Trial Outcomes & Findings for Evaluation of EXPAREL for Prolonged Postsurgical Analgesia in Subjects Undergoing Third Molar Extraction (NCT NCT02517905)

Last Updated: 2020-12-10

Results Overview

AUC of NRS pain intensity scores through 48 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

166 participants

Primary outcome timeframe

0-48 hours

Results posted on

2020-12-10

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration	EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration
Overall Study STARTED	59	107
Overall Study COMPLETED	57	97
Overall Study NOT COMPLETED	2	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration	EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration
Overall Study Lost to Follow-up	0	4
Overall Study Withdrawal by Subject	0	4
Overall Study Screen failure	2	2

Baseline Characteristics

Evaluation of EXPAREL for Prolonged Postsurgical Analgesia in Subjects Undergoing Third Molar Extraction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	EXPAREL 133 mg n=105 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=57 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration	Total n=162 Participants Total of all reporting groups
Age, Continuous	20.9 years STANDARD_DEVIATION 3.81 • n=5 Participants	20.9 years STANDARD_DEVIATION 4.76 • n=7 Participants	20.9 years STANDARD_DEVIATION 4.15 • n=5 Participants
Sex: Female, Male Female	53 Participants n=5 Participants	33 Participants n=7 Participants	86 Participants n=5 Participants
Sex: Female, Male Male	52 Participants n=5 Participants	24 Participants n=7 Participants	76 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants n=5 Participants	7 Participants n=7 Participants	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	89 Participants n=5 Participants	50 Participants n=7 Participants	139 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	1 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) White	94 Participants n=5 Participants	53 Participants n=7 Participants	147 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	105 participants n=5 Participants	57 participants n=7 Participants	162 participants n=5 Participants
Body Mass Index	25.8 kg/m2 STANDARD_DEVIATION 6.87 • n=5 Participants	24.5 kg/m2 STANDARD_DEVIATION 4.72 • n=7 Participants	25.3 kg/m2 STANDARD_DEVIATION 6.21 • n=5 Participants
Impaction Scores 4 fully bony impacted teeth	23 Participants n=5 Participants	19 Participants n=7 Participants	42 Participants n=5 Participants
Impaction Scores 3 fully bony impacted teeth, 1 partially impacted	14 Participants n=5 Participants	7 Participants n=7 Participants	21 Participants n=5 Participants
Impaction Scores 3 fully bony impacted teeth	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Impaction Scores 2 fully bony impacted teeth, 2 partially impacted	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Impaction Scores 2 fully bony impacted teeth, 1 partially impacted	9 Participants n=5 Participants	2 Participants n=7 Participants	11 Participants n=5 Participants
Impaction Scores 2 fully bony impacted teeth	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Impaction Scores 1 fully bony impacted tooth, 3 partially impacted	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Impaction Scores 1 fully bony impacted tooth, 2 partially impacted	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Impaction Scores 1 fully bony impacted tooth, 1 partially impacted	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Impaction Scores 1 fully bony impacted tooth	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Impaction Scores 4 partially impacted teeth	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Impaction Scores 3 partially impacted teeth	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Impaction Scores 2 partially impacted teeth	16 Participants n=5 Participants	1 Participants n=7 Participants	17 Participants n=5 Participants
Impaction Scores 1 partially impacted tooth	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Impaction Scores No impactions	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 0-48 hours

Population: Primary efficacy population: all participants who received study drug, underwent the surgery, and were enrolled under protocol amendment 2, according to which pain intensity scores were collected before each use of rescue medication. Analysis was based on randomized treatment.

AUC of NRS pain intensity scores through 48 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain)

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 48 Hours	178.9 units on NRS scale*hr Standard Error 10.30	181.6 units on NRS scale*hr Standard Error 13.63

SECONDARY outcome

Timeframe: 0-24 hours

AUC of NRS pain intensity scores through 24 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain) 0-24 hours

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 24 Hours	102.4 units on NRS scale*hr Standard Error 4.73	106.4 units on NRS scale*hr Standard Error 6.26

SECONDARY outcome

Timeframe: 0-72 hours

AUC of NRS pain intensity scores through 72 hours. Pain intensity scores were measured on a 10-point scale (0=no pain and 10=worst possible pain)

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Area Under the Curve (AUC) of Numeric Rating Scale (NRS) Pain Intensity Scores Through 72 Hours	241.5 units on NRS scale*hr Standard Error 15.40	235.6 units on NRS scale*hr Standard Error 20.38

SECONDARY outcome

Timeframe: 0-24 hours

Percentage of opioid-free subjects through 24 hours.

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Percentage of Opioid-free Subjects Through 24 Hours.	19 Participants	12 Participants

SECONDARY outcome

Timeframe: 0-48 hours

Percentage of opioid-free subjects through 48 hours.

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Percentage of Opioid-free Subjects Through 48 Hours.	19 Participants	12 Participants

SECONDARY outcome

Timeframe: 0-72 hours

Percentage of opioid-free subjects through 72 hours.

Outcome measures

Outcome measures
Measure	EXPAREL 133 mg n=99 Participants 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=51 Participants 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Percentage of Opioid-free Subjects Through 72 Hours.	18 Participants	12 Participants

Adverse Events

EXPAREL 133 mg

Serious events: 0 serious events

Other events: 105 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Pacira Medical Information

Pacira Pharmaceuticals, Inc.

Phone: 1-855-793-9727

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Site shall reasonably cooperate with the sponsor to prepare an abstract and/or manuscript reporting trial results within 90 and 120 days, respectively, after final CSR is available and should not otherwise publish any results within 120 days. Scientific meeting and journal are to be determined by the sponsor. Site shall give sponsor ≥60 days before submitting materials and upon sponsor request shall withhold publication for an additional 90 days.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	EXPAREL 133 mg n=105 participants at risk 10 mL EXPAREL (bupivacaine liposome injectable suspension) injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Bupivacaine liposome: Local administration	Placebo n=57 participants at risk 10 mL normal saline injected into the maxilla (4 mL; 2 mL per side) and mandible (6 mL; 3 mL per side) at the end of surgery and ≥20 min after lidocaine administration Placebo: Local administration
Nervous system disorders Hypoesthesia oral	99.0% 104/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	100.0% 57/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Nervous system disorders Dysgeusia	76.2% 80/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	56.1% 32/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Nervous system disorders Muscle contractions involuntary	15.2% 16/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	21.1% 12/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Nervous system disorders Dizziness	10.5% 11/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	14.0% 8/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Nervous system disorders Headache	5.7% 6/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	15.8% 9/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Nervous system disorders Paresthesia oral	0.95% 1/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Gastrointestinal disorders Nausea	30.5% 32/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	28.1% 16/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Gastrointestinal disorders Vomiting	17.1% 18/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	15.8% 9/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Gastrointestinal disorders Alveolar osteitis	1.9% 2/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Gastrointestinal disorders Constipation	0.00% 0/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Injury, poisoning and procedural complications Post procedural edema	9.5% 10/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	12.3% 7/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Injury, poisoning and procedural complications Post procedural swelling	2.9% 3/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Musculoskeletal and connective tissue disorders Muscle twitching	7.6% 8/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	7.0% 4/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Skin and subcutaneous tissue disorders Dermatitis contact	1.9% 2/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Infections and infestations Upper respiratory tract infection	3.8% 4/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Infections and infestations Wound infection	2.9% 3/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	0.00% 0/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.95% 1/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
General disorders Hot flush	0.95% 1/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.
Eye disorders Blurred Vision	0.95% 1/105 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.	3.5% 2/57 • From screening to postsurgical day 29 An AE was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov. The safety analysis set included all subjects who received study drug, based on the treatment received.