Tramadol Hydrochloride

TRAMADOL HYDROCHLORIDE- tramadol hydrochloride tablet, film coated
ALPHAPHARM PTY LTD

Description

Tramadol hydrochloride tablet is a centrally acting analgesic. The chemical

name for tramadol hydrochloride is (+)cis- 2-[(dimethylamino)methyl]-

1-(3-methoxyphenyl)cyclohexanol hydro chloride and it has the molecular formula of C16H25NO2.HCl. Its structural formula is:

Image from Drug Label Content

The molecular weight of tramadol hydrochloride is 299.8. 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 contain 50 mg of tramadol hydrochloride. In addition, each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene

glycol, sodium starch glycolate and titanium dioxide

Clinical Pharmacology

Pharmacodynamics

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. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

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. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of tramadol 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. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption:

Racemic tramadol is rapidly and almost completely absorbed after oral administration. 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 q.i.d. 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 aSingle 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Dosesof Tramadol HCl given q.i.d.

Image from Drug Label Content
(click image for full-size original)
Table 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
Population/ Dosage Regimena Parent Drug/ Metabolite Peak Conc. (ng/mL) Time to Peak (hrs) Clearance/Fb (mL/min/Kg) t1/2 (hrs)
Healthy Adults, 100 mg q.i.d.,MD p.o. Tramadol 592 (30) 2.3 (61) 5.90 (25) 6.7 (15)
M1 110 (29) 2.4 (46) c 7.0 (14)
Healthy Adults, 100 mgSD p.o. Tramadol 308 (25) 1.6 (63) 8.50 (31) 5.6 (20)
M1 55.0 (36) 3.0 (51) c 6.7 (16)
Geriatric,(>75 yrs)50 mg SD p.o. Tramadol 208 (31) 2.1 (19) 6.89 (25) 7.0 (23)
M1 d d c d
Hepatic Impaired,50 mgSD p.o. Tramadol 217 (11) 1.9 (16) 4.23 (56) 13.3 (11)
M1 19.4 (12) 9.8 (20) c 18.5 (15)
Renal Impaired,CLcr 10-30 mL/min100 mg SD i.v. Tramadol c c 4.23 (54) 10.6 (31)
M1 c c c 11.5 (40)
Renal Impaired, CLcr <5 mL/min100 mg SD i.v. Tramadol c c 3.73 (17) 11.0 (29)
M1 c c c 16.9 (18)

a SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous administration, q.i.d. = Four times daily

b F represents the oral bioavailability of tramadol c Not applicable d Not measured

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