e in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION (2.1)].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION (2.1, 2.2)].
12.3 Pharmacokinetics
Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.
Absorption
The absolute bioavailability of tramadol from tramadol hydrochloride and acetaminophen tablets has not been determined. Tramadol has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol hydrochloride tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two tramadol hydrochloride and acetaminophen tablets occurs at approximately two and three hours, respectively, post-dose.
The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one tramadol hydrochloride and acetaminophen tablet are shown in Table 3. Tramadol has a slower absorption and longer half-life when compared to acetaminophen.
Table 3: Summary of Mean (±SD) Pharmacokinetic Parameters of the (+)- and (-) Enantiomers of Tramadol and M1 and Acetaminophen Following A Single Oral Dose Of One Tramadol/Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers
Parametera
(+)-Tramadol
(-)-Tramadol
(+)-M1
(-)-M1
acetaminophen
Cmax (ng/mL)
64.3
(9.3)
55.5
(8.1)
10.9
(5.7)
12.8
(4.2)
4.2
(0.8)
tmax (h)
1.8
(0.6)
1.8
(0.7)
2.1
(0.7)
2.2
(0.7)
0.9
(0.7)
CL/F (mL/min)
588
(226)
736
(244)
-
-
-
-
365
(84)
t1/2 (h)
5.1
(1.4)
4.7
(1.2)
7.8
(3.0)
6.2
(1.6)
2.5
(0.6)
a For acetaminophen, Cmax was measured as mcg/mL.
A single-dose pharmacokinetic study of tramadol hydrochloride and acetaminophen in volunteers showed no drug interactions between tramadol and acetaminophen.
Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite M1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1, and 24.2% for (-)-M1. The cause of this reduced bioavailability is not clear.
Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. Following single- or multiple-dose administration of tramadol hydrochloride and acetaminophen, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone.
Food Effect
When tramadol hydrochloride and acetaminophen was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentrations, and the extents of absorption, of tramadol and acetaminophen were not affected. The clinical significance of this difference is u |
