Tramadol Hydrochloride (Page 6 of 8)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tramadol Hydrochloride Extended-Release contains 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 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.

12.2 Pharmacodynamics

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 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.

12.3 Pharmacokinetics

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol Hydrochloride Extended-Release is administered as a racemate and both tramadol and M1 are detected in the circulation. The Cmax and AUC of Tramadol Hydrochloride Extended-Release capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

Absorption:

After a single dose administration of Tramadol Hydrochloride Extended-Release, Tmax occurs around 10-12 hours.

The mean Cmax and AUC of Tramadol Hydrochloride Extended-Release capsules after a 300 mg single dose was 308 ng/mL and 6777 ng*hr/mL, respectively under fasting conditions. Tramadol Hydrochloride Extended-Release is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.

At steady-state, Tramadol Hydrochloride Extended-Release at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions (Table 2). Following administration of Tramadol Hydrochloride Extended-Release 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.

Table 2. Mean (%CV) Steady-State Pharmacokinetic Parameter Values (N= 38)
Tramadol O-Desmethyl-Tramadol (M1 Metabolite)
Parameter Tramadol hydrochloride Extended- Release Capsules200 mg A Reference Extended- Release Tramadol Product200 mg Tramadol hydrochloride Extended- Release Capsules200 mg A Reference Extended- Release Tramadol Product200 mg
AUC0-24(ng.h/mL) 5678 (27%) 5563 (32%) 1319 (34%) 1302 (40%)
Cmax (ng/mL) 332 (25%) 350 (31%) 70 (34%) 74 (41%)
Cmin (ng/mL) 128 (39%) 125 (45%) 35 (34%) 33 (42%)
Tmax 5.9 (66%) 10 (30%) 11 (37%) 13 (29%)
% Fluctuation 88 (19%) 101 (30%) 64 (22%) 76 (30%)

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

Food Effects:

The rate and extent of absorption of Tramadol Hydrochloride Extended-Release capsules (300 mg) are similar following oral administration with or without food. Therefore, Tramadol Hydrochloride Extended-Release capsules can be administered without regard to meals.

Distribution:

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 tramadol 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.

Metabolism:

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 and polymorphism, which may affect the therapeutic response [see DRUG INTERACTIONS ( 7)].

Elimination:

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. The mean plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Tramadol Hydrochloride Extended-Release capsules are approximately 10 and 11 hours, respectively.

Special Populations:

Renal Impairment

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol was studied in patients with mild or moderate renal impairment after receiving multiple doses of an extended-release tramadol product at 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function (CLcr > 80 mL/min). However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION ( 2.5), and USE IN SPECIFIC POPULATIONS ( 8.6)]. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.

Hepatic Impairment

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of an extended-release tramadol product at 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION ( 2.6) and USE IN SPECIFIC POPULATIONS ( 8.7)].

Gender

Based on pooled multiple-dose pharmacokinetics studies for an extended-release tramadol product in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.

Age

The effect of age on pharmacokinetics of Tramadol Hydrochloride Extended-Release has not been studied. 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 ( 2.4)].

Drug Interactions:

Poor / Extensive Metabolizers, CYP2D6

The formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450 metabolizing enzyme system. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower.

CYP2D6 Inhibitors

In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Quinidine

Tramadol is metabolized to active metabolite M1 by CYP2D6. Coadministration of quinidine, a selective inhibitor of CYP2D6, with tramadol ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown.

To evaluate the effect of tramadol, a CYP2D6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. The results from this study indicate that tramadol has no effect on quinidine metabolism. [See DRUG INTERACTIONS ( 7.2, 7.6)].

CYP3A4 Inhibitors and Inducers

Since tramadol is also metabolized by CYP3A4, administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John’s Wort, with Tramadol Hydrochloride Extended-Release may affect the metabolism of tramadol leading to altered tramadol exposure [see WARNINGS AND PRECAUTIONS ( 5.1) and DRUG INTERACTIONS ( 7.2)].

Cimetidine

Concomitant administration of tramadol immediate-release tablets with cimetidine, a weak CYP3A4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the Tramadol Hydrochloride Extended-Release dosage regimen with cimetidine is recommended.

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant administration of Tramadol Hydrochloride Extended-Release and carbamazepine is not recommended.

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