INDICATIONS AND USAGE

Tramadol hydrochloride and acetaminophen tablets, USP are indicated for the short-term (five days or less) management of acute pain.

CLINICAL PHARMACOLOGY

The following information is based on studies of tramadol alone or acetaminophen alone, except where otherwise noted:

Pharmacodynamics

Tramadol hydrochloride and acetaminophen tablets contain tramadol hydrochloride and acetaminophen. 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 (seeCLINICAL PHARMACOLOGY, 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 pruritus) similar to that of other opioids.

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 (37.5 mg/325 mg) in Volunteers.
Parameter a	(+)-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	(1.4)	4.7	(1.2)	7.8	(3)	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 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 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.

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 concentrations, and the extents of absorption, of tramadol and 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 binding 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 (seePRECAUTIONS, 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 indicates 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 (seeWARNINGS) 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 in patients with renal impairment has 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. (seeDOSAGE 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 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 in patients with hepatic impairment is not recommended (seePRECAUTIONS andDOSAGE 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, 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 (seePRECAUTIONS, Geriatric Use).

Gender

Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of tramadol hydrochloride and acetaminophen in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.

Pediatric

The pharmacokinetics of tramadol hydrochloride and acetaminophen tablets has not been studied in pediatric patients below 16 years of age.

CLINICAL STUDIES

Single-Dose Studies for Treatment of Acute Pain

In pivotal single-dose studies in acute pain, two tablets of tramadol hydrochloride and acetaminophen administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after tramadol hydrochloride and acetaminophen was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after tramadol hydrochloride and acetaminophen tablets was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen.