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Mechanism Of Action
Oxycodone HCl is a pure opioid agonist and is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all pure opioid agonists, there is no ceiling effect to analgesia.
The relationship between the plasma level of oxycodone and the analgesic response will depend on the patient's age, state of health, medical condition, and extent of previous opioid treatment.
The minimum effective plasma concentration of oxycodone to achieve analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. Thus, patients need to be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time with repeated dosing due to an increase in pain and/or development of tolerance.
Effects on Central Nervous System
Oxycodone produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
Oxycodone depresses the cough reflex by direct effect on the cough center in the medulla. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary, and pancreatic secretions are decreased by oxycodone HCl. Oxycodone, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone located in the medulla. The frequency and severity of emesis gradually diminishes with time.
Oxycodone may cause a decrease in the secretion of hydrochloric acid in the stomach that reduces motility while increasing the tone of the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on Cardiovascular System
Oxycodone, in therapeutic doses, produces peripheral vasodilation (arterial and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Caution must be used in hypovolemic patients, such as those suffering acute myocardial infarction, because oxycodone may cause or further aggravate their hypotension. Caution must also be used in patients with cor pulmonale who have received therapeutic doses of opioids.
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats, and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as symptoms of hypogonadism.
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.
The analgesic activity of OXECTA is primarily due to the parent drug oxycodone.
The pharmacokinetics of oxycodone after OXECTA administration are characterized by peak plasma concentrations occurring on average within 1.2 to 1.4 hours of the first dose under fasted conditions. Thereafter, oxycodone concentrations fall with an average terminal half-life ranging between 3-4 hours. OXECTA is bioequivalent with Oxycodone immediate-release tablets in the fasted state, with no differences identified in the time to peak exposure (Tmax) and terminal elimination half-life (T½) of oxycodone between administration of OXECTA and Oxycodone immediate-release tablets. Dose proportionality was established for OXECTA at doses of 5 mg, 10 mg, and 15 mg (oxycodone HCl) based on proportional increases in oxycodone Cmax and AUC exposure levels.
When administered with a high fat meal, mean AUC values are increased by 21% and peak concentrations are decreased by 14%. Food causes a delay in Tmax from 1.25 to 3.00 hours. These changes in oxycodone pharmacokinetics are not considered clinically relevant; therefore, OXECTA can be taken without regard to food.
The oral bioavailability of oxycodone is 60% to 87%. The high oral bioavailability of oxycodone (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone compared to other oral opioids.
Following intravenous administration, the volume of distribution for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was approximately 45%. Oxycodone has been found in breast milk [see Use In Specific Populations].
Oxycodone HCl is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. 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.
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%; and conjugated oxymorphone ≤ 14%. Both free and conjugated noroxycodone have been found in urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone was 3.5 to 4 hours.
Elderly: Information obtained from oxycodone indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
Gender: Information obtained from oxycodone support the lack of gender effect on the pharmacokinetics of oxycodone.
Renal Insufficiency: Information obtained from oxycodone indicate that patients with renal impairment (defined as creatinine clearance < 60 mL/min) had higher plasma concentrations of oxycodone than subjects with normal renal function [see DOSAGE AND ADMINISTRATION].
CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the coadministration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.
Last reviewed on RxList: 1/29/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Oxecta Information
- Oxecta Drug Interactions Center: oxycodone oral
- Oxecta Side Effects Center
- Oxecta FDA Approved Prescribing Information including Dosage
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