Prescription Drug Information: Oxycodone HCl Controlled-Release

OXYCODONE HCL CONTROLLED-RELEASE — oxycodone hydrochloride tablet
OXYCODONE HCL CONTROLLED-RELEASE- oxycodone hydrochloride tablet
Ranbaxy Pharmaceuticals Inc

WARNING

Oxycodone HCl Controlled-Release Tablets are an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine.

Oxycodone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Oxycodone HCl Controlled-Release Tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Oxycodone HCl Controlled-Release Tablets are a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.

Oxycodone HCl Controlled-Release Tablets are NOT intended for use as a prn analgesic.

OXYCODONE HCl CONTROLLED-RELEASE 80 mg, and 160 mg Tablets, or a single dose greater than 40 mg, ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. A single dose greater than 40 mg, or total daily doses greater than 80 mg , may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids.

OXYCODONE HCl CONTROLLED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED OXYCODONE HCl CONTROLLED-RELEASE TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE.

DESCRIPTION

Oxycodone HCl Controlled-Release Tablets are an opioid analgesic supplied in 10 mg and 20 mg tablet strengths for oral administration. The tablet strengths describe the amount of oxycodone per tablet as the hydrochloride salt. The structural formula for oxycodone hydrochloride is as follows:

this is the structural formula
(click image for full-size original)

C18 H21 NO4 • HCl MW 351.83

The chemical formula is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride.

Oxycodone is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL). It is slightly soluble in alcohol (octanol water partition coefficient 0.7). The tablets contain the following inactive ingredients: ammonio methacrylate copolymer, hypromellose, lactose, magnesium stearate, polyethylene glycol 400, povidone, sodium hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide, and triacetin.

The 10 mg tablets also contain: hydroxypropyl cellulose.

The 20 mg tablets also contain: polysorbate 80 and red iron oxide.

Oxycodone HCL controlled-release 10 mg and 20 mg tablets are tested using USP dissolution test 2 and meet the associated tolerances provided in acceptance table 2 of the oxycodone hydrochloride extended-release tablets USP monograph.

CLINICAL PHARMACOLOGY

Oxycodone is a pure agonist opioid whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, hydromorphone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression, as well as analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.

Central Nervous System

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.

Oxycodone produces respiratory depression by direct action on brain stem 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. Antitussive effects may occur with doses lower than those usually required for analgesia.

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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of Oxycodone HCl Controlled-Release Tablets overdose (See OVERDOSAGE).

Gastrointestinal Tract And Other Smooth Muscle

Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in 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 gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Oxycodone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Concentration – Efficacy Relationships

Studies in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall “drug effect”, analgesia and feelings of “relaxation”.

As with all opioids, the minimum effective plasma concentration for analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. As a result, patients must 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 due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

Concentration – Adverse Experience Relationships

Oxycodone HCl Controlled-Release Tablets are associated with typical opioid-related adverse experiences. There is a general relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation is altered by the development of tolerance to opioid-related side effects, and the relationship is not clinically relevant.

As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION), because the effective analgesic dose for some patients will be too high to be tolerated by other patients.

PHARMACOKINETICS AND METABOLISM

The activity of Oxycodone HCl Controlled-Release Tablets is primarily due to the parent drug oxycodone. Oxycodone HCl Controlled-Release Tablets are designed to provide controlled delivery of oxycodone over 12 hours.

Breaking, chewing or crushing Oxycodone HCl Controlled-Release Tablets eliminates the controlled delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Oxycodone release from Oxycodone HCl Controlled-Release Tablets is pH independent. Oxycodone is well absorbed from Oxycodone HCl Controlled-Release Tablets with an oral bioavailability of 60% to 87%. The relative oral bioavailability of Oxycodone HCl Controlled-Release Tablets to immediate-release oral dosage forms is 100%. Upon repeated dosing in normal volunteers in pharmacokinetic studies, steady-state levels were achieved within 24-36 hours. Dose proportionality and/or bioavailability has been established for the 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for both peak plasma levels (Cmax) and extent of absorption (AUC). Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life of oxycodone following the administration of Oxycodone HCl Controlled-Release Tablets was 4.5 hours compared to 3.2 hours for immediate-release oxycodone.

Absorption

About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. In normal volunteers, the t½ of absorption is 0.4 hours for immediate-release oral oxycodone. In contrast, Oxycodone HCl Controlled-Release Tablets exhibit a biphasic absorption pattern with two apparent absorption half-lives of 0.6 and 6.9 hours, which describes the initial release of oxycodone from the tablet followed by a prolonged release.

Plasma Oxycodone by Time

Dose proportionality has been established for the 10 mg, 20 mg, 40 mg, and 80 mg tablet strengths for both peak plasma concentrations (Cmax ) and extent of absorption (AUC) (see Table 1 below). Another study established that the 160 mg tablet is bioequivalent to 2 x 80 mg tablets as well as to 4 x 40 mg for both peak plasma concentrations (Cmax ) and extent of absorption (AUC) (see Table 2 below). Given the short half-life of elimination of oxycodone from Oxycodone HCl Controlled-Release Tablets, steady-state plasma concentrations of oxycodone are achieved within 24-36 hours of initiation of dosing with Oxycodone HCl Controlled-Release Tablets. In a study comparing 10 mg of Oxycodone HCl Controlled-Release Tablets every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two treatments were found to be equivalent for AUC and Cmax , and similar for Cmin (trough) concentrations.

this is the first graph in the insert

TABLE 1 Mean [% coefficient variation]
Regimen/Dosage Form AUC (ng•hr/mL) x (n g/mL)x (h rs)Trough Conc. (ng/mL)
Single Dose 10 mg Oxycodone HCl Controlled-Release Tablets100.7 [26.6]10.6 [20.1]2.7 [44.1]n.a.
20 mg Oxycodone HCl Controlled-Release Tablets207.5 [35.9]21.4 [36.6]3.2 [57.9]n.a.
40 mg Oxycodone HCl Controlled-Release Tablets423.1 [33.3]39.3 [34.0]3.1 [77.4]n.a.
80 mg Oxycodone HCl Controlled-Release Tablets1085.5 [32.3]98.5 [32.1]2.1 [52.3]n.a.
Multiple Dose 10 mg Oxycodone HCl Controlled-Release Tablets q12h103.6[38.6]15.1 [31.0]3.2 [69.5]7.2 [48.1]
5 mg immediate-release q6h90.0 [36.2]15.5 [28.8]1.6 [49.7]7.4 [50.9]
TABLE 2 Mean [% coefficient variation]

† for single-dose AUC = AUC0-inf ; for multiple-dose AUC = AUC0-T

* data obtained while volunteers received naltrexone which can enhance absorption

Regimen/ Dosage FormAUC (ng•hr/mL)†Cmax (ng/mL)Tmax (hrs)Trough Conc. (ng/mL)
Single Dose4 x 40 mg Oxycodone HCl Controlled- Release Tablets*1935.3 [34.7]152.0 [28.9]2.56 [42.3]n.a.
2 x 80 mg Oxycodone HCl Controlled- Release Tablets*1859.3 [30.1]153.4 [25.1]2.78 [69.3]n.a.
1 x 160 mg Oxycodone HCl Controlled-Release Tablets*1856.4 [30.5]156.4 [24.8]2.54 [36.4]n.a.

Oxycodone HCl Controlled-Release Tablets are NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a study involving 21 normal volunteers show that Oxycodone HCl Controlled-Release 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.

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