A Study to Compare the Bioavailability of Two Tramadol Hydrochloride Tablet Products (50 mg and 200 mg, Respectively) at Steady-state Under Fasting Conditions
Condition: Healthy Subjects; Pharmacokinetics; Bioavailability
Intervention: Tramadol HCl; Tramadol HCl
Intervention description: 1x200 mg Tramadol HCl OAD tablet daily; 1x50 mg Tramadol HCl IR (Ultram®) tablet 6-hourly
Intervention MeSH terms: Tramadol
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Healthy subjects; Pharmacokinetics; Bioavailability

Summary:

      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.
    

Eligibility criteria:

        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:

               -  had been postmenopausal for at least two years, or

               -  had been surgically sterilized, or

               -  was of childbearing potential, and all of the following conditions were met:

               -  had a normal menstrual flow within one month before study entry, and

               -  had negative urine pregnancy test at screening and on Day 1 of each study period.
                  If the result of either test was positive, the subject would have been excluded
                  from the study before receiving study medication.

               -  had to agree to use an accepted method of contraception. The subject had to agree
                  to continue with the same method throughout the study. Hormonal contraceptives
                  were not allowed.

        Exclusion Criteria:

          -  Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional
             or intellectual problems likely to limit the validity of consent to participate in the
             study or limit the ability to comply with protocol requirements.

          -  History of, or current compulsive alcohol abuse (> 10 drinks weekly), or regular
             exposure to other substances of abuse.

          -  Use of any medication, prescribed or over-the-counter, within 2 weeks prior to the
             first administration of study medication except if this would not have affected the
             outcome of the study in the opinion of the clinical investigator. Use of hormonal
             contraceptives agents by females was not allowed.

          -  Participation in another study with an experimental drug within 8 weeks before the
             first administration of study medication.

          -  Treatment within the previous 3 months with any drug with a well-defined potential for
             adversely affecting a major organ or system with evidence to this effect.

          -  Major illness during the 3 months before commencement of the screening period.

          -  History of hypersensitivity to the study drug or any related drugs.

          -  History of bronchial asthma.

          -  History of epilepsy.

          -  Relevant history or laboratory or clinical findings indicative of acute or chronic
             disease, likely to influence study outcome.

          -  Donation or loss of blood equal to or exceeding 500 ml during the 8 weeks before the
             first administration of study medication.

          -  Diagnosis of hypotension made during the screening period.

          -  Diagnosis of hypertension made during the screening period or current diagnosis of
             hypertension.

          -  Resting pulse of > 100 beats per minutes or < 45 beats per minutes during the
             screening period, either supine or standing.

          -  Positive testing for hepatitis B antigen.

          -  Significant liver disease, defined as active hepatitis or elevated liver enzymes
             (e.g., AST, ALT) > 3 times the upper boundary of the normal range.

          -  Positive urine screen for drugs of abuse.

          -  Positive urine screen for tobacco use.

          -  History of marijuana, barbiturates, amphetamine, or narcotic abuse within 12 months
             prior to study start.

          -  Previous participation in a tramadol study.

          -  pregnancy or lactation.