RYZOLT — tramadol hydrochloride tablet, delayed release
PD-Rx Pharmaceuticals, Inc.
C16 H25 NO2 ·HCl
The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride is a white crystalline powder that is freely soluble in water and ethanol. RYZOLT™ extended-release tablets are for oral administration and contain 100 mg, 200 mg or 300 mg of tramadol hydrochloride. The tablets are white to off-white in color. The inactive ingredients in the tablet are colloidal silicon dioxide, pregelatinized modified starch, hydrogenated vegetable oil, magnesium stearate, polyvinyl acetate, povidone, sodium lauryl sulfate and xanthan gum.
RYZOLT™ 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™ 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™ 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™ 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™ tablet compared to a 50 mg immediate-release tablet dosed every six hours was approximately 95% in healthy subjects.
|Pharmacokinetic Parameter||Tramadol||M1 Metabolite|
200 mg Tablet
50 mg Tablet
Every 6 Hours
200 mg Tablet
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)|
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™ 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™ 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™ 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™, 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.
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