OxyContin® is NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a study involving 21 normal volunteers show that OxyContin Tablets administered per rectum resulted in an AUC 39% greater and a Cmax 9% higher than tablets administered by mouth. Therefore, there is an increased risk of adverse events with rectal administration.

Food Effects

Food has no significant effect on the extent of absorption of oxycodone from OxyContin. However, the peak plasma concentration of oxycodone increased by 25% when a OxyContin 160 mg Tablet was administered with a high-fat meal.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was about 45%. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk (see PRECAUTIONS).

Metabolism

Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.

The formation of oxymorphone, but not noroxycodone, is mediated by cytochrome P450 2D6 and, as such, its formation can, in theory, be affected by other drugs (see Drug-Drug Interactions).

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults.

Special Populations

Elderly

The plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects.

Gender

Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Renal Impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance < 60 mL/min) show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively. This is accompanied by an increase in sedation but not by differences in respiratory rate, pupillary constriction, or several other measures of drug effect. There was an increase in t½ of eliminat ion for oxycodone of only 1 hour (see PRECAUTIONS).

Hepatic Impairment

Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, than normal subjects. AUC values are 95% and 65% higher, respectively. Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%. These differences are accompanied by increases in some, but not other, drug effects. The t½ elimination for oxycodone increased by 2.3 hours (see PRECAUTIONS).

Drug-Drug Interactions

(see PRECAUTIONS)

Oxycodone is metabolized in part by cytochrome P450 2D6 to oxymorphone which represents less than 15% of the total administered dose. This route of elimination may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic anti-depressants). However, in a study involving 10 subjects using quinidine, a known inhibitor of cytochrome P450 2D6, the pharmacodynamic effects of oxycodone were unchanged.

Pharmacodynamics

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