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The purpose of this study was to compare the pharmacokinetic profiles at steady-state of the test product, Tramadol HCl Once-A-Day (OAD) 200 mg tablets and the reference product, Tramadol HCl 50 mg (IR) tablets (Ortho-McNeil Ultram®). For this purpose, the extent of absorption of tramadol and formation of O-desmethyltramadol (measures of systemic exposure) after multiple administration of 50 mg 6-hourly at 07:30, 13:30, 19:30 and 01:30 (reference product) and 200 mg 24-hourly at 07:30 (test product), were compared.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1: 1x200 mg Tramadol HCl OAD tablet daily | Experimental |
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| 2: 1x50 mg Tramadol HCl IR (Ultram®) tablet 6-hourly | Active Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tramadol HCl | Drug | 1x200 mg Tramadol HCl OAD tablet daily |
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| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Data Pairs at Steady State (AUCss) | Area under the plasma concentration versus time data pairs over 24 hours (24h) at steady state, on day 5. ss = steady state. AUCss is also known as AUCtau. | 24 hours (day 5) |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration at Steady State(Cmax,ss) | Maximum plasma concentration over 24 hours (24h) at steady state, on day 5. ss = steady state. | 24 hours (day 5) |
| Minimum Plasma Concentration at Steady State(Cmin,ss) |
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Inclusion Criteria:
Healthy, non-smoking, male and female subjects between the ages 18 to 55 years (inclusive).
Body mass within 10% of the ideal mass in relation to height and age, according to the BMI
Body mass not less than 70 kg.
Findings within the range of clinical acceptability in medical history and physical examination, and laboratory results with the "normal ranges" for the relevant laboratory tests (unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study).
Normal ECG and vital signs, or abnormalities which the clinical investigator did not consider a disqualification for participation in the study
Willingness to undergo a pre-study physical examination and pre- and post-study laboratory investigations.
Ability to comprehend and willingness to sign both statements of Informed Consent (for screening and phase-related procedures)
Non-smokers or past smokers who stopped smoking at least three months before entering the study
For females, the following conditions had to be met:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20051587 | Result | Karhu D, Fradette C, Potgieter MA, Ferreira MM, Terblanche J. Comparative pharmacokinetics of a once-daily tramadol extended-release tablet and an immediate-release reference product following single-dose and multiple-dose administration. J Clin Pharmacol. 2010 May;50(5):544-53. doi: 10.1177/0091270009347673. Epub 2010 Jan 5. |
| Label | URL |
|---|---|
| Approved labelling | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Test (Tramadol HCl OAD 200 mg) First | 1 x 200 mg Tramadol OAD (Once-A-Day) Tablet Daily test product dosed in first period followed by Tramadol IR (Ultram®) 50 mg 6-hourly) reference product dosed in the second period. The two treatment phases each started with a run-in period of 4 days (Days 1 to 4), a profile period and clinic stay of 3 days (Days 5 to 7) (clinic days and observation period) and a drug-free period of 16 days between treatment phases (Day 7 of Treatment phase I until Day 1 of the run-in period of Treatment phase II). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Treatment Phase I |
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| Tramadol HCl |
| Drug |
1x50 mg Tramadol HCl IR (Ultram®) tablet 6-hourly |
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Minimum plasma concentration over 24 hours (24h) at steady state on day 5. ss = steady state.
| 24 hours (day 5) |
| Time to Peak Exposure (Tmax) | Time to peak exposure over 24 hours (24h) at steady state on day 5. | 24 hours (day 5) |
| Percentage Peak-trough Fluctuation (% PTF) | Percentage peak-trough fluctuation over 24 hours (24h) at steady state on day 5. Percent peak-to-trough fluctuation is calculated as (Cmax - Cmin)/Cav*100, where Cmax is the maximum observed concentration, Cmin is the minimum observed concentration and Cav is the average concentration over 24 hours (where Cav = AUCss/24). | 24 hours (day 5) |
| Percentage Swing | Percentage swing is a pharmacokinetic parameter recommended by the FDA for submission and is calculated as follows:((Cmax,ss - Cmin,ss)/Cmin,ss)*100. It was calculated over 24 hours on day 5. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. | 24 hours (day 5) |
| Half-value Duration (HVD) | Time over which plasma concentrations were above one half Cmax on day 5. 24h = 24 hours. | 24 hours (day 5) |
| Plateau Time (T75%Cmax) | Time over which plasma concentrations were above 75% Cmax on day 5. 24h = 24 hours. | 24 hours (day 5) |
| FG001 | Reference (Trazodone IR (Desyrel®) 100 mg 8-hourly) First | 1 x 100 mg Trazodone HCl IR (Desyrel®) Tablet 8-Hourly reference product dosed in first period followed by Trazodone OAD (Once-A-Day) Tablet Daily test product dosed in the second period. The two periods were separated by a washout of at least 7 calendar days. IR = Immediate Release. |
| COMPLETED |
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| NOT COMPLETED |
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| Treatment Phase II |
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| ID | Title | Description |
|---|---|---|
| BG000 | Test (Tramadol HCl OAD 200 mg) First | 1 x 200 mg Tramadol OAD (Once-A-Day) Tablet Daily test product dosed in first period followed by Tramadol IR (Ultram®) 50 mg 6-hourly) reference product dosed in the second period. The two treatment phases each started with a run-in period of 4 days (Days 1 to 4), a profile period and clinic stay of 3 days (Days 5 to 7) (clinic days and observation period) and a drug-free period of 16 days between treatment phases (Day 7 of Treatment phase I until Day 1 of the run-in period of Treatment phase II). |
| BG001 | Reference (Tramadol IR (Ultram®) 50 mg 6-hourly) First | 1 x 50 mg Tramadol HCl IR (Ultram®) Tablet 6-Hourly reference product dosed in first period followed by Tramadol OAD (Once-A-Day) Tablet Daily test product dosed in the second period. The two treatment phases each started with a run-in period of 4 days (Days 1 to 4), a profile period and clinic stay of 3 days (Days 5 to 7) (clinic days and observation period) and a drug-free period of 16 days between treatment phases (Day 7 of Treatment phase I until Day 1 of the run-in period of Treatment phase II). IR = Immediate Release. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Area Under the Plasma Concentration Versus Time Data Pairs at Steady State (AUCss) | Area under the plasma concentration versus time data pairs over 24 hours (24h) at steady state, on day 5. ss = steady state. AUCss is also known as AUCtau. | Posted | Mean | Standard Deviation | ng*h/mL | 24 hours (day 5) |
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| Secondary | Maximum Plasma Concentration at Steady State(Cmax,ss) | Maximum plasma concentration over 24 hours (24h) at steady state, on day 5. ss = steady state. | Posted | Mean | Standard Deviation | ng/mL | 24 hours (day 5) |
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| Secondary | Minimum Plasma Concentration at Steady State(Cmin,ss) | Minimum plasma concentration over 24 hours (24h) at steady state on day 5. ss = steady state. | Posted | Mean | Standard Deviation | ng/mL | 24 hours (day 5) |
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| Secondary | Time to Peak Exposure (Tmax) | Time to peak exposure over 24 hours (24h) at steady state on day 5. | Posted | Median | Full Range | hours | 24 hours (day 5) |
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| Secondary | Percentage Peak-trough Fluctuation (% PTF) | Percentage peak-trough fluctuation over 24 hours (24h) at steady state on day 5. Percent peak-to-trough fluctuation is calculated as (Cmax - Cmin)/Cav*100, where Cmax is the maximum observed concentration, Cmin is the minimum observed concentration and Cav is the average concentration over 24 hours (where Cav = AUCss/24). | Posted | Mean | Standard Deviation | percentage of fluctuation | 24 hours (day 5) |
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| Secondary | Percentage Swing | Percentage swing is a pharmacokinetic parameter recommended by the FDA for submission and is calculated as follows:((Cmax,ss - Cmin,ss)/Cmin,ss)*100. It was calculated over 24 hours on day 5. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. | Posted | Mean | Standard Deviation | percentage of fluctuation | 24 hours (day 5) |
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| Secondary | Half-value Duration (HVD) | Time over which plasma concentrations were above one half Cmax on day 5. 24h = 24 hours. | Posted | Mean | Standard Deviation | hours | 24 hours (day 5) |
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| Secondary | Plateau Time (T75%Cmax) | Time over which plasma concentrations were above 75% Cmax on day 5. 24h = 24 hours. | Posted | Mean | Standard Deviation | hours | 24 hours (day 5) |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tramadol HCl OAD 200 mg | Tramadol HCl OAD 200 mg Group includes the treatment period 1 data from subjects in the "Test (Tramadol HCl OAD 200 mg) First" treatment sequence and the treatment period 2 data from subjects in the "Reference (Tramadol IR (Ultram®) 50 mg 6-hourly) First" treatment sequence. | 0 | 26 | 12 | 26 | ||
| EG001 | Tramadol IR (Ultram®) 50 mg 6-hourly | Tramadol IR (Ultram®) 50 mg 6-hourly Group includes the treatment period 1 data from subjects in the "Reference (Tramadol IR (Ultram®) 50 mg 6-hourly) First" treatment sequence and the treatment period 2 data from subjects in the "Test (Tramadol HCl OAD 200 mg) First" treatment sequence. | 0 | 26 | 10 | 26 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
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| Constipation | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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| Dry mouth | General disorders | MedDRA | Non-systematic Assessment |
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| ALT elevated/raised | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
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| Headache | General disorders | MedDRA | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA | Non-systematic Assessment |
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If a publication based on the results of this study is envisaged, approval from the sponsor will be obtained and a draft manuscript will be submitted to the sponsor for scrutiny and comment.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of Regulatory Affairs | Labopharm Inc. | 1 450 686 1017 |
| ID | Term |
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| D014147 | Tramadol |
| ID | Term |
|---|---|
| D003511 | Cyclohexanols |
| D000441 | Hexanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D004123 | Dimethylamines |
| D008744 | Methylamines |
| D000588 | Amines |
| D008055 | Lipids |
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| >=65 years |
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| Male |
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