Healthy
Conditions
Keywords
bioequivalence, morphine sulfate sustained release capsules, KADIAN capsules, 200 mg, applesauce
Brief summary
The objective of this single-dose, open-label, randomized, two-period crossover study was to compare the rate of absorption and oral bioavailability of a test formulation of morphine sulfate 200 mg sustained-release capsules manufactured by Alpharma Branded Products Division Inc. to an equivalent oral dose of the commercially available reference product, KADIAN 2 x 100 mg capsules manufactured by Alpharma Branded Products Division Inc. when administered as a sprinkle on applesauce after a 10-hour overnight fast.
Interventions
1 x 200 mg, single-dose capsule
2 x 100 mg, single-dose capsule
Sponsors
Actavis Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject must be a male or non-pregnant, non-breast-feeding female. * Subject must be between 18 and 50 years of age inclusive. * Subject's body weight should be within +/- 15% of the ideal body weight for their height and estimated frame based on the Metropolitan Life Insurance Company Table and weigh a minimum of 50 kg (110 lbs). * Female subjects - not surgically sterile or at least two years postmenopausal - must agree to utilize one of the following forms of contraception, if sexually active with a male partner, from screening through completion of the study. Approved forms of contraception are abstinence, hormonal (oral, implant, transdermal or injection), double barrier (condom and diaphragm with spermicide), IUD, or vasectomized partner (6 months minimum). * Subject must voluntarily consent to participate in this study and provide their written informed consent prior to completion of any study-specific procedures. * Subject is willing and able to remain in the study unit for the entire duration of each confinement period and return to the study site for any outpatient visits.
Exclusion criteria
* History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic or psychiatric disease or any other condition which, in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results. * Has a clinically significant abnormal finding on the physical exam, medical history or clinical laboratory results at screening. * History or presence of allergic or adverse response to the study drug or related drugs. * Has been on a significantly abnormal diet during the four weeks preceding the first dose of study medication. * Has donated blood or plasma within 30 days prior to the first dose of study medication. * Has participated in another clinical trial within 30 days prior to first dose of study medication. * Has used any over-the-counter (OTC) medication including vitamins, within 7 days prior to the first dose of study medication without evaluation and approval by the study investigator. * Has used any prescription medication, except hormonal contraceptive or hormonal replacement therapy, within 7 days prior to the first dose of study medication without evaluation and approval by the study investigator. * Has been treated with any known enzyme altering drugs such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication. * Has smoked or used tobacco products within 60 days prior to the first dose of study medication. * Has a history of substance abuse (including alcohol) in the past 5 years. * Is a female with a positive pregnancy test result. * Has a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates). * Has had a positive test for, or has been treated for hepatitis B, hepatitis C or HIV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Morphine Concentration | 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose | calculated from drug concentration over time |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time of Maximum Plasma Morphine Concentration | 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose | calculated from drug concentration over time |
| Area Under the Curve to the Last Measurable Time Point for Plasma Morphine | 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose | calculated from drug concentration over time |
| Area Under the Curve to Infinity for Plasma Morphine | 0, 2, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 18, 24, 30, 36, and 48 hrs post dose | — |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from general public. The signed consent forms were obtained during the period of September 7 - 13, 2004.
Pre-assignment details
Wash out period was 7 days. No enrolled participants were excluded from the trial before assignment to groups
Participants by arm
| Arm | Count |
|---|---|
| Period 1: Treatment A or B Treatment A (test product) followed by Treatment B (reference product) | 18 |
| Period 2: Treatment Aor B Treatment B (reference product)followed by Treatment A (test product) | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Personal reason | 1 | 0 |
Baseline characteristics
| Characteristic | Period 2: Treatment Aor B | Period 1: Treatment A or B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 18 Participants | 36 Participants |
| Age Continuous | 29.61 years STANDARD_DEVIATION 8.81 | 26.50 years STANDARD_DEVIATION 5.93 | 28.06 years STANDARD_DEVIATION 7.57 |
| Region of Enrollment United States | 18 participants | 18 participants | 36 participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / — | 10 / — |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Maximum Plasma Morphine Concentration
calculated from drug concentration over time
Time frame: 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Sulfate 200 mg SR Caps by Alpharma | Maximum Plasma Morphine Concentration | 37.5 ng/mL | Standard Deviation 16.8 |
| KADIAN® 2 × 100 mg Caps by Alpharma | Maximum Plasma Morphine Concentration | 38.0 ng/mL | Standard Deviation 14.6 |
p-value: <0.0590% CI: [91.31, 103.45]ANOVA
Secondary
Area Under the Curve to Infinity for Plasma Morphine
Time frame: 0, 2, 4, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 18, 24, 30, 36, and 48 hrs post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Sulfate 200 mg SR Caps by Alpharma | Area Under the Curve to Infinity for Plasma Morphine | 800.7 ng*hr/mL | Standard Deviation 232.6 |
| KADIAN® 2 × 100 mg Caps by Alpharma | Area Under the Curve to Infinity for Plasma Morphine | 814.5 ng*hr/mL | Standard Deviation 222.5 |
p-value: <0.0590% CI: [94.2, 102.1]ANOVA
Secondary
Area Under the Curve to the Last Measurable Time Point for Plasma Morphine
calculated from drug concentration over time
Time frame: 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Morphine Sulfate 200 mg SR Caps by Alpharma | Area Under the Curve to the Last Measurable Time Point for Plasma Morphine | 717.3 ng*hr/mL | Standard Deviation 213.2 |
| KADIAN® 2 × 100 mg Caps by Alpharma | Area Under the Curve to the Last Measurable Time Point for Plasma Morphine | 744.1 ng*hr/mL | Standard Deviation 195 |
p-value: <0.0590% CI: [92.93, 98.8]ANOVA
Secondary
Time of Maximum Plasma Morphine Concentration
calculated from drug concentration over time
Time frame: 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose
Population: Subjects completed the study without protocol violations.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Morphine Sulfate 200 mg SR Caps by Alpharma | Time of Maximum Plasma Morphine Concentration | 10.50 hour | Full Range 3.91 |
| KADIAN® 2 × 100 mg Caps by Alpharma | Time of Maximum Plasma Morphine Concentration | 9.25 hour | Full Range 5.21 |