Trial Outcomes & Findings for Study of Octaplex (Human Prothrombin Complex Concentrate) and Fresh Frozen Plasma in Patients Under Vitamin K Therapy Antagonist Needing Urgent Surgery or Invasive Procedures (NCT NCT00618098)

Last Updated: 2023-01-31

Results Overview

Number of patients who had an INR response, defined as the correction of patient's INR to \<1.5, 15 minutes after the end of first infusion with study medication

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

200 participants

Primary outcome timeframe

15 minutes after the end of first infusion of OCTAPLEX or FFP

Results posted on

2023-01-31

Participant Flow

Participant milestones

Participant milestones
Measure	Octaplex (Human Prothrombin Complex Concentrate) Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.
Overall Study STARTED	97	103
Overall Study COMPLETED	66	69
Overall Study NOT COMPLETED	31	34

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Octaplex (Human Prothrombin Complex Concentrate) and Fresh Frozen Plasma in Patients Under Vitamin K Therapy Antagonist Needing Urgent Surgery or Invasive Procedures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Octaplex (Human Prothrombin Complex Concentrate) n=97 Participants Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma n=103 Participants Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.	Total n=200 Participants Total of all reporting groups
Age, Continuous	65.5 years STANDARD_DEVIATION 12.9 • n=5 Participants	67.6 years STANDARD_DEVIATION 14.8 • n=7 Participants	66.6 years STANDARD_DEVIATION 19.9 • n=5 Participants
Age, Customized 18-60 years	36 Participants n=5 Participants	30 Participants n=7 Participants	66 Participants n=5 Participants
Age, Customized 61-74 years	35 Participants n=5 Participants	34 Participants n=7 Participants	69 Participants n=5 Participants
Age, Customized ≥75 years	26 Participants n=5 Participants	39 Participants n=7 Participants	65 Participants n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Sex: Female, Male Male	66 Participants n=5 Participants	71 Participants n=7 Participants	137 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian, non-Hispanic	88 Participants n=5 Participants	96 Participants n=7 Participants	184 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized African American	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: 15 minutes after the end of first infusion of OCTAPLEX or FFP

Number of patients who had an INR response, defined as the correction of patient's INR to \<1.5, 15 minutes after the end of first infusion with study medication

Outcome measures

Outcome measures
Measure	Octaplex (Human Prothrombin Complex Concentrate) n=97 Participants Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma n=103 Participants Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.	Octaplex (Human Prothrombin Complex Concentrate)(Post-interim Analysis) Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5 and had surgery post interim analysis Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma (Post Interim Analysis) Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5 and required surgery post interim analysis Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.
INR Response	74 Participants	31 Participants	—	—

PRIMARY outcome

Timeframe: Intra-operative; throughout the duration of operation

Total number of intra-operative units of red blood cell (RBC) given to patients

Outcome measures

Outcome measures
Measure	Octaplex (Human Prothrombin Complex Concentrate) n=41 Participants Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma n=42 Participants Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.	Octaplex (Human Prothrombin Complex Concentrate)(Post-interim Analysis) n=56 Participants Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5 and had surgery post interim analysis Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma (Post Interim Analysis) n=61 Participants Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5 and required surgery post interim analysis Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.
RBC Transfusion Units	0.4 mL of RBC Transfusion During Surgery Standard Deviation 2.35	0.3 mL of RBC Transfusion During Surgery Standard Deviation 0.77	0.2 mL of RBC Transfusion During Surgery Standard Deviation 0.50	0.0 mL of RBC Transfusion During Surgery Standard Deviation 0.13

Adverse Events

Octaplex (Human Prothrombin Complex Concentrate)

Serious events: 27 serious events

Other events: 57 other events

Deaths: 19 deaths

Fresh Frozen Plasma

Serious events: 28 serious events

Other events: 58 other events

Deaths: 13 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Octaplex (Human Prothrombin Complex Concentrate) n=97 participants at risk Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma n=103 participants at risk Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.
Gastrointestinal disorders Constipation	7.2% 7/97 • Number of events 7 • 21 day Observation Period Post Study Treatment Start (Safety set)	4.9% 5/103 • Number of events 5 • 21 day Observation Period Post Study Treatment Start (Safety set)
Gastrointestinal disorders Diarrhea	4.1% 4/97 • Number of events 4 • 21 day Observation Period Post Study Treatment Start (Safety set)	6.8% 7/103 • Number of events 7 • 21 day Observation Period Post Study Treatment Start (Safety set)
Gastrointestinal disorders Nausea	9.3% 9/97 • Number of events 9 • 21 day Observation Period Post Study Treatment Start (Safety set)	12.6% 13/103 • Number of events 13 • 21 day Observation Period Post Study Treatment Start (Safety set)
General disorders Pyrexia	4.1% 4/97 • Number of events 4 • 21 day Observation Period Post Study Treatment Start (Safety set)	6.8% 7/103 • Number of events 7 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Pneumonia	4.1% 4/97 • Number of events 4 • 21 day Observation Period Post Study Treatment Start (Safety set)	6.8% 7/103 • Number of events 7 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Procedural Pain	9.3% 9/97 • Number of events 9 • 21 day Observation Period Post Study Treatment Start (Safety set)	1.9% 2/103 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)
Metabolism and nutrition disorders Hypokalaemia	8.2% 8/97 • Number of events 8 • 21 day Observation Period Post Study Treatment Start (Safety set)	5.8% 6/103 • Number of events 6 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Hypotension	12.4% 12/97 • Number of events 12 • 21 day Observation Period Post Study Treatment Start (Safety set)	10.7% 11/103 • Number of events 11 • 21 day Observation Period Post Study Treatment Start (Safety set)

Additional Information

Patrick Murphy

CRMG

Phone: 4138210022

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Octaplex (Human Prothrombin Complex Concentrate) n=97 participants at risk Participants to receive1 or more Octaplex infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Octaplex (human prothrombin complex concentrate): INR is determined 15 minutes after the end of each infusion. Each dose (mL/kg body weight) was calculated as = ln(INR/1.4)/0.52. The maximum dose for initial treatment was not to exceed 5500 IU. If the INR is ≥ 1.5 after the initial infusion, additional infusions will be repeated until the INR was \< 1.5. Octaplex (500 units, IU) is supplied in vials and was reconstituted with 20 mL of Water for Injection (Ph.Eur.).	Fresh Frozen Plasma n=103 participants at risk Participants to receive1 or more fresh frozen plasma infusions intravenously until their International Normalized Ratio (INR) was \< 1.5. Fresh frozen plasma: INR is determined 15 minutes after the end of each infusion. The initial dose is 10 mL/kg for a participant with an initial INR of \< 3 and 15 mL/kg for a participant with an initial INR of ≥ 3. If the INR is ≥ 1.5 after the initial infusion, additional infusions of 5 mL/kg will be repeated until the INR was \< 1.5. Fresh frozen plasma is supplied by the blood bank at each study site and will be prepared and handled according to the site's standard practice.
Blood and lymphatic system disorders Anemia	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Blood and lymphatic system disorders Coagulopathy	2.1% 2/97 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Blood and lymphatic system disorders Hemmorhagic Anemia	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Acute Myocardial Infarction	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Blood and lymphatic system disorders Bradycardia	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Cardiac Failute	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Cardiac Failure Acute	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	1.9% 2/103 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Cardiac Failure Congestive	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Cardiogenic Shock	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Coronary Artery Disease	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Right Ventricular Failure	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Cardiac disorders Supraventricular Tachycardia	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
General disorders Condition Aggravated	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
General disorders Multi-organ failure	2.1% 2/97 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Cardiac Valve Abscess	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Diverticulitis	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Endocarditis, Bacterial	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Gangrene	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Pneumonia	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	2.9% 3/103 • Number of events 3 • 21 day Observation Period Post Study Treatment Start (Safety set)
Infections and infestations Sepsis	2.1% 2/97 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Drug Toxicity	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Gastrointestinal Stoma Complication	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Medical Device Complication	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Postoperative Respiratory Distress	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Procedural Pain	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Thrombosis in Device	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Injury, poisoning and procedural complications Vascular Pseudoaneurysm	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Cancer	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Nervous system disorders Brain Compression	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Acute Respiratory Distress Syndrome	2.1% 2/97 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Hemothorax	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Pneumonia Aspiration	2.1% 2/97 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Pulmonary Edema	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Respiratory Arrest	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Respiratory Distress	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.97% 1/103 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)
Respiratory, thoracic and mediastinal disorders Respiratory Failure	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	1.9% 2/103 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)
Vascular disorders Cardiovascular Insufficiency	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Vascular disorders Deep Vein Thrombosis	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)
Vascular disorders Hypotension	0.00% 0/97 • 21 day Observation Period Post Study Treatment Start (Safety set)	1.9% 2/103 • Number of events 2 • 21 day Observation Period Post Study Treatment Start (Safety set)
Vascular disorders Thrombosis	1.0% 1/97 • Number of events 1 • 21 day Observation Period Post Study Treatment Start (Safety set)	0.00% 0/103 • 21 day Observation Period Post Study Treatment Start (Safety set)