation
AE Leading to Study Drug Interruption
|
34.0 Percentage of participants
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PRIMARY outcome
Timeframe: Baseline up to 28 days post end of treatment (maximum up to 46 months)Population: Safety population
AEs of special interest included cutaneous squamous cell carcinoma (SCC), rash, photosensitivity, liver injury, arthralgia, fatigue, gastrointestinal (GI) polyps, pancreatitis, potentiation of radiation toxicity, prolongation of cardiac repolarization or arrhythmia, non-cutaneous SCC and other primary malignancies (other than cutaneous SCC or new primary melanoma).
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants With AEs of Special Interest
Arthralgia
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42.3 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Photosensitivity
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28.4 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Fatigue
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36.8 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Rash
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47.9 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Cutaneous SCC
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14.6 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Non Cutaneous SCC
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0.1 Percentage of participants
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Percentage of Participants With AEs of Special Interest
New Primary Melanoma
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1.7 Percentage of participants
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Percentage of Participants With AEs of Special Interest
GI Polyps
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0.03 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Pancreatitis
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0.2 Percentage of participants
|
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Percentage of Participants With AEs of Special Interest
Potentiation of radiation toxicity
|
1.4 Percentage of participants
|
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Percentage of Participants With AEs of Special Interest
Prolongation of Cardiac Repolarization/ Arrhythmia
|
17.0 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Other primary malignancy
|
3.2 Percentage of participants
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Percentage of Participants With AEs of Special Interest
Liver Injury
|
14.1 Percentage of participants
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PRIMARY outcome
Timeframe: Baseline up to end of treatment or death (maximum up to 46 months)Population: Safety population
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Mean Cumulative Dose of Vemurafenib
|
501.283 Grams
Standard Deviation 510.9121
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PRIMARY outcome
Timeframe: Baseline up to end of treatment or death (maximum upto 46 months)Population: Safety population
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose-taken due to adverse events, non-compliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose - date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Duration of Vemurafenib Treatment
Exposure excluding interruptions
|
9.383 Months
Standard Deviation 9.6755 • Interval 0.03 to 11.24
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Duration of Vemurafenib Treatment
Exposure including interruptions
|
9.724 Months
Standard Deviation 9.9072
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PRIMARY outcome
Timeframe: Baseline up to end of treatment or death (maximum up to 46 months)Population: Safety population
Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose-taken due to adverse events, non-compliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose - date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Average total dose per day: total actual dose taken divided by total actual days on treatment.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Mean Total Vemurafenib Dose Per Day
Average Total Dose Per Day Excluding Interruptions
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1.802 Grams
Standard Deviation 0.2314
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Mean Total Vemurafenib Dose Per Day
Average Total Dose Per Day Including Interruptions
|
1.732 Grams
Standard Deviation 0.2874
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PRIMARY outcome
Timeframe: Baseline up to end of treatment or death (maximum upto 46 months)Population: Safety Population
Dose intensity was defined as (total actual doses taken/total planned doses) \*100, where total planned doses = prescribed doses \* planned days on treatment, where planned days on treatment were defined as the interval between date of first dose and date of last dose.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Dose Intensity of Vemurafenib
|
90.21 Percentage of planned dose
Standard Deviation 14.966
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SECONDARY outcome
Timeframe: Baseline, Day 1 of each 28 day cycle up to end of treatment (up to 46 months)Population: Safety population
ECOG Performance Status was measured on-therapy assessed participant's performance status on 5 point scale: 0 = fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than \[\>\] 50% of waking hours \[hrs\]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Percentage of participants who had at least one point improvement from baseline at any assessment visit as well as at last study visit was reported.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants With Improvement in Eastern Cooperative Group (ECOG) Performance Status
At Least 1 Point Improvement at Last Visit
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9.9 Percentage of Participants
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Percentage of Participants With Improvement in Eastern Cooperative Group (ECOG) Performance Status
At Least 1 Point Improvement at Any Visit
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24.7 Percentage of Participants
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SECONDARY outcome
Timeframe: Baseline up to 46 monthsPopulation: Safety population
Concomitant medications were all medications taken during the study, including those started before but ongoing at first dose. No medications for Melanoma were included. Percentage of participants who received at least one concomitant medication was reported.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants Who Received Any Concomitant Medications
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93.8 Percentage of Participants
Interval 3.9 to 4.5
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SECONDARY outcome
Timeframe: Baseline until first documentation of confirmed CR or PR (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])Population: Safety population. Number of participants analyzed = participants with measurable disease at baseline.
BOR was assessed by the investigator according to RECIST v1.1. BOR was defined as having confirmed CR or PR. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to less than (\<) 10 millimeter (mm) in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging greater than or equal to (\>=) 4 weeks after initial response.
Outcome measures
| Measure |
Vemurafenib
n=2982 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants With Best Overall Response (BOR) of Confirmed Complete Response (CR) or Partial Response (PR), as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
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33.4 Percentage of Participants
Interval 31.7 to 35.1
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SECONDARY outcome
Timeframe: From 1st documentation of confirmed CR or PR to PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until end of the study [up to 46 months])Population: Safety population. Number of participants analysed=participants who achieved CR or PR.
The duration of response was defined as the time between the date of first confirmed CR or PR and date of first progression of disease (PD), or death, from any cause. Responses were assessed as per RECIST v1.1. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to \< 10 mm in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging \>= 4 weeks after initial response. PD: at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion.
Outcome measures
| Measure |
Vemurafenib
n=996 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Duration of Response
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7.4 Months
Interval 7.1 to 8.3
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SECONDARY outcome
Timeframe: Baseline until first documentation of confirmed CR or PR, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])Population: Safety population. Number of participants analyzed = participants with measurable disease at baseline.
Time to response was defined as the time between the date of first treatment and date of first confirmed CR or PR (assessed as per RECIST v1.1). CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to \< 10 mm in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging \>= 4 weeks after initial response.
Outcome measures
| Measure |
Vemurafenib
n=2982 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Time to Response
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1.84 Months
Interval 0.8 to 26.7
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SECONDARY outcome
Timeframe: Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])Population: Safety population
PD was assessed according to RECIST v1.1. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants With PD Assessed According to RECIST v1.1 or Death
|
87.3 Percentage of Participants
Interval 0.8 to 26.7
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SECONDARY outcome
Timeframe: Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])Population: Safety population
PFS was defined as the time between the date of the first treatment and the date of first progression or death from any cause. PD was assessed according to RECIST v1.1. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Progression Free Survival (PFS)
|
5.6 Months
Interval 5.5 to 5.8
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SECONDARY outcome
Timeframe: Baseline until death (maximum up to 46 months)Population: Safety population
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Percentage of Participants Who Died
|
63.8 Percentage of participants
Interval 11.5 to 12.7
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SECONDARY outcome
Timeframe: Baseline until death (maximum up to 46 months)Population: Safety population
Overall Survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death.
Outcome measures
| Measure |
Vemurafenib
n=3219 Participants
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Overall Survival (OS)
|
12.1 Months
Interval 11.5 to 12.7
|
Adverse Events
Vemurafenib
Serious events: 1114 serious events
Other events: 2956 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Vemurafenib
n=3219 participants at risk
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
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|---|---|
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Blood and lymphatic system disorders
Anaemia
|
0.68%
22/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Disseminated intravascular coagulation
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Eosinophilia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Neutropenia
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Acute myocardial infarction
|
0.31%
10/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Angina pectoris
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Arrhythmia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Atrial fibrillation
|
0.47%
15/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Atrial flutter
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiac failure
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Coronary artery disease
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Left ventricular dysfunction
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Myocardial infarction
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Pericardial effusion
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Pericardial haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Pericarditis
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Tachycardia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Torsade de pointes
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Ear and labyrinth disorders
Deafness
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Ear and labyrinth disorders
Vertigo
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Endocrine disorders
Hyperadrenalism
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Neovascular age-related macular degeneration
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Diplopia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Iridocyclitis
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Uveitis
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Vitreous haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Abdominal distension
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Abdominal pain
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Abdominal pain lower
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Abdominal pain upper
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Ascites
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Constipation
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Diarrhoea
|
0.50%
16/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Diverticular perforation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Duodenal ulcer
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Gastrointestinal haemorrhage
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Gastrooesophageal reflux disease
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Heamatemesis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Ileus
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Inguinal hernia
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Intestinal obstruction
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Intestinal perforation
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Jejunal perforation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Nausea
|
0.40%
13/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Oesophagitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Pancreatitis
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Pancreatitis acute
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Small intestinal obstruction
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Vomiting
|
0.53%
17/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Chest pain
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Chills
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Chronic fatigue syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Death
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Device dislocation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Drug interaction
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Fatigue
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
General physical health deterioration
|
0.28%
9/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Malaise
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Multi-organ disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Multi-organ failure
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Oedema
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Oedema peripheral
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Visceral pain
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Pyrexia
|
0.99%
32/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Sudden cardiac death
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Cholecystitis acute
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Cholelithiasis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Drug-induced liver injury
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Hepatic function abnormal
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Hepatitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Hepatotoxicity
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Immune system disorders
Drug hypersensitivity
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Immune system disorders
Hypersensitivity
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Immune system disorders
Food allergy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Abscess limb
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Anal abscess
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Blastocystis infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Bronchitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Cellulitis
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Clostridium difficile infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Device related infection
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Diverticulitis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Erysipelas
|
0.28%
9/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Escherichia bacteraemia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Escherichia sepsis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Gastroenteritis
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Groin abscess
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Herpes zoster
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
H1N1 influenza
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Infection
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Lower respiratory tract infection
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Lung infection
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Oesophageal candidiasis
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Oral candidiasis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Otitis externa
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Pilonidal cyst
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Pharyngotonsillitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Pneumocystis jiroveci pneumonia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Pneumonia
|
0.96%
31/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Postoperative wound infection
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Rash pustular
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Respiratory tract infection
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Salmonella sepsis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Sepsis
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Septic shock
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Skin infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Subcutaneous abscess
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Upper respiratory tract infection
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Urinary tract infection
|
0.34%
11/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Urosepsis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Viral infection
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Vulvitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Wound infection
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Wound infection staphylococcal
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Alcohol Poisoning
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Fall
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Femoral neck fracture
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Over dose
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Hip fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Post procedural haemorrhage
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Radiation injury
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Respiratory fume inhalation disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Spinal fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Aspartate aminotransferase increased
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Blood creatinine increased
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
C-reactive protein increased
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Gamma glutamyltransferase increased
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Hepatic enzyme increased
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Lipase increased
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Liver function test abnormal
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Cachexia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Dehydration
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Diabetes mellitus
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Diabetic ketoacidosis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hyperglycaemia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hyperuricaemia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hyponatraemia
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Tumour lysis syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
0.37%
12/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Bursitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Muscular weakness
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Arthritis
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Neck pain
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Osteoporosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Pathological fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
|
2.1%
68/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukaemia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibrous histiocytoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Keratoacanthoma
|
8.1%
260/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma
|
1.3%
43/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ
|
0.31%
10/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mycosis fungoides
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papilloma
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
|
8.0%
259/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour ulceration
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour necrosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Brain oedema
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebral haematoma
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebral haemorrhage
|
0.43%
14/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebrovascular accident
|
0.31%
10/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cognitive disorder
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Depressed level of consciousness
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Dizziness
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Dysarthria
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Epilepsy
|
0.31%
10/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Facial paresis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Generalised tonic clonic seizure
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Haemorrhage intracranial
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Haemorrhagic stroke
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Headache
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Intracranial pressure increased
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Hydrocephalus
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Ischaemic stroke
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Nervous system disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Neuralgia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Neuropathy peripheral
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Sciatica
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Stupor
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Syncope
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Transient ischaemic attack
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Tremor
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
VIIth nerve paralysis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Anxiety
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Completed suicide
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Confusional state
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Psychotic disorder
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Suicidal ideation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Calculus ureteric
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Glomerulonephritis minimal lesion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Haematuria
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Renal colic
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Urinary tract disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Cervical polyp
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Uterine haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Haemoptysis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pleural effusion
|
0.19%
6/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
|
0.40%
13/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Acanthosis
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Actinic keratosis
|
0.28%
9/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Angioedema
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Dermatitis exfoliative
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Hypersensitivity vasculitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Photosensitivity reaction
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash maculo-papular
|
0.22%
7/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash pruritic
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Skin mass
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Intermittent claudication
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Extremity necrosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Hypotension
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Thrombophlebitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Lichenoid keratosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Agranulocytosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Febrile neutropenia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Lymph node pain
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Microcytic anaemia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Ear and labyrinth disorders
Hearnig impaired
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Acute coronary syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Angina unstable
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Atrioventricular block
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiac arrest
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiac failure acute
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiac failure congestive
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiogenic shock
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Cardiomyopathy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Coronary artery stenosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Sinus node dysfunction
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Cardiac disorders
Supraventricular tachycardia
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Cataract
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Glaucoma
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Macular oedema
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Papilloedema
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Retinal artery occlusion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Retinal detachment
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Retinopathy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Eye disorders
Iritis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Anal fistula
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Anal skin tags
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Colitis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Dyspepsia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Dysphagia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Enteroocolitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Faeces pale
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Food poisoning
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Gastritis haemorrhagic
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Gastrointestinal necrosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Gastrointestinal toxicity
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Haemorrhoidal haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Intestinal ischaemia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Intussusception
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Large intestine perforation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Leukoplakia oral
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Lower gastrointestinal haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Melaena
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Mouth ulceration
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Paraesthesia oral
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Rectal haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Retroperitoneal haematoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Circulatory collapse
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Deep vein thrombosis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Haematoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Hypertension
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Hypertensive Crisis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Dermal cyst
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Dermatitis exfoliative generalised
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Drug eruption
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Asthenia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Generalised oedema
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Impaired healing
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Surgical failure
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Euthanasia
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Cholangitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Cholecystitis
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Hepatic failure
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Hepatobiliary disorders
Hepatitis toxic
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Erythema nodosum
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Hyperkeratosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Panniculitis
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash erythematous
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash follicular
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash generalised
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash macular
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash papular
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Bronchial haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Hydrothorax
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pleurisy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pleuritic pain
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary toxicity
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Vocal cord leukoplakia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Adnexal torsion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Endometrial hyperplasia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Metrorrhagia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Peyronie's disease
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Reproductive system and breast disorders
Uterine cervical erosion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Acute kidney injury
|
0.25%
8/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Nephrolithiasis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Nephropathy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Nephhropathy toxic
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Tubulointerstitial nephritis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Renal and urinary disorders
Urinary fistula
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Bipolar disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Delirium
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Mania
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Mood altered
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Dupuytren's contracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Osteitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Spinal pain
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Decreased appetite
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hypoglycaemia
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Type 2 diabetes mellitus
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Blood glucose increased
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Electrocardiogram QT prolonged
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Cystitis radiation
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Facial bone fracture
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Femur fracture
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Fracture displacement
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Head injury
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Humerus fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Lumbar vertebral fracture
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Multiple injuries
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Patella fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Radiation necrosis
|
0.12%
4/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Radius fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Road traffic accident
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Spinal compression fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Splenic rupture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Subdural haematoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Sunburn
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Tendon injury
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Tibia fracture
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Toxicity to various agents
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Acinetobacter infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Appendicitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Appendicitis perforated
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Arthritis bacterial
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Brain Abscess
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Atypical pneumonia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Cholecystitis infective
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Colonic abscess
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Cystitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Gastroenteritis viral
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Gastrointestinal infection
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Hypopyon
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Infected dermal cyst
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Infectious pleural effusion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Localised infection
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Lymph gland infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Ophthalmic herpes zoster
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Perineal abscess
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Skin bacterial infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Soft tissue infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Subdiaphragmatic abscess
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Tonsillitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Tooth abscess
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Tooth infection
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acanthoma
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adrenocarcinoma of colon
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of skin
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bowen's disease
|
0.16%
5/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoma in situ of skin
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma stage 0
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholesteatoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chondrosarcoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ependymoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Eye naevus
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Infected neoplasm
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Kaposi's sarcoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myxoid liposarcoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroendocrine carcinoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroendocrine carcinoma of the skin
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroendocrine tumour
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oral papilloma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin neoplasm bleeding
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of the oral cavity
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of the vulva
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Superficial spreading melanoma stage unspecified
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Synovial sarcoma
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Transitional cell carcinoma
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lentigo maligna
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Aphasia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Balance disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Carpal tunnel syndrome
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebral disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebrospinal fluid leakage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Facial nerve disorder
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Metabolic encephalopathy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Migraine
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Monoplegia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Neurotoxicity
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Partial seizures
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Peripheral sensorimotor neuropathy
|
0.06%
2/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Polyneuropathy
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Seizure
|
0.37%
12/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Simple partial seizure
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Spinal cord compression
|
0.09%
3/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Status epilepticus
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Subarachnoid haemorrhage
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Vasogenic cerebral oedema
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Clostridium colitis
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Electrolyte imbalance
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Hypertriglyceridaemia
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Cerebellar infarction
|
0.03%
1/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
Other adverse events
| Measure |
Vemurafenib
n=3219 participants at risk
Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant's safety, death or study termination by the Sponsor.
|
|---|---|
|
Gastrointestinal disorders
Diarrhoea
|
18.1%
584/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Nausea
|
22.3%
718/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Vomiting
|
13.9%
449/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Fatigue
|
25.9%
834/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Pyrexia
|
11.3%
363/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Weight decreased
|
12.9%
414/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Metabolism and nutrition disorders
Decreased appetite
|
15.0%
482/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
42.2%
1357/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
9.6%
308/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
|
19.3%
621/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Headache
|
14.2%
458/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
27.1%
873/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
16.7%
538/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Erythema
|
10.2%
327/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Hyperkeratosis
|
25.8%
830/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Photosensitivity reaction
|
21.1%
678/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
9.9%
320/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash
|
17.3%
556/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Abdominal Pain
|
5.3%
170/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Gastrointestinal disorders
Constipation
|
6.1%
196/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Blood and lymphatic system disorders
Anaemia
|
6.7%
215/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Asthenia
|
11.9%
382/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
General disorders
Oedema Peripheral
|
7.4%
238/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Investigations
Electrocardiogram QT prolonged
|
16.2%
521/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Conjunctivitis
|
5.3%
170/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Infections and infestations
Nasopharyngitis
|
5.3%
171/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Injury, poisoning and procedural complications
Sunburn
|
9.9%
318/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Back Pain
|
5.9%
191/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Muscloskeletal Pain
|
6.9%
222/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Musculoskeletal and connective tissue disorders
Pain in Extremity
|
8.6%
276/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
|
7.1%
227/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis
|
8.3%
266/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Nervous system disorders
Dysgeusia
|
5.9%
191/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Psychiatric disorders
Insomnia
|
5.1%
163/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
5.9%
191/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Actinic keratosis
|
7.6%
246/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Palmar plantar erythrodysaesthesia syndrome
|
6.0%
193/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash erythematous
|
6.1%
195/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Skin and subcutaneous tissue disorders
Rash Maculo- Papular
|
5.6%
179/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
|
Vascular disorders
Hypertension
|
8.2%
264/3219 • Baseline up to 28 days post end of treatment (maximum up to 46 months)
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
- Publication restrictions are in place
Restriction type: OTHER