ULTRAM ER- tramadol hydrochloride tablet, extended release
Ortho-McNeil-Janssen Pharmaceuticals, Inc.
ULTRAM® ER (tramadol hydrochloride) is a centrally acting synthetic analgesic in an extended-release formulation. The chemical name is (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:
The molecular weight of tramadol HCl is 299.8. It is a white, bitter, crystalline and odorless powder that 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. ULTRAM ER tablets contain 100, 200 or 300 mg of tramadol HCl in an extended-release formulation. The tablets are white to off-white in color and contain the inactive ingredients ethylcellulose, dibutyl sebacate, polyvinyl pyrrolidone, sodium stearyl fumarate, colloidal silicon dioxide, and polyvinyl alcohol.
Mechanism of Action
ULTRAM ER 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.
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. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the ULTRAM ER clinical studies.
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.
The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation.
The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known.
In healthy subjects, the bioavailability of a ULTRAM ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following ULTRAM ER administration. The mean peak plasma concentrations of tramadol and M1 after administration of ULTRAM ER tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration of the ULTRAM ER, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing.
The mean (%CV) pharmacokinetic parameter values for ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours are provided in Table 1.
|Mean (%CV) Steady-State Pharmacokinetic Parameter Values (n=32)|
|Pharma-cokineticParameter||ULTRAM ER200-mgTabletOnce-Daily||ULTRAM50-mgTablet Every6 Hours||ULTRAM ER200-mgTabletOnce-Daily||ULTRAM50-mgTablet Every6 Hours|
|AUC0-24 : Area Under the Curve in a 24-hour dosing interval; Cmax : Peak Concentration in a 24-hour dosing interval;|
|Cmin : Trough Concentration in a 24-hour dosing interval; Tmax : Time to Peak Concentration|
|AUC0-24 (ng∙h/mL)||5975 (34)||6613 (27)||1890 (25)||2095 (26)|
|Cmax (ng/mL)||335 (35)||383 (21)||95 (24)||104 (24)|
|Cmin (ng/mL)||187 (37)||228 (32)||69 (30)||82 (27)|
|Tmax (h)||12 (27)||1.5 (42)||15 (27)||1.9 (57)|
|% Fluctuation||61 (57)||59 (35)||34 (72)||26 (47)|
Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours.
After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal, the Cmax and AUC0-∞ of tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While ULTRAM ER may be taken without regard to food, it is recommended that it be taken in a consistent manner.
The volume of distribution of tramadol was 2.6 and 2.9 liters/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 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) 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).
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