Pharmacokinetic Non-interaction Study With a Fixed-dose Combination Tablet With Tramadol and Diclofenac

Study of Non-pharmacokinetic Interaction Between Diclofenac 25 mg and 25 mg Tramadol With the Fixed-dose Combination Tablets of the Two Drugs Administered to Healthy Subjects of Both Genders in Fasting State

The objective of the study was to evaluate whether or not there is a substantial pharmacokinetic interaction between diclofenac and tramadol in a new formulation of a fixed-dose combination of diclofenac 25 milligrams (mg) and tramadol 25 mg for oral administration. The study was conducted in healthy participants of both genders.

After a screening period of about 2 weeks, 36 eligible healthy men and women were randomly allocated to receive 3 sequential treatments in the following order:

• a single dose of diclofenac followed by a single dose of the fixed-dose combination of diclofenac/tramadol followed by a single dose of tramadol
• a single dose of tramadol followed by a single dose of the fixed-dose combination of diclofenac/tramadol followed by a single dose of diclofenac.

There were washout periods of 7 days between treatments.

Sixteen blood samples were collected per participant: at pre-dose and 0.16, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 36 hours after administration of each of the study drugs.

The pharmacokinetic parameters and relative bioavailabilities of diclofenac and tramadol (and of the tramadol metabolite M1) were determined for the new fixed-dose combination product and were compared to the single compound reference products.

Furthermore, the safety (frequency of adverse events) and tolerability of the new fixed-dose combination of diclofenac 25 mg and 25 mg tramadol in healthy men and women was assessed.

Inclusion Criteria:

• Man or woman between 18 and 55 years of age.
• Women with use of a barrier method as a contraceptive.
• Body mass index equal to or above 18.0 and equal to or less than 27.0 kilograms per square meter.
• Clinically healthy. If the clinical history, the registration of vital signs and the physical examination did not show abnormal deviations that avoid their participation in a clinical study.
• Without a history of allergic reactions to the study drug.
• Stable vital signs during the selection (heart rate, respiratory rate, blood pressure at rest and axillary body temperature).
• Laboratory studies: complete blood count, blood chemistry of 24 items, urinalysis, anti-human immunodeficiency virus (HIV) 1, anti-HIV2, anti-hepatitis B surface antigen (HBs) and anti-hepatitis C virus (HCVs) antibodies, and serologic test for syphilis [Venereal Disease Research Laboratory test]) within normal ranges according to the reference laboratory, or that the deviations are not clinically significant. If the deviation has no clinical significance, it may be justified the inclusion of the participant to the clinical study. The age of the report of the clinical laboratory studies must not be greater than 3 months.
• Electrocardiogram (ECG) with no pathological alterations, with validity of no more than 3 months.
• The participant accepts the restrictions and indications described in the protocol and internal regulations.
• The participant has read and understood the relevant aspects of the clinical study and gives its authorization for participation by signing the informed consent form before inclusion on the clinical study and performing any procedure.

Exclusion Criteria:

• Findings in the clinical history, vital signs and/or physical examination that show abnormal conditions of the general state of health of the participant that avoid its participation in a clinical study.
• Recent exposure to the study drug between the 30 days prior or any other medication by prescription or self consumed between the 14 days prior to the start of the study, or that do not accept to avoid its consumption during the course of the study.
• Surgery during the 30 days prior to the start of the study.
• Suspicion or evidence of infection by Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV).
• Serologic test for syphilis (Venereal Disease Research Laboratory test) positive.
• Known hypersensitivity to any medication.
• Blood donation equal to or above 1 unit (0.5 liters) during the 30 days prior to the selection.
• Participants who have special food requirements or food restrictions.
• Women in the breastfeeding period and/or pregnant.
• Positive results in the qualitative test of pregnancy in urine (only women).
• Positive result in the qualitative detection of drugs of abuse.
• Participation in a clinical study Phase 1, 2 or 3 or bioavailability/ bioequivalence studies during the 3 months previous to the selection.
• The participant does not give his or her authorization to participate in the study through the signing of an informed consent, or is not willing to follow the indications and/or restrictions of the protocol and rules of the procedure.
• The participant is vulnerable or potentially vulnerable by which cannot freely express his/her consent by subordination of the principal investigator or by coercion of any third party.