Trial Outcomes & Findings for Study in Healthy Volunteers to Prove That Two Different Formulations of Rotigotine Patches Deliver Equivalent Drug Amount to the Body (NCT NCT01059903)

NCT ID: NCT01059903

Last Updated: 2012-05-22

Results Overview

The AUC(0-tz) is the area under the concentration-time curve from zero up to the last analytically quantifiable concentration.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 50 participants
• Primary outcome timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h
• Results posted on: 2012-05-22

Participant Flow

A total of 50 healthy, male subjects have been randomized in order to complete the trial with at least 38 subjects qualified for the Pharmacokinetic Set (PKS). Baseline characteristics refer to the PKS which is the primary analysis set.

Eight subjects that fulfilled predefined criteria for patch adhesiveness were excluded from the statistical analysis on the PKS. The predefined criteria were patch adhesiveness smaller than 75% at any timepoint or an adhesiveness lower than 90% for 12 hours or more.

Participant milestones

Measure	Rotigotine PR2.2.1 First Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 separated by a washout phase of at least 5 days	Rotigotine PR2.1.1 First Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 separated by a washout phase of at least 5 days
Period 1: First Intervention- 24 Hours STARTED	25	25
Period 1: First Intervention- 24 Hours COMPLETED	24	24
Period 1: First Intervention- 24 Hours NOT COMPLETED	1	1
Period 2: Washout Period (>= 5 Days) STARTED	24	24
Period 2: Washout Period (>= 5 Days) COMPLETED	24	24
Period 2: Washout Period (>= 5 Days) NOT COMPLETED	0	0
Period 3: Second Intervention- 24 Hours STARTED	24	24
Period 3: Second Intervention- 24 Hours Pharmacokinetic Set (PKS)	18	22
Period 3: Second Intervention- 24 Hours COMPLETED	24	24
Period 3: Second Intervention- 24 Hours NOT COMPLETED	0	0

Reasons for withdrawal

Measure	Rotigotine PR2.2.1 First Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 separated by a washout phase of at least 5 days	Rotigotine PR2.1.1 First Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 separated by a washout phase of at least 5 days
Period 1: First Intervention- 24 Hours Adverse Event	1	1

Baseline Characteristics

Study in Healthy Volunteers to Prove That Two Different Formulations of Rotigotine Patches Deliver Equivalent Drug Amount to the Body

Baseline characteristics by cohort

Measure	Rotigotine PR2.2.1 First n=18 Participants Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 separated by a washout phase of at least 5 days	Rotigotine PR2.1.1 First n=22 Participants Rotigotine transdermal patch 4.5 mg/10cm\^2, reference drug product PR2.1.1 followed by Rotigotine transdermal patch 4.5 mg/10cm\^2, test drug product PR2.2.1 separated by a washout phase of at least 5 days	Total n=40 Participants Total of all reporting groups
Age Continuous	37.1 years STANDARD_DEVIATION 12.6 • n=5 Participants	35.6 years STANDARD_DEVIATION 9.6 • n=7 Participants	36.3 years STANDARD_DEVIATION 11.0 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	22 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants	22 Participants n=7 Participants	40 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	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	22 Participants n=7 Participants	40 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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
Body Mass Index (BMI)	24.42 kg/m^2 STANDARD_DEVIATION 2.71 • n=5 Participants	24.16 kg/m^2 STANDARD_DEVIATION 2.75 • n=7 Participants	24.28 kg/m^2 STANDARD_DEVIATION 2.70 • n=5 Participants
Height	1.807 meter (m) STANDARD_DEVIATION 0.083 • n=5 Participants	1.807 meter (m) STANDARD_DEVIATION 0.058 • n=7 Participants	1.807 meter (m) STANDARD_DEVIATION 0.069 • n=5 Participants
Weight	79.94 kilogramm (kg) STANDARD_DEVIATION 11.74 • n=5 Participants	78.88 kilogramm (kg) STANDARD_DEVIATION 9.14 • n=7 Participants	79.36 kilogramm (kg) STANDARD_DEVIATION 10.26 • n=5 Participants

PRIMARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz) is the area under the concentration-time curve from zero up to the last analytically quantifiable concentration.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0-tz) of Unconjugated Rotigotine	5.2704 ng/ mL*h Standard Deviation 3.1435	5.4724 ng/ mL*h Standard Deviation 2.4755

PRIMARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The Cmax is the maximum plasma concentration.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Cmax of Unconjugated Rotigotine	0.26156 ng/ mL Standard Deviation 0.15594	0.25774 ng/ mL Standard Deviation 0.11184

PRIMARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0- ∞) is the area under the plasma concentration-time curve from zero up to infinity

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0- ∞) of Unconjugated Rotigotine	5.36933 ng/ mL*h Standard Deviation 3.17013	5.56925 ng/ mL*h Standard Deviation 2.49370

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz) norm (apparent dose) is the area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration normalized by apparent dose (mg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0-tz) Norm (Apparent Dose) of Unconjugated Rotigotine	2.56504 ng/ mL*h/ mg Standard Deviation 0.88171	2.66067 ng/ mL*h/ mg Standard Deviation 1.02321

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0-tz) norm (BW) is the area under the plasma concentration-time curve from zero up to the last analytically quantifiable concentration normalized by body weight (kg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0-tz) Norm (Body Weight) of Unconjugated Rotigotine	412.942 ng*h*kg/ mL Standard Deviation 239.918	434.101 ng*h*kg/ mL Standard Deviation 206.274

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0-inf) norm (apparent dose) is the area under the plasma concentration-time curve from zero up to infinity normalized by apparent dose (mg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0- ∞) Norm (Apparent Dose)	2.62042 ng/ mL*h/ mg Standard Deviation 0.88891	2.71397 ng/ mL*h/ mg Standard Deviation 1.03223

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The AUC(0-inf) norm (BW) is the area under the plasma concentration-time curve from zero up to infinity normalized by body weight (kg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
AUC(0- ∞) Norm (Body Weight)	420.811 ng*h*kg/ mL Standard Deviation 242.327	441.761 ng*h*kg/ mL Standard Deviation 207.793

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The Cmax, norm (apparent dose) is the maximum plasma concentration normalized by apparent dose (mg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Cmax, Norm (Apparent Dose) of Unconjugated Rotigotine	0.128863 ng/ mL/ mg Standard Deviation 0.045903	0.126144 ng/ mL/ mg Standard Deviation 0.046104

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The Cmax, norm (BW) is the maximum plasma concentration normalized by body weight (kg).

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Cmax, Norm (Body Weight) of Unconjugated Rotigotine	20.4935 ng/ mL*kg Standard Deviation 11.9380	20.4489 ng/ mL*kg Standard Deviation 9.3456

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The tmax is the time to reach maximum plasma concentration after patch application.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Tmax of Unconjugated Rotigotine	16.78 hours (h) Standard Deviation 5.23	15.75 hours (h) Standard Deviation 5.24

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The MRT is the mean residence time.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Mean Residence Time (MRT) of Unconjugated Rotigotine	18.473 hours (h) Standard Deviation 1.936	18.186 hours (h) Standard Deviation 2.056

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The λz of unconjugated rotigotine is the rate constant of elimination.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Rate Constant of Elimination (λz) of Unconjugated Rotigotine	0.162587 1/ h Standard Deviation 0.033663	0.165400 1/ h Standard Deviation 0.033405

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

the t1/2 of unconjugated rotigotine is the terminal half-life, calculated as t1/2=ln2/ λz.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Terminal Half-Life (t1/2) of Unconjugated Rotigotine	4.4523 hours (h) Standard Deviation 0.9701	4.3752 hours (h) Standard Deviation 0.9677

SECONDARY outcome

Timeframe: 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h

Population: Pharmacokinetic Set (PKS)

The CL/f of unconjugated rotigotine is the apparent total body clearance.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Apparent Total Body Clearance (CL/f) of Unconjugated Rotigotine	1125.11 L/ h Standard Deviation 621.56	1041.47 L/ h Standard Deviation 640.57

SECONDARY outcome

Timeframe: 24 hours

Population: Pharmacokinetic Set (PKS)

Apparent dose of unconjugated rotigotine in mg. The apparent dose was calculated by subtraction of the determined residual content of each rotigotine patch from the nominal content of rotigotine in the patch.

Outcome measures

Measure	Rotigotine PR2.2.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=40 Participants Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Apparent Dose	1.970 mg Standard Deviation 0.637	2.036 mg Standard Deviation 0.597

Adverse Events

Rotigotine PR2.2.1

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Rotigotine PR2.1.1

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Rotigotine PR2.2.1 n=49 participants at risk Rotigotine transdermal patch 4.5 mg/10 cm\^2, test drug product PR2.2.1 ; single application of 1 patch for 24 hours	Rotigotine PR2.1.1 n=49 participants at risk Rotigotine transdermal patch 4.5 mg/10 cm\^2, reference drug product PR2.1.1 ; single application of 1 patch for 24 hours
Gastrointestinal disorders Nausea	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Vomiting	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Dyspepsia	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Constipation	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Abdominal Pain	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Gastrointestinal disorders Gingival Bleeding	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
General disorders Application Site Pruritus	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	10.2% 5/49 • Number of events 5 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
General disorders Application Site Oedema	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
General disorders Application Site Paraesthesia	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
General disorders Fatigue	12.2% 6/49 • Number of events 7 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
General disorders Thirst	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Investigations Lipase Increased	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	6.1% 3/49 • Number of events 3 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Investigations Blood Amylase Increased	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Investigations Blood Creatine Phosphokinase Increased	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Investigations Alanine Aminotransferase Increased	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Investigations Blood Bilirubin Increased	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Metabolism and nutrition disorders Anorexia	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Pain in Jaw	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Renal and urinary disorders Proteinuria	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal Pain	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Vascular disorders Flushing	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Vascular disorders Hot Flush	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Vascular disorders Orthostatic Hypotension	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Infections and infestations Herpes Simplex	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Infections and infestations Rhinitis	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Headache	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	10.2% 5/49 • Number of events 5 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Dizziness	10.2% 5/49 • Number of events 7 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Dizziness Postural	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Nervous system disorders Somnolence	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Psychiatric disorders Insomnia	2.0% 1/49 • Number of events 1 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	0.00% 0/49 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
Skin and subcutaneous tissue disorders Hyperhidrosis	8.2% 4/49 • Number of events 4 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.	4.1% 2/49 • Number of events 2 • Adverse Events were collected up to 14 days after the last patch removal. Adverse Events (AEs) refer to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.

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