Open-Label, Extension Study to Evaluate the Safety of Hydrocodone Bitartrate Extended-Release Tablets

An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Time frame: Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Population: Safety Analysis Set for the Titration/Adjustment period; Post-Titration/Post-Adjustment Safety Analysis Set for the Open-Label Treatment Period

Pure tone audiometry was performed by trained personnel. Hearing loss was classified in degrees of hearing from normal to profound. This classification was determined by the hearing threshold (or the softest sound detected at a specific frequency). The exact ranges that classified hearing loss depended on the exact technique used during testing and on the patient's age. These values were provided by each audiology laboratory that performed the test. For serial audiograms, the criteria for a clinically significant hearing change were based on guidance from the American Speech Language Hearing Association (ASHA 1994, cited in \[Konrad-Martin et al 2005\]). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to no response at 3 consecutive test frequencies.

Time frame: Baseline was within two weeks of the final study visit in study 3103; during study exam was within two weeks of the end of trial visit for study 3104 (up to study week 26)

Population: Safety Analysis Set

Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: * Blood urea nitrogen: \>=10.71 mmol/L * Creatinine: \>=177 μmol/L * Uric acid: M\>=625, F\>=506 μmol/L * Aspartate aminotransferase (AST): \>=3\* upper limit of normal (ULN) * Alkaline phosphatase: \>=3\* upper limit of normal (ULN) * Gamma-glutamyl transpeptidase (GGT): \>=3\* upper limit of normal (ULN) * Serum white blood cells: \>=20 \* 10\^9/L * Hemoglobin: M\<=115, F\<=95 g/dL * Hematocrit: M\<0.37, F\<0.32 L/L * Eosinophils: \>=10.0 % * Platelets: \<=75 \* 10\^9/L * Absolute neutrophils: \<=1.0 \* 10\^9/L * Urinalysis: Glucose, Ketones, and Total Protein: \>=2 unit increase from baseline

Time frame: End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Population: The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline result for each test are counted as part of the number of participants analyzed for that test.

Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria * Pulse - high: \>=120 and increase of \>= 15 beats/minute from baseline * Pulse - low: \<=50 and decrease of \>=15 beats/minute * Systolic blood pressure - high: \>=180 and increase \>=20 mmHg * Systolic blood pressure - low: \<=90 and decrease \>=20 mmHg * Diastolic blood pressure - high: \>=105 and increase of \>=15 mmHg * Diastolic blood pressure - low: \<=50 and decrease of \>=15 mmHg

Time frame: Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Population: The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline vital sign result are counted as part of the number of participants analyzed.

The endpoint visit or early termination visit was an abbreviated exam. Endpoint refers to the last observation carried forward.

Time frame: End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Population: Post-Titration Safety Analysis Set

A 12-lead ECG was conducted at the final visit for study 3103 which is used as baseline for this study, and at week 22 of the treatment period \[or early termination\]). A qualified physician at the study center was responsible for providing interpretation of the ECG. Endpoint refers to the last observation carried forward.

Time frame: Baseline (final visit for study 3103), End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Population: Post-Titration Safety Analysis Set. Includes participants who have both baseline and endpoint data.

The API was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their average pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.

Time frame: Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

Population: Full Analysis Set includes participants who had at least one post-baseline efficacy assessment. Participants contributing to each time point are counted as part of the number of participants analyzed for that test.

The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.

Time frame: Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

Population: Full Analysis Set includes participants who had at least one post-baseline efficacy assessment. Participants contributing to each time point are counted as part of the number of participants analyzed for that test.

Percentage of patients who withdrew from the study for lack of efficacy, as indicated on the early termination form of the case report form (CRF).

Time frame: Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Population: Safety Analysis Set