Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

The Area Under the Curve (AUC) from dose to 15 hours (AUC 0-15) is a summary measure of data from each pharmacokinetic blood sample taken over the 15 hour time period.

The area is that below the line fitted to the data points.

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol (active drug) occurs.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample.

Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol-O-glucuronide (metabolite) is assessed to study absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of metabolite observed in the blood sample.

Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol-O-glucuronide (metabolite) occurs. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

Pain intensity assessments were with a 0 (no pain) to 10 (worst pain) scored McGrath color analog scale (CAS) in participants aged 6 years to less than 18 years, i.e. in Adolescents and Older Children. Participants were presented with the CAS and instructed to place the sliding bar on the color that best represented their pain intensity level at the time of assessment. The CAS is a pocket size tool used to measure the self-reported pain intensity of the older participants. The CAS consists of a 145 mm long triangular shaped strip of plastic, varying in width and hue from 1 mm wide and light pink hue at the bottom (and text no pain), to 3 mm wide and deep red hue at the top (most pain). This instrument includes 2 sides. One side shows the color pain intensity scale as described and the other shows a graduated scale, which provides a specific numeric value for the participant-reported level of pain.

This assessment tool was used in 3 to less than 12 year old participants, i.e. Older Children and Young Children.

The Faces Pain Scale (Revised) [FPS-R] score as allocated to a selected face by the participant. There are 6 faces and the participant is asked to indicate on a face to express how much it hurts.

The numeric value 0 (no pain) to 10 (very much pain) is read off the reverse side of the scale by the clinician.

The Face Legs Activity Cry Consolability (FLACC) Scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. The FLACC Scale is a behavioral scale for scoring postoperative pain in children between the ages of two months and seven years or in persons unable to communicate. In this trial the scale was used in the young and very young children, i.e. in participants aged 2 to less than 6 years. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. The clinician observes the participant for 5 minutes or more and scores each category with a 0, 1 or 2. The scores are added together for a total score ranging from 0 (no pain) to 10 (worst pain). The higher the total score the higher the pain.

Different pain intensity assessment tools were used in the different age groups. Therefore the sum of pain intensities were calculated and are reported for each age group based on the tool used.

Adolescents - Age 12 to Less Than 18 Years.

Older Children - Age 6 to Less Than 12 Years.

Young Children - Age 3 to Less Than 6 Years.

Very Young Children - Age 2 to Less Than 3 Years.

• CAS (McGrath color analog scale) [Theoretical Range: -40 to + 40],
• VAS (100 mm Visual Analog Scale) [Theoretical Range: -400 to + 400],
• FPS-R (6-point Faces Pain Scale - Revised) [Theoretical Range: -40 to + 40],
• FLACC (Face, Legs, Activity, Cry, and Consolability score) [Theoretical Range: -40 to + 40].

A mean score of zero indicates that there was no pain intensity change over the 4 hours.

The positive values indicate that in the group as a whole the sum of all pain intensity values over the first 4 hours lead to a reduction in pain in the time period.

Respiratory rate assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

Oxygen saturation assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Oxygen saturation was assessed using pulse oximetry. The uppermost value is 100%.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

Systolic and Diastolic blood pressure assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

12-lead electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.

The changes in ECG parameters are reported. Negative mean values indicate that the millisecond intervals decreased from the enrollment to the discharge visit. Positive mean values indicate that the millisecond intervals increased from the enrollment to the discharge visit. The Letters P,Q,R,S and T refer to specific medically defined points on an ECG tracing and correspond to specific heart activities.

12-lead Electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.

The changes in heart rate (beats per minute) parameters are reported per treatment group between the visits.

A positive value indicates that the heart rate was higher at discharge than at enrollment.

The intensity of all treatment emergent adverse events (TEAEs) were scored by the investigator. Treatment emergent adverse events were those adverse events documented from the time of investigational medicinal product (IMP), study drug, up to 48 hours post dosing.

The clinical "intensity" of an adverse event was classified as:

• Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the subject is distracted.
• Moderate: Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration.
• Severe: Symptoms which affect usual daily activity.

For adverse events where the intensity changes over time, the maximum intensity observed was documented.

Number of participants with intakes of supplemental analgesic medication between investigational medicinal product (IMP) intake and Site Discharge grouped according to preparation taken (non-opioid/opioid).

The hemoglobin test is a commonly ordered blood test and was done as part of a complete blood count (CBC). It is routinely done before and after surgery to check for anemia, the presence of chronic kidney disease or other chronic medical problems. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Hematocrit is a blood test that measures the percentage of the volume of whole blood that is made up of red blood cells (RBC). This measurement depends on the number of red blood cells and the size of red blood cells. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Erythrocyte Mean Corpuscular volume is a measurement of the average size of Red Blood Cells (RBC). It is also referred to as Mean Corpuscular Volume. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Platelets are cell fragments that are vital for normal blood clotting. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Leukocytes are also called white blood cells (WBC). These were measured to assess immune function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

A blood glucose test measures the amount of a sugar called glucose in blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Sodium is required by the body for the body to function properly. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Potassium is a mineral that the body needs to work normally. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

All cells need calcium in order to function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Chloride with other electrolytes help keep the proper balance of body fluids and maintain the body's acid-base balance. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care

Phosphate is needed by the body. This test was done to see how much phosphate is in the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

This test is to measure the amount of urea nitrogen in the blood. It was used to test liver and kidney function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Creatinine is removed from the body entirely by the kidneys. If kidney function is not normal, creatinine level increases in the blood. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

AST is considered to be one of the two most important tests to detect liver injury. During liver damage the enzyme is released into the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Triglycerides are a group of fat. Triglycerides were measured as part of metabolic and cardiac assessments. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Albumin is a protein made by the liver. Albumin prevents fluid leaking into the tissues. Albumin also transports many small molecules. Serum albumin was measured in the clear liquid portion of the blood called serum. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Uric acid (urate is the salt) is a chemical created when the body breaks down substances called purines. Most urate dissolves in blood and travels to the kidneys. From there, it passes out in the urine. The test is used to determine kidney function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Glomerular filtration rate (GFR) was done to check how well the kidneys are working. It estimates how much blood passes through the glomeruli in the kidney each minute. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

This test was used to test for the water balance and urine concentration. A urine sample was tested right away. A dipstick with a color-sensitive pad was used. The color the dipstick changes and the specific gravity of the urine was read off the color chart. In the study there were 2 planned safety urine collections. At Visit 1 in the enrollment period, after consent and assent obtained. The second sample was obtained at Visit 3 prior to discharge from the hospital. The discharge visit was as per standard of care.

A urine sample was tested right away. A dipstick made with a color-sensitive pad was used. The color indicated the acidity of the urine. In the study there were 2 planned safety urine collections. At Visit 1 in the enrollment period, after consent and assent obtained. The second sample was obtained at Visit 3 prior to discharge from the hospital. The discharge visit was as per standard of care.

This test was done in combination with other tests (such as AST, ALP, and bilirubin) to diagnose and monitor the liver function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The gamma-glutamyl transferase (GGT) test was used in combination with the alkaline phosphatase (ALP) test. Both ALP and GGT can be elevated in bile duct or liver complications. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Old red blood cells are replaced by new blood cells every day. Bilirubin is made by the body when the old blood cells are removed. The concentration of bilirubin in the blood measures liver function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Lactate Dehydrogenase (LDH) was used to check for tissue damage. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The test was done to verify kidney and liver function. It is done in combination with the albumin test. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The creatine kinase (CK) test was used to detect inflammation of muscles. The test was done in combination with other tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The Alkaline Phosphatase activity was used to detect bone or hepatobiliary disease. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

A triacylglycerol lipase test was done to check for pancreatic function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to investigational medicinal product administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

Single Dose of Tapentadol Oral Solution in Children Age 2 to Less Than 6 Years. Tapentadol oral solution single dose (1mg/kg body weight).

Total of all reporting groups

At predefined times after investigational medicinal product administration, participants were asked to rate their pain on a 100 mm line (visual analog scale - VAS) by marking a point on the line in response to:

"My pain at this time is". The mark was scored between "no pain" and " pain as bad as it could be". The distance was then measured by a clinician and reported.

A value of 0 indicates "no pain". A value of 100 indicates "pain as bad as it could be".

Protocol pre-specified reporting groups.

Pain intensity assessments were with a 0 (no pain) to 10 (worst pain) scored McGrath color analog scale (CAS) in participants aged 6 years to less than 18 years, i.e. in Adolescents and Older Children. Participants were presented with the CAS and instructed to place the sliding bar on the color that best represented their pain intensity level at the time of assessment. The CAS is a pocket size tool used to measure the self-reported pain intensity of the older participants. The CAS consists of a 145 mm long triangular shaped strip of plastic, varying in width and hue from 1 mm wide and light pink hue at the bottom (and text no pain), to 3 mm wide and deep red hue at the top (most pain). This instrument includes 2 sides. One side shows the color pain intensity scale as described and the other shows a graduated scale, which provides a specific numeric value for the participant-reported level of pain.

Protocol pre-specified reporting groups.

This assessment tool was used in 3 to less than 12 year old participants, i.e. Older Children and Young Children.

The Faces Pain Scale (Revised) [FPS-R] score as allocated to a selected face by the participant. There are 6 faces and the participant is asked to indicate on a face to express how much it hurts.

The numeric value 0 (no pain) to 10 (very much pain) is read off the reverse side of the scale by the clinician.

The protocol pre-specified that the Faces Pain Scale (Revised) would not be administered in the very young participants (aged 2 to less than 3 years).

The Face Legs Activity Cry Consolability (FLACC) Scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. The FLACC Scale is a behavioral scale for scoring postoperative pain in children between the ages of two months and seven years or in persons unable to communicate. In this trial the scale was used in the young and very young children, i.e. in participants aged 2 to less than 6 years. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. The clinician observes the participant for 5 minutes or more and scores each category with a 0, 1 or 2. The scores are added together for a total score ranging from 0 (no pain) to 10 (worst pain). The higher the total score the higher the pain.

The protocol pre-specified that the young and very young children will be reported as one group.

Different pain intensity assessment tools were used in the different age groups. Therefore the sum of pain intensities were calculated and are reported for each age group based on the tool used.

Adolescents - Age 12 to Less Than 18 Years.

Older Children - Age 6 to Less Than 12 Years.

Young Children - Age 3 to Less Than 6 Years.

Very Young Children - Age 2 to Less Than 3 Years.

• CAS (McGrath color analog scale) [Theoretical Range: -40 to + 40],
• VAS (100 mm Visual Analog Scale) [Theoretical Range: -400 to + 400],
• FPS-R (6-point Faces Pain Scale - Revised) [Theoretical Range: -40 to + 40],
• FLACC (Face, Legs, Activity, Cry, and Consolability score) [Theoretical Range: -40 to + 40].

A mean score of zero indicates that there was no pain intensity change over the 4 hours.

The positive values indicate that in the group as a whole the sum of all pain intensity values over the first 4 hours lead to a reduction in pain in the time period.

Protocol pre-specified reporting groups.

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Pharmacokinetic Set

Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Pharmacokinetic Set

Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Pharmacokinetic Set

Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.

Pharmacokinetic Set

Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.

Pharmacokinetic Set

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

The Area Under the Curve (AUC) from dose to 15 hours (AUC 0-15) is a summary measure of data from each pharmacokinetic blood sample taken over the 15 hour time period.

The area is that below the line fitted to the data points.

The protocol planned that this analysis would only be performed for the adolescent participants.

Respiratory rate assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at and after 2 hours: N=20; Older Children Group at 30 minutes and 1 hour N=27, at 2 hours N=24, and at and after 4 hours N=22; Young and Very Young Children Group at and after 4 hours: N=16).

Oxygen saturation assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Oxygen saturation was assessed using pulse oximetry. The uppermost value is 100%.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at and after 2 hours: N=20; Older Children Group at 30 minutes and 1 hour N=27, at 2 hours N=24, at and after 4 hours N=22; Young and Very Young Children Group at and after 4 hours: N=16).

Systolic and Diastolic blood pressure assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.

Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at and after 2 hours: N=20; Older Children Group at 30 minutes and 1 hour N=27, at 2 hours N=24, at and after 4 hours N=22; Young and Very Young Children Group at and after 4 hours: N=16).

12-lead electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.

The changes in ECG parameters are reported. Negative mean values indicate that the millisecond intervals decreased from the enrollment to the discharge visit. Positive mean values indicate that the millisecond intervals increased from the enrollment to the discharge visit. The Letters P,Q,R,S and T refer to specific medically defined points on an ECG tracing and correspond to specific heart activities.

The protocol pre-specified that the young and very young children will be reported as one group.

(For older children N=27 at Visit 1)

12-lead Electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.

The changes in heart rate (beats per minute) parameters are reported per treatment group between the visits.

A positive value indicates that the heart rate was higher at discharge than at enrollment.

The protocol pre-specified that the young and very young children will be reported as one group.

(For older children: N=27 at Visit 1)

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample

The protocol planned that this analysis would only be performed for the adolescent participants.

The intensity of all treatment emergent adverse events (TEAEs) were scored by the investigator. Treatment emergent adverse events were those adverse events documented from the time of investigational medicinal product (IMP), study drug, up to 48 hours post dosing.

The clinical "intensity" of an adverse event was classified as:

• Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the subject is distracted.
• Moderate: Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration.
• Severe: Symptoms which affect usual daily activity.

For adverse events where the intensity changes over time, the maximum intensity observed was documented.

The protocol pre-specified that the young and very young children will be reported as one group.

Number of participants with intakes of supplemental analgesic medication between investigational medicinal product (IMP) intake and Site Discharge grouped according to preparation taken (non-opioid/opioid).

The protocol pre-specified that the young and very young children will be reported as one group.

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol (active drug) occurs.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

The protocol planned that this analysis would only be performed for the adolescent participants.

Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.

Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample.

The protocol planned that this analysis would only be performed for the adolescent participants.

Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol-O-glucuronide (metabolite) is assessed to study absorption and distribution.

The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of metabolite observed in the blood sample.

The protocol planned that this analysis would only be performed for the adolescent participants.

Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol-O-glucuronide (metabolite) occurs. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.

The protocol planned that this analysis would only be performed for the adolescent participants.

The hemoglobin test is a commonly ordered blood test and was done as part of a complete blood count (CBC). It is routinely done before and after surgery to check for anemia, the presence of chronic kidney disease or other chronic medical problems. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant with missing data at each of these visits).

Hematocrit is a blood test that measures the percentage of the volume of whole blood that is made up of red blood cells (RBC). This measurement depends on the number of red blood cells and the size of red blood cells. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant with missing data at each of these visits).

Erythrocyte Mean Corpuscular volume is a measurement of the average size of Red Blood Cells (RBC). It is also referred to as Mean Corpuscular Volume. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant with missing data at each of these visits).

Platelets are cell fragments that are vital for normal blood clotting. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant with missing data at each of these visits).

Leukocytes are also called white blood cells (WBC). These were measured to assess immune function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant with missing data at each visit).

A blood glucose test measures the amount of a sugar called glucose in blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

Sodium is required by the body for the body to function properly. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

Potassium is a mineral that the body needs to work normally. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

All cells need calcium in order to function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Older children Group at Visit 2: N=27 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

Chloride with other electrolytes help keep the proper balance of body fluids and maintain the body's acid-base balance. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Older children Group at Visit 2: N=27 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

Phosphate is needed by the body. This test was done to see how much phosphate is in the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

This test is to measure the amount of urea nitrogen in the blood. It was used to test liver and kidney function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

Creatinine is removed from the body entirely by the kidneys. If kidney function is not normal, creatinine level increases in the blood. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Young and Very Young Children Group at Visit 3: N=16 one participant with missing data).

AST is considered to be one of the two most important tests to detect liver injury. During liver damage the enzyme is released into the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant with missing data; Older children at Visits 2 and 3: N=26 two participants with missing data; Young and Very Young Children Group at Visits 1 and 3: N=16 one participant with missing data).

Triglycerides are a group of fat. Triglycerides were measured as part of metabolic and cardiac assessments. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.

The protocol pre-specified that the young and very young children will be reported as one group.

(Adolescents Group at Visit 3: N=20 one participant data missing; Older children Visits 2 and 3: N=27 and N=26 one and two participant data missing; Young and Very Young Children Group at Visits 2 and 3: N=16 one participant data missing).