Tramadol Hydrochloride and Acetaminophen

TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN- acetaminophen and tramadol hydrochloride tablet, film coated
Aidarex Pharmaceuticals LLC

Full Prescribing Information

HEPATOTOXICITY

Tramadol hydrochloride and acetaminophen tablets, USP contains tramadol HCl and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product (see WARNINGS).

DESCRIPTION

Tramadol hydrochloride and acetaminophen tablet, USP combines two analgesics, tramadol 37.5 mg and acetaminophen 325 mg.

The chemical name for tramadol hydrochloride is (±)cis -2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Tramadol HCl and Acetaminophen Tablets

The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride, USP is a white, crystalline powder.

The chemical name for acetaminophen is N -acetyl-p -aminophenol. Its structural formula is:

Tramadol HCl and Acetaminophen Tablets
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The molecular weight of acetaminophen is 151.16. Acetaminophen, USP is an analgesic and antipyretic agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.

Each tramadol hydrochloride and acetaminophen tablets, USP intended for oral administration contains tramadol hydrochloride, 37.5 mg and acetaminophen, 325 mg. In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, talc and titanium dioxide.

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 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 (see CLINICAL 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/Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers
Parameter * (+)- Tramadol (-)- Tramadol (+)- M1 (-)- M1 acetaminophen
*
For acetaminophen, Cmax was measured as mcg/mL.
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 single-dose pharmacokinetic study of tramadol hydrochloride and acetaminophen tablet 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.

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