CLINICAL PHARMACOLOGY
Oxycodone HCl component:
Oxycodone HCl is a semisynthetic opioid analgesic with multiple actions which involve the central nervous system and smooth muscle. The mechanism of action of oxycodone is not known but is thought to be related to its binding to opiate receptors in the central nervous system. In addition to analgesia, opioids may produce sedation and respiratory depression.
Ibuprofen component:
Ibuprofen is a nonsteroidal anti-inflammatory agent that possesses analgesic and antipyretic activities. Its mode of action, similar to other NSAIDs, is not completely understood, but is thought to be related to its inhibition of cyclooxygenase activity and prostaglandin synthesis. Ibuprofen is a peripherally acting analgesic. Ibuprofen does not have any known effects on opiate receptors.
Pharmacokinetics:
Absorption:
Oxycodone is rapidly absorbed after single dose administration of Combunox. Maximum concentrations (Cmax) of oxycodone, ranging from 9.8 ng/mL to 11.7 ng/mL, are obtained within 1.3 hr to 2.1 hr after administration of Combunox. Repeated administration of Combunox every 6 hours results in approximately 50-65% increase in Cmax. In the presence of food, the bioavailability of oxycodone is slightly (25%) increased.
Ibuprofen is rapidly absorbed after oral administration of Combunox. Cmax values range from 18.5 mcg/mL to 34.3 mcg/mL and are reached 1.6 hr to 3.1 hr after oral administration of Combunox. Repeated administration of Combunox every 6 hours does not result in any accumulation of ibuprofen. The bioavailability of ibuprofen is not altered in the presence of food.
Distribution:
Oxycodone binding to protein in serum is approximately 45%.
Ibuprofen is extensively bound to plasma proteins (99%).
Metabolism:
Oxycodone is metabolized in the liver by means of N-demethylation and O-demethylation, 6-ketoreduction and glucuronidation. The major circulating metabolite is noroxycodone, which possesses weak analgesic activity.
Oxymorphone, the end product of O-demethylation, has analgesic activity but is present in the plasma at low concentrations. Metabolism of oxycodone to oxymorphone occurs via CYP2D6.
Ibuprofen is present as a racemate and following absorption, it undergoes interconversion in the plasma from the R-isomer to the S-isomer.
Both the R- and S- isomers are metabolized to two primary metabolites: (+)-2-4'-(2-hydroxy-2-methyl-propyl) phenyl propionic acid and (+)-2-4'-(2-carboxypropyl) phenyl propionic acid, both of which circulate in the plasma at low levels relative to the parent.
Elimination:
Oxycodone is eliminated from the systemic circulation with half life (T1/2) values ranging from 3.1 hr to 3.7 hr after single dose administration of Combunox. Urinary excretion of unchanged oxycodone amounts to approximately 4% of the administered oxycodone dose.
Ibuprofen is eliminated from the systemic circulation with half life (T1/2) values ranging from 1.8 hr to 2.6 hr after single dose administration of Combunox. Urinary excretion of unchanged ibuprofen is minimal (less than 0.2% of administered ibuprofen dose).
Special Populations:
Gender: There are no gender effects on the pharmacokinetics of oxycodone or ibuprofen after administration of Combunox.
Age: The effects of age on the pharmacokinetics of oxycodone and ibuprofen after administration of Combunox have not been evaluated.
When either drug was administered alone, the pharmacokinetics of oxycodone and ibuprofen were similar in elderly subjects, compared to young healthy subjects.
Pediatrics: The pharmacokinetics of oxycodone and ibuprofen after administration of Combunox have not been evaluated in a pediatric population.
Renal Impairment: The effects of renal impairment on the pharmacokinetics of oxycodone and ibuprofen after administration of Combunox have not been evaluated.
Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of oxycodone and ibuprofen after administration of Combunox have not been evaluated. (See PRECAUTIONS; Hepatic Effects)
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