Tramadol

TRAMADOL- tramadol hydrochloride tablet
Accord Healthcare, Inc.

Full Prescribing Information Rx only

DESCRIPTION

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

diagram
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The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.Tramadol hydrochloride tablets USP contain 50 mg of tramadol hydrochloride and are white to off white in color. Inactive ingredients in the tablet are corn starch, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Tramadol hydrochloride tablets contain tramadol, 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 re-uptake 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 hydrochloride. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Apart from analgesia, tramadol hydrochloride administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol hydrochloride has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of tramadol hydrochloride is due to both parent drug and the M1 metabolite (see CLINICAL PHARMACOLOGY, Pharmacodynamics ). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption

The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below).

Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per day.

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Table 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
Population/Dosage Regimen *Parent Drug/ Metabolite PeakConc. (ng/mL) Time to Peak (hrs) Clearance/F (mL/min/Kg) t 1/2 (hrs)
*
SD = Single dose, MD = Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. = Four times daily
F represents the oral bioavailability of tramadol
Not applicable
§
Not measured
Healthy Adults, 100 mg qid, MD p.o Tramadol M1 592 (30) 110 (29) 2.3 (61) 2.4 (46) 5.90 (25) 6.7 (15) 7.0 (14)
Healthy Adults, 100 mg SD p.o Tramadol M1 308 (25) 55.0 (36) 1.6 (63) 3.0 (51) 8.50 (31) 5.6 (20) 6.7 (16)
Geriatric, (>75 yrs) 50 mg SD p.o. Tramadol M1 208 (31) § 2.1 (19) § 6.89 (25) 7.0 (23) §
Hepatic Impaired, 50 mg SD p.o. Tramadol M1 217 (11) 19.4 (12) 1.9 (16) 9.8 (20) 4.23 (56) 13.3 (11) 18.5 (15)
Renal Impaired, CL cr 10 to 30 mL/min 100 mg SD i.v. Tramadol M1 4.23 (54) 10.6 (31) 11.5 (40)
Renal Impaired, CL cr <5 mL/min 100 mg SD i.v. Tramadol M1 3.73 (17) 11.0 (29) 16.9 (18)

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