The following
information is based on studies of tramadol alone or acetaminophen alone, except
where otherwise noted:
PharmacodynamicsTramadol
Tramadol is a centrally
acting synthetic opioid analgesic. Although its mode of action is not completely
understood, from animal tests, at least two complementary mechanisms appear
applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak
inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due
to both low affinity binding of the parent compound and higher affinity binding
of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1
is up to 6 times more potent than tramadol in producing analgesia and 200 times
more potent in µ-opioid binding. Tramadol-induced analgesia is only partially
antagonized by the opiate antagonist naloxone in several animal tests. The
relative contribution of both tramadol and M1 to human analgesia is dependent
upon the plasma concentrations of each compound (see CLINICAL
PHARMAMCOLOGY, Pharmacokinetics).
Tramadol has been shown
to inhibit reuptake of norepinephrine and serotonin in
vitro, as have some other opioid analgesics. These mechanisms may
contribute independently to the overall analgesic profile of tramadol. Apart
from analgesia, tramadol administration may produce a constellation of symptoms
(including dizziness, somnolence, nausea, constipation, sweating and pruritis)
similar to that of other opioids.
Acetaminophen
Acetaminophen is a
non-opiate, non-salicylate analgesic.
Pharmacokinetics
Tramadol is administered
as a racemate and both the [-] and [+] forms of both tramadol and M1 are
detected in the circulation. The pharmacokinetics of plasma tramadol and
acetaminophen following oral administration of one tramadol hydrochloride and
acetaminophen tablet are shown in Table 1. Tramadol has a slower absorption and
longer half-life when compared to acetaminophen.
Table 1: Summary of Mean (±SD) Pharmacokinetic Parameters of the (+) – and (-) Enantiomers of Tramadol and M1 and Acetaminophen Following A Single Oral Dose of One Tramadol Hydrochloride and Acetaminophen Combination Tablet in Volunteers| Parameter[1] | (+)-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)
|
| t½ (h) | 5.1 91.4)
| 4.7 (1.2)
| 7.8 (3.0)
| 6.2 (1.6)
| 2.5 (0.6)
|
a For acetaminophen Cmax was measured in mcg/mL.
A single dose
pharmacokinetic study of tramadol hydrochloride and acetaminophen tablets 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. Following single or multiple dose administration
of tramadol hydrochloride and acetaminophen tablets, no significant change in
acetaminophen pharmacokinetics was observed when compared to acetaminophen given
alone.
Absorption:The absolute
bioavailability of tramadol from tramadol hydrochloride and acetaminophen
tablets has not been determined. Tramadol hydrochloride has a mean absolute
bioavailability of approximately 75% following administration of a single 100 mg
oral dose of Tramadol HCl 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.
Peak plasma
concentrations of acetaminophen occur within one hour and are not affected by
co-administration with tramadol. Oral absorption of acetaminophen following
administration of tramadol hydrochloride and acetaminophen tablets occurs
primarily in the small intestine.
Food Effects:When tramadol
hydrochloride and acetaminophen tablets were 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 concentration or the
extent of absorption of either tramadol or acetaminophen were not affected. The
clinical significance of this difference is unknown.
Distribution:The volume of
distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects,
respectively, following a 100 mg intravenous dose. The binding of tramadol to
human plasma proteins is approximately 20% and binding also appears to be
independent of concentration up to 10 mcg/mL. Saturation of plasma protein
bindings occurs only at concentrations outside the clinically relevant
range.
Acetaminophen appears to
be widely distributed throughout most body tissues except fat. Its apparent
volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of
acetaminophen is bound to plasma protein.
Metabolism:Following oral
administration, tramadol is extensively metabolized by a number of pathways,
including CYP2D6 and CYP3A4, as well as by conjugation of parent and
metabolites. Approximately 30% of the dose is excreted in the urine as unchanged
drug, whereas 60% of the dose is excreted as metabolites. The major metabolic
pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the
liver. Metabolite M1 (O-desmethyltramadol) is
pharmacologically active in animal models. Formation of M1 is dependent on
CYP2D6 and as such is subject to inhibition, which may affect the therapeutic
response (see PRECAUTIONS, Drug Interactions).
Approximately 7% of the
population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450.
These individuals are “poor metabolizers" of debrisoquine, dextromethorphan,
tricyclic antidepressants, among other drugs. Based on a population PK analysis
of Phase 1 studies in healthy subjects, concentrations of tramadol were
approximately 20% higher in "poor metabolizers" versus "extensive metabolizers,"
while M1 concentrations were 40% lower. In vitro drug
interaction studies in human liver microsomes indicate that inhibitors of CYP2D6
such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine
inhibit the metabolism of tramadol to various degrees. The full pharmacological
impact of these alterations in terms of either efficacy or safety is unknown.
Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance
the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome.
Acetaminophen is
primarily metabolized in the liver by first-order kinetics and involves three
principal separate pathways:
a) conjugation with
glucuronide;
b) conjugation with
sulfate; and
c) oxidation via the
cytochrome; P450-dependent, mixed-function oxidase enzyme pathway to form a
reactive intermediate metabolite, which conjugates with glutathione and is then
further metabolized to form cysteine and mercapturic acid conjugates. The
principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2
and CYP3A4 as additional pathways.
In adults, the majority
of acetaminophen is conjugated with glucuronic acid and, to a lesser extent,
with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites
lack biologic activity. In premature infants, newborns, and young infants, the
sulfate conjugate predominates.
Elimination:Tramadol is eliminated
primarily through metabolism by the liver and the metabolites are eliminated
primarily by the kidneys. The plasma elimination half-lives of racemic tramadol
and M1 are approximately 5 to 6 and 7 hours, respectively, after administration
of tramadol hydrochloride and acetaminophen tablets. The apparent plasma
elimination half-life of racemic tramadol increased to 7 to 9 hours upon
multiple dosing of tramadol hydrochloride and acetaminophen tablets.
The half-life of
acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in
children and somewhat longer in neonates and in cirrhotic patients.
Acetaminophen is eliminated from the body primarily by formation of glucuronide
and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen
is excreted unchanged in the urine.
Special Populations
Renal:The pharmacokinetics of
tramadol hydrochloride and acetaminophen tablets in patients with renal
impairment have not been studied. Based on studies using tramadol alone,
excretion of tramadol and metabolite M1 is reduced in patients with creatinine
clearance of less than 30 mL/min, adjustment of dosing regimen in this patient
population is recommended. (See DOSAGE AND
ADMINISTRATION.) The total amount of tramadol and M1 removed during a
4-hour dialysis period is less than 7% of the administered dose based on studies
using tramadol alone.
Hepatic:The pharmacokinetics and
tolerability of tramadol hydrochloride and acetaminophen tablets in patients
with impaired hepatic function has not been studied. Since tramadol and
acetaminophen are both extensively metabolized by the liver, the use of tramadol
hydrochloride and acetaminophen tablets in patients with hepatic impairment is
not recommended (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
Geriatric:A population
pharmacokinetic analysis of data obtained from a clinical trial in patients with
chronic pain treated with tramadol hydrochloride and acetaminophen tablets which
included 55 patients between 65 and 75 years of age and 19 patients over 75
years of age, showed no significant changes in pharmacokinetics of tramadol and
acetaminophen in elderly patients with normal renal and hepatic function (see
PRECAUTIONS, Geriatric Use).
Gender:Tramadol clearance was
20% higher in female subjects compared to males on four phase I studies of
tramadol hydrochloride and acetaminophen tablets in 50 male and 34 female
healthy subjects. The clinical significance of this difference is unknown.
Pediatric:Pharmacokinetics of
tramadol hydrochloride and acetaminophen tablets have not been studied in
pediatric patients below 16 years of age.
