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Mechanism of Action
RYZOLT™ (tramadol hydrochloride extended-release tablets) is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, at least two complementary mechanisms that demonstrate three different types of activity 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 mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-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.
Apart from analgesia, tramadol hydrochloride administration may produce various 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 hydrochloride is due to both parent drug and the M1 metabolite (See CLINICAL PHARMACOLOGY, Mechanism of Action).
RYZOLT™ (tramadol hydrochloride extended-release tablets) is formulated as a racemate and both tramadol and M1 are detected in the circulation.
The pharmacokinetics of tramadol and M1 are dose-proportional over a 100 to 300 mg dose range in healthy subjects.
The median time to peak plasma concentrations of tramadol and M1 after multiple-dose administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) 200 mg tablets to healthy subjects are attained at about 4 h and 5 h, respectively (Table 1 and Figure 1).
The pharmacokinetic parameter values for RYZOLT™ (tramadol hydrochloride extended-release tablets) 200 mg administered once daily and tramadol immediate-release 50 mg administered every six hours are provided in Table 1. The relative bioavailability of a 200 mg RYZOLT™ (tramadol hydrochloride extended-release tablets) tablet compared to a 50 mg immediate-release tablet dosed every six hours was approximately 95% in healthy subjects.
Table 1. Mean (%CV) Steady-State Pharmacokinetic Parameter
|Pharmacokinetic Parameter||Tramadol||M1 Metabolite|
|RYZOLT™ 200 mg Tablet Once-Daily||Immediate-release tramadol 50 mg Tablet Every 6 Hours||RYZOLT™ 200 mg Tablet Once-Daily||Immediate-release tramadol 50 mg Tablet Every 6 Hours|
|AUC0-24 (ng·h/mL)||5991 (22)||6399 (28)||1361 (27)||1438 (23)|
|Cmax (ng/mL)||345 (21)||423 (23)||71 (27)||79 (22)|
|Cmin (ng/mL)||157 (31)||190 (34)||41 (30)||50 (29)|
|Tmax (hr)*||4.0 (3.0 – 9.0)||1.0 (1.0 – 3.0)||5.0 (3.0 – 20)||1.5 (1.0 – 3.0)|
|Fluctuation (%)||77 (26)||91 (22)||53 (29)||49 (26)|
|*Tmax is presented as Median (Range)|
Steady-state plasma concentrations are reached within approximately 48 hours.
Figure 1. Mean Tramadol Plasma Concentrations at Steady State
Following Five Days of Oral Administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) 200 mg Once Daily
and Immediate-Release Tramadol 50 mg Every 6 Hours.
Figure 2. Mean M1 Plasma Concentrations at Steady State Following
Five Days of Oral Administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) 200 mg Once Daily and Immediate-Release
Tramadol 50 mg Every 6 Hours
Co-administration with a high fat meal did not significantly affect AUC (overall exposure to tramadol); however, Cmax (peak plasma concentration) increased 67% following a single 300 mg tablet administration and 54% following a single 200 mg tablet administration. RYZOLT™ (tramadol hydrochloride extended-release tablets) was administered without regard to food in all clinical trials.
The volume of distribution of tramadol is 2.6 and 2.9 L/kg in males and females, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20%. Protein 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- and O-demethylation and glucuronidation or sulfation in the liver. N-demethylation is mediated by CYP3A4 and CYP2B6. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response (See PRECAUTIONS: DRUG INTERACTIONS).
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. After single administration of RYZOLT™ (tramadol hydrochloride extended-release tablets) , the mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.5 ± 1.5 and 7.5 ± 1.4 hours, respectively.
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1 in patients taking an immediate-release formulation of tramadol. RYZOLT™ (tramadol hydrochloride extended-release tablets) has not been studied in patients with renal impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ (tramadol hydrochloride extended-release tablets) do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, RYZOLT™ (tramadol hydrochloride extended-release tablets) should not be used in patients with severe renal impairment (creatinine clearance less than 30 mL/min) (See WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
The metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve (AUC) for tramadol and longer mean tramadol and M1 elimination half-lives (13 hours for tramadol and 19 hours for M1) after the administration of tramadol immediate-release tablets. RYZOLT™ (tramadol hydrochloride extended-release tablets) has not been studied in patients with hepatic impairment. The limited availability of dose strengths and once daily dosing of RYZOLT™ (tramadol hydrochloride extended-release tablets) do not permit the dosing flexibility required for safe use in patients with hepatic impairment. Therefore, RYZOLT (tramadol hydrochloride extended-release tablets) ™ should not be used in patients with hepatic impairment (see WARNINGS, Use in Renal and Hepatic Disease and DOSAGE AND ADMINISTRATION).
Healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/mL) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (See DOSAGE AND ADMINISTRATION).
Following a 100 mg IV dose of tramadol, plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females. Following a single oral dose of immediate-release tramadol, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.
The formation of the active metabolite of tramadol, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of CYP2D6. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. In studies in healthy subjects administered immediate-release tramadol products, 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 indicate that inhibitors of CYP2D6 (amitriptyline, quinidine and fluoxetine and its metabolite norfluoxetine,) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown.
Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with RYZOLT™ (tramadol hydrochloride extended-release tablets) may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS).
Quinidine is a selective inhibitor of CYP2D6, so that concomitant administration of quinidine and RYZOLT™ (tramadol hydrochloride extended-release tablets) may result in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown (see PRECAUTIONS). In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of RYZOLT™ and carbamazepine is not recommended (see PRECAUTIONS).
Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the RYZOLT™ (tramadol hydrochloride extended-release tablets) dosage regimen with cimetidine is recommended.
RYZOLT™ (tramadol hydrochloride extended-release tablets) was studied in four 12-week, randomized, double-blind, controlled studies in patients with moderate to severe pain due to osteoarthritis. Efficacy was demonstrated in one double-blind, placebo-controlled, randomized withdrawal design study. In this study, patients who experienced a reduction of pain and were able to tolerate RYZOLT™ (tramadol hydrochloride extended-release tablets) during an open-label titration period, were then randomized to RYZOLT™ (tramadol hydrochloride extended-release tablets) or to placebo for 12 weeks. Sixty-five percent of patients were able to successfully titrate onto RYZOLT™ (tramadol hydrochloride extended-release tablets) . After a washout, patients randomized to RYZOLT™ (tramadol hydrochloride extended-release tablets) were titrated to 200 mg or 300 mg of RYZOLT™ (tramadol hydrochloride extended-release tablets) based on tolerability and remained on that dose for the following 12-week period. Approximately 24% of patients discontinued during the randomized period of the study, with more patients discontinuing from the RYZOLT™ (tramadol hydrochloride extended-release tablets) arm than the placebo arm due to adverse events (10% vs. 5%, respectively) and more patients discontinuing from the placebo arm than the RYZOLT™ (tramadol hydrochloride extended-release tablets) arm due to lack of efficacy (10% vs. 8%, respectively). Patients treated with RYZOLT™ (tramadol hydrochloride extended-release tablets) demonstrated a greater improvement in pain intensity, measured on an 11-point numerical rating scale, at the end of treatment compared to patients randomized to placebo. Figure 3 shows the fraction of patients achieving various degree of improvement in pain from baseline to the end of treatment (week 12). The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 3. Proportion of Patients Achieving Various Levels
of Pain Relief as Measured by 12-Week Pain Intensity.
Last reviewed on RxList: 3/2/2009
This monograph has been modified to include the generic and brand name in many instances.
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