Healthy
Conditions
Keywords
Healthy Subjects
Brief summary
The objective of this study is to compare the rate and extent of absorption of two Tramadol Contramid® OAD 300 mg controlled-release tablets from two different manufacturing sites, administered as 1 x 300 mg controlled-release tablet under fasting conditions. The effect of food on the to-be-marketed formulation was also assessed.
Interventions
DRUGTramadol hydrochloride
1x300mg Tramadol Hydrochloride (HCl) tablet (Confab Laboratories), fasting condition. Taken for one treatment period only, then subjects switched treatment at each period as per randomization schedule. Results are presented per treatment group overall.
DRUGTramadol HCl
1x300mg Tramadol Hydrochloride (HCl) tablet (Confab Laboratories), fed condition. Taken for one treatment period only, then subjects switched treatment at each period as per randomization schedule. Results are presented per treatment group overall.
Sponsors
Labopharm Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female, non-smoker, ≥18 and ≤55 years of age. * Capable of consent. * Body Mass Index (BMI) ≥19.0 and \<30.0 kg/m2.
Exclusion criteria
* Clinically significant illness or surgery within 4 weeks prior to dosing. * Any clinically significant abnormality or abnormal laboratory test results found during medical screening. * Any reason which, in the opinion of the Medical Sub-Investigator, would prevent the subject from participating in the study. * Positive test for hepatitis B, hepatitis C, or HIV at screening. * Electrocardiogram (ECG) abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 or over 100 beats per minute \[bpm\]) at screening. * History of significant alcohol abuse or drug abuse within one year prior to the screening visit. * Regular use of alcohol within six months prior to the screening visit (more than fourteen units of alcohol per week \[1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol\]). * Use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine \[PCP\] and crack) within 1 year prior to the screening visit or positive urine drug screen at screening. * History of allergic reactions to tramadol or other related drugs. * Use of any drugs known to induce or inhibit hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; examples of inhibitors: antidepressants (Selective serotonin reuptake inhibitors \[SSRIs\]), cimetidine, diltiazem, macrolides, imidazoles, neuroleptics, verapamil, fluoroquinolones, antihistamines) within 30 days prior to administration of the study medication. * Use of an investigational drug or participation in an investigational study within 30 days prior to dosing. * Clinically significant history or presence of any gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of the drug. * Any clinically significant history or presence of neurological, endocrinal, cardiovascular, pulmonary, hematologic, immunologic, psychiatric, or metabolic disease. * Use of prescription medication within 14 days prior to administration of study medication or over-the-counter products (including natural food supplements, vitamins, garlic as a supplement) within 7 days prior to administration of study medication, except for topical products without systemic absorption and hormonal contraceptives. * Difficulty to swallow study medication. * Use of any tobacco products in the 3 months preceding drug administration. * Any food allergy, intolerance, restriction or special diet that, in the opinion of the Medical Sub-Investigator, could contraindicate the subject's participation in this study. * A depot injection or an implant of any drug (other than hormonal contraceptives) within 3 months prior to administration of study medication. * Donation of plasma (500 mL) within 7 days prior to drug administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the screening procedures of this study) prior to administration of the study medication as follows: * 50 mL to 499 mL of whole blood within 30 days, * more than 499 mL of whole blood within 56 days prior to drug administration. * Consumption of food or beverages containing grapefruit (e.g. fresh, canned, or frozen) within 7 days prior to administration of the study medication. * History or presence of substance addiction. * History of anaphylactoid reactions to codeine and other opioids. * History of respiratory depression. * History of increased intracranial pressure or head injury. * History or presence of asthma, chronic obstructive pulmonary disease or other pulmonary condition that may predispose to hypoventilation. * Opioid consumption in the 3 months preceding drug administration or history of drug dependence to any opioids. * Positive urine pregnancy test at screening. * Breast-feeding subject. * Female subjects of childbearing potential having unprotected sexual intercourse with any non-sterile male partner (i.e. male who has not been sterilized by vasectomy for at least 6 months) within 14 days prior to study drug administration. Acceptable methods of contraception are: * intra-uterine contraceptive device (placed at least 4 weeks prior to study drug administration; * condom or diaphragm + spermicide; * hormonal contraceptives (starting at least 4 weeks prior to study drug administration).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-t) | 48 hours | Area under the plasma concentration (AUC) versus time curve to the last measurable concentration. |
| AUC(0-∞) | 48 hours | The area under the plasma concentration (AUC) curve was estimated by extrapolating to infinity AUC0-t. The extrapolation to infinity was done by regression with the last log-transformed data to estimate the terminal area by means of the line that maximized R'2 (coefficient of determination). The units are ng.h/mL. h=hours |
| Cmax | 48 hours | Maximum plasma concentration (Cmax) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 48 hours | Time to maximum plasma concentration (Tmax) |
| t1/2 | 48 hours | Apparent terminal elimination half-life (t1/2) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Confab Fasting / Confab Fed / Trillium Fasting Confab fasting / Confab fed / Trillium fasting Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1 x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 1, 1x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 2, and 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 3. | 6 |
| Confab Fasting / Trillium Fasting / Confab Fed Confab fasting / Trillium fasting / Confab fed Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1 x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 1, 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 2, and 1x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 3. | 6 |
| Confab Fed / Confab Fasting / Trillium Fasting Confab fed / Confab fasting / Trillium fasting Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 1, 1 x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 2, 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 3. | 6 |
| Confab Fed / Trillium Fasting / Confab Fasting Confab fed / Trillium fasting / Confab fasting Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 1, 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 2, and 1 x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 3. | 6 |
| Trillium Fasting / Confab Fasting / Confab Fed Trillium fasting / Confab fasting / Confab fed Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 1, 1 x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 2, and 1x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 3. | 6 |
| Trillium Fasting / Confab Fed / Confab Fasting Trillium fasting / Confab fasting / Confab fed Group includes patients receiving once daily administration of the following Tramadol Hydrochloride (HCl) treatment: 1 x 300 mg tablet manufactured at Trillium Healthcare Inc., fasting condition in treatment period 1, 1 x 300 mg tablet manufactured at Confab Laboratories, fed condition in treatment period 2, and 1x 300 mg tablet manufactured at Confab Laboratories, fasting condition in treatment period 3. | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 1 | 0 | 1 | 0 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Confab Fasting / Confab Fed / Trillium Fasting | Confab Fasting / Trillium Fasting / Confab Fed | Confab Fed / Confab Fasting / Trillium Fasting | Confab Fed / Trillium Fasting / Confab Fasting | Trillium Fasting / Confab Fasting / Confab Fed | Trillium Fasting / Confab Fed / Confab Fasting | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 36 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 4 Participants | 21 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 36 | 27 / 36 | 19 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 | 0 / 36 |
Outcome results
Primary
AUC(0-∞)
The area under the plasma concentration (AUC) curve was estimated by extrapolating to infinity AUC0-t. The extrapolation to infinity was done by regression with the last log-transformed data to estimate the terminal area by means of the line that maximized R'2 (coefficient of determination). The units are ng.h/mL. h=hours
Time frame: 48 hours
Population: Data from all randomized subjects who completed at least 2 periods of the study are presented. The pharmacokinetic variables AUC(0-∞) of one subject for Tramadol HCl 300 mg (Confab Laboratories) fasting were not used in the analyses due to the morphology of the plasma concentration-time curves.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 300 mg (Confab Laboratories) Fasting | AUC(0-∞) | 9882 ng.h/mL | Standard Deviation 3933 |
| 2: Tramadol HCl 300 mg (Confab Laboratories) Fed | AUC(0-∞) | 9898 ng.h/mL | Standard Deviation 3970 |
| 3: Tramadol HCl 300 mg (Trillium Healthcare) Fasting | AUC(0-∞) | 10095 ng.h/mL | Standard Deviation 4070 |
Primary
AUC(0-t)
Area under the plasma concentration (AUC) versus time curve to the last measurable concentration.
Time frame: 48 hours
Population: Data from all randomized subjects who completed at least 2 periods of the study are presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 300 mg (Confab Laboratories) Fasting | AUC(0-t) | 9708 ng.h/mL | Standard Deviation 3875 |
| 2: Tramadol HCl 300 mg (Confab Laboratories) Fed | AUC(0-t) | 9696 ng.h/mL | Standard Deviation 3750 |
| 3: Tramadol HCl 300 mg (Trillium Healthcare) Fasting | AUC(0-t) | 9431 ng.h/mL | Standard Deviation 3225 |
Primary
Cmax
Maximum plasma concentration (Cmax)
Time frame: 48 hours
Population: Data from all randomized subjects who completed at least 2 periods of the study are presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 300 mg (Confab Laboratories) Fasting | Cmax | 433 ng/mL | Standard Deviation 206 |
| 2: Tramadol HCl 300 mg (Confab Laboratories) Fed | Cmax | 728 ng/mL | Standard Deviation 317 |
| 3: Tramadol HCl 300 mg (Trillium Healthcare) Fasting | Cmax | 402 ng/mL | Standard Deviation 201 |
Secondary
t1/2
Apparent terminal elimination half-life (t1/2)
Time frame: 48 hours
Population: Data from all randomized subjects who completed at least 2 periods of the study are presented. The pharmacokinetic variable T1/2 of one subject for Tramadol HCl 300 mg (Confab Laboratories) fasting were not used in the analyses due to the morphology of the plasma concentration-time curves.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 300 mg (Confab Laboratories) Fasting | t1/2 | 7.70 hours | Standard Deviation 1.97 |
| 2: Tramadol HCl 300 mg (Confab Laboratories) Fed | t1/2 | 6.61 hours | Standard Deviation 1.66 |
| 3: Tramadol HCl 300 mg (Trillium Healthcare) Fasting | t1/2 | 8.32 hours | Standard Deviation 2.84 |
Secondary
Tmax
Time to maximum plasma concentration (Tmax)
Time frame: 48 hours
Population: Data from all randomized subjects who completed at least 2 periods of the study are presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1: Tramadol HCl 300 mg (Confab Laboratories) Fasting | Tmax | 7 hours |
| 2: Tramadol HCl 300 mg (Confab Laboratories) Fed | Tmax | 8 hours |
| 3: Tramadol HCl 300 mg (Trillium Healthcare) Fasting | Tmax | 12 hours |