s.
In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.
Excretion
Approximately 30% of the tramadol dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.
Less than 9% of acetaminophen is excreted unchanged in the urine.
Special Populations
Hepatic Impairment
Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of tramadol extended-release 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 after the administration of tramadol extended-release 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 [see USE IN SPECIFIC POPULATIONS (8.6)].
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 were studied in patients with mild or moderate renal impairment after receiving multiple doses of tramadol extended-release 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50 to 80 mL/min) or moderate (CLcr: 30 to 50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20 to 40% with increased severity of the renal impairment (from normal to mild and moderate). Tramadol extended-release has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose [see DOSAGE AND ADMINISTRATION (2.3), USE IN SPECIFIC POPULATIONS (8.7)].
Geriatric Population
A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with tramadol hydrochloride and acetaminophen, which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in the pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function [see USE IN SPECIFIC POPULATIONS (8.5)].
Sex
Tramadol clearance was 20% higher in female subjects compared to males on four Phase 1 studies of tramadol hydrochloride and acetaminophen in 50 male and 34 female healthy subjects.
Poor/Extensive Metabolizers, CYP2D6
The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK a |
