Oxycodone HCl Controlled-Release Tablets are an opioid analgesic supplied in 10 mg, 20 mg, 40 mg, and 80 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:
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.
The 40 mg tablets also contain: polysorbate 80 and yellow iron oxide.
The 80 mg tablets also contain: FD&C blue No. 2, hydroxypropyl cellulose, and yellow iron oxide.
Oxycodone HCl controlled-release 10 mg, 20 mg, 40 mg, and 80 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.
Oxycodone Extended-Release Tablets - 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.
TABLE 1 Mean [% coefficient variation]
| Regimen/ |
Dosage Form |
AUC
(ng•hr/mL)† |
Cmax
(ng/mL) |
Tmax
(hrs) |
Trough Conc.
(ng/mL) |
|---|
| |
Single
Dose |
10 mg Oxycodone HCl Controlled-Release Tablets |
100.7 [26.6] |
10.6 [20.1] |
2.7 [44.1] |
n.a. |
|
20 mg Oxycodone HCl Controlled-Release Tablets |
207.5 [35.9] |
21.4 [36.6] |
3.2 [57.9] |
n.a. |
|
40 mg Oxycodone HCl Controlled-Release Tablets |
423.1 [33.3] |
39.3 [34.0] |
3.1 [77.4] |
n.a. |
|
80 mg Oxycodone HCl Controlled-Release Tablets* |
1085.5 [32.3] |
98.5 [32.1] |
2.1 [52.3] |
n.a. |
| |
Multiple
Dose |
10 mg Oxycodone HCl Controlled-Release Tablets q12h |
103.6 [38.6] |
15.1 [31.0] |
3.2 [69.5] |
7.2 [48.1] |
|
5 mg immediate-
release q6h |
99.0 [36.2] |
15.5 [28.8] |
1.6 [49.7] |
7.4 [50.9] |
TABLE 2 Mean [% coefficient variation]
| Regimen/ |
Dosage Form |
AUC∞
(ng•hr/mL)† |
Cmax
(ng/mL) |
Tmax
(hrs) |
Trough Conc.
(ng/mL) |
|---|
| † for single-dose AUC = AUC0-inf; for multiple-dose AUC = AUC0-T |
| * data obtained while volunteers received naltrexone which can enhance absorption |
Single
Dose |
4 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.
Food Effects
Food has no significant effect on the extent of absorption of oxycodone from Oxycodone HCl Controlled-Release Tablets. However, the peak plasma concentration of oxycodone increased by 25% when an Oxycodone HCl Controlled-Release Tablets 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, noroxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone. 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.
CYP3A mediated N-demethylation (to noroxycodone) is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation (to oxymorphone). Therefore, the formation of these and related metabolites 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 elimination 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)
CYP3A mediated N-demethylation is the principal metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-demethylation and in theory can be affected by drugs affecting cytochrome P450 enzymes.
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
A single-dose, double-blind, placebo- and dose-controlled study was conducted using Oxycodone HCl Controlled-Release Tablets (10, 20, and 30 mg) in an analgesic pain model involving 182 patients with moderate to severe pain. Twenty and 30 mg of Oxycodone HCl Controlled-Release Tablets were superior in reducing pain compared with placebo, and this difference was statistically significant. The onset of analgesic action with Oxycodone HCl Controlled-Release Tablets occurred within 1 hour in most patients following oral administration.
Clinical Trials
A double-blind placebo-controlled, fixed-dose, parallel group, two-week study was conducted in 133 patients with chronic, moderate to severe pain, who were judged as having inadequate pain control with their current therapy. In this study, 20 mg Oxycodone HCl Controlled-Release Tablets q12h but not 10 mg Oxycodone HCl Controlled-Release Tablets q12h decreased pain compared with placebo, and this difference was statistically significant.
Indications and Usage for Oxycodone Extended-Release Tablets
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.
Physicians should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen to opioids in a plan of pain management such as outlined by the World Health Organization, the Agency for Healthcare Research and Quality (formerly known as the Agency for Health Care Policy and Research), the Federation of State Medical Boards Model Guidelines, or the American Pain Society.
Oxycodone HCl Controlled-Release Tablets are not indicated for pain in the immediate postoperative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. Oxycodone HCl Controlled-Release Tablets are only indicated for postoperative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines.)
Contraindications
Oxycodone HCl Controlled-Release Tablets are contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindicated. This includes patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone HCl Controlled-Release Tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.
Warnings
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.
Oxycodone HCl Controlled-Release 80 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.
Patients should be instructed against use by individuals other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death.
Misuse, Abuse and Diversion of Opioids
Oxycodone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
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 have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Oxycodone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
DRUG ABUSE AND ADDICTION
Oxycodone HCl Controlled-Release Tablets contain oxycodone which is a full mu-agonist opioid with an abuse liability similar to morphine and is a Schedule II controlled substance. Oxycodone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. There is a potential for drug addiction to develop following exposure to opioids, including oxycodone. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Oxycodone HCl Controlled-Release Tablets, like other opioids, have been diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Oxycodone HCl Controlled-Release Tablets consist of a dual-polymer matrix, intended for oral use only. Abuse of the crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Respiratory Depression
Respiratory depression is the chief hazard from oxycodone, the active ingredient in Oxycodone HCl Controlled-Release Tablets, as with all opioid agonists. Respiratory depression is a particular problem in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
Oxycodone should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.
Head Injury
The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Oxycodone produces effects on pupillary response and consciousness which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.
Hypotensive Effect
Oxycodone HCl Controlled-Release Tablets may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone may produce orthostatic hypotension in ambulatory patients. Oxycodone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.
Precautions
General
Opioid analgesics have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.
Use of Oxycodone HCl Controlled-Release Tablets is associated with increased potential risks and should be used only with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); CNS depression or coma; delirium tremens; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis.
The administration of oxycodone may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.
Interactions with other CNS Depressants
Oxycodone HCl Controlled-Release Tablets should be used with caution and started in a reduced dosage (1/3 to 1/2 of the usual dosage) in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of Oxycodone HCl Controlled-Release Tablets.
Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone and/or may precipitate withdrawal symptoms in these patients.
Ambulatory Surgery and Postoperative Use
Oxycodone HCl Controlled-Release Tablets are not indicated for pre-emptive analgesia (administration pre-operatively for the management of postoperative pain).
Oxycodone HCl Controlled-Release Tablets are not indicated for pain in the immediate postoperative period (the first 12 to 24 hours following surgery) for patients not previously taking the drug, because its safety in this setting has not been established.
Oxycodone HCl Controlled-Release Tablets are not indicated for pain in the postoperative period if the pain is mild or not expected to persist for an extended period of time.
Oxycodone HCl Controlled-Release Tablets are only indicated for postoperative use if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate (See American Pain Society guidelines).
Patients who are already receiving Oxycodone HCl Controlled-Release Tablets as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs given, and the temporary changes in physiology caused by the surgical intervention (seeDOSAGE AND ADMINISTRATION).
Oxycodone HCl Controlled-Release Tablets and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented.
Use in Pancreatic/Biliary Tract Disease
Oxycodone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like oxycodone may cause increases in the serum amylase level.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).
Information for Patients/Caregivers
If clinically advisable, patients receiving Oxycodone HCl Controlled-Release Tablets or their caregivers should be given the following information by the physician, nurse, pharmacist, or caregiver:
- Patients should be aware that Oxycodone HCl Controlled-Release Tablets contain oxycodone, which is a morphine-like substance.
- Patients should be advised that Oxycodone HCl Controlled-Release Tablets were designed to work properly only if swallowed whole. Oxycodone HCl Controlled-Release Tablets will release all their contents at once if broken, chewed, or crushed, resulting in a risk of fatal overdose.
- Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.
- Patients should be advised not to adjust the dose of Oxycodone HCl Controlled-Release Tablets without consulting the prescribing professional.
- Patients should be advised that Oxycodone HCl Controlled-Release Tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
- Patients should not combine Oxycodone HCl Controlled-Release Tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
- Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
- Patients should be advised that Oxycodone HCl Controlled-Release Tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
- Patients should be advised that they may pass empty matrix "ghosts" (tablets) via colostomy or in the stool, and that this is of no concern since the active medication has already been absorbed.
- Patients should be advised that if they have been receiving treatment with Oxycodone HCl Controlled-Release Tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Oxycodone HCl Controlled-Release Tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
- Patients should be instructed to keep Oxycodone HCl Controlled-Release Tablets in a secure place out of the reach of children. When Oxycodone HCl Controlled-Release Tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.
Use in Drug and Alcohol Addiction
Oxycodone HCl Controlled-Release Tablets are an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid analgesia.
Drug-Drug Interactions
Opioid analgesics, including Oxycodone HCl Controlled-Release Tablets, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Inhibitors of CYP3A4:
Since the CYP3A4 isoenzyme plays a major role in the metabolism of oxycodone, co-administration of drugs that inhibit CYP3A4 activity, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. Although clinical studies have not been conducted, the expected clinical results would be increased or prolonged opioid effects. If co-administration with Oxycodone HCl Controlled-Release Tablets is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP450 inhibitors. These patients should be evaluated at frequent intervals and dose adjustments considered until stable drug effects are achieved.
Inducers of CYP3A4:
Although clinical studies have not been conducted, CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug, which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy, or, possibly, development of abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with Oxycodone HCl Controlled-Release Tablets is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP450 inducers. These patients should be evaluated at frequent intervals and dose adjustments considered until stable drug effects are achieved.
Inhibitors of CYP2D6:
Oxycodone is metabolized in part to oxymorphone via cytochrome P450 2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs including amiodarone and quinidine as well as polycyclic antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. Clinicians should be aware of this possible interaction, however.
Use with CNS Depressants
Oxycodone HCl Controlled-Release Tablets, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dosage in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, centrally acting anti-emetics, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxycodone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies of oxycodone to evaluate its carcinogenic potential have not been conducted.
Oxycodone was not mutagenic in the following assays: Ames Salmonella and E. coli test with and without metabolic activation at doses of up to 5000 µg, chromosomal aberration test in human lymphocytes in the absence of metabolic activation at doses of up to 1500 µg/mL and with activation 48 hours after exposure at doses of up to 5000 µg/mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 µg/mL). Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation in the human chromosomal aberration test (at greater than or equal to 1250 µg/mL) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 µg/mL or greater with metabolic activation and at 400 µg/mL or greater without metabolic activation.
Pregnancy
Teratogenic Effects - Category B: Reproduction studies have been performed in rats and rabbits by oral administration at doses up to 8 mg/kg and 125 mg/kg, respectively. These doses are 3 and 46 times a human dose of 160 mg/day, based on mg/kg basis. The results did not reveal evidence of harm to the fetus due to oxycodone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
Oxycodone HCl Controlled-Release Tablets are not recommended for use in women during and immediately prior to labor and delivery because oral opioids may cause respiratory depression in the newborn. Neonates whose mothers have been taking oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.
Nursing Mothers
Low concentrations of oxycodone have been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving Oxycodone HCl Controlled-Release Tablets because of the possibility of sedation and/or respiratory depression in the infant.
Pediatric Use
Safety and effectiveness of Oxycodone HCl Controlled-Release Tablets have not been established in pediatric patients below the age of 18. It must be remembered that Oxycodone HCl Controlled-Release Tablets cannot be crushed or divided for administration.
Geriatric Use
In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone appeared to be slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% (see PHARMACOKINETICS AND METABOLISM). Of the total number of subjects (445) in clinical studies of Oxycodone HCl Controlled-Release Tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected side effects were seen in the elderly patients who received Oxycodone HCl Controlled-Release Tablets. Thus, the usual doses and dosing intervals are appropriate for these patients. As with all opioids, the starting dose should be reduced to 1/3 to 1/2 of the usual dosage in debilitated, non-tolerant patients. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
Laboratory Monitoring
Due to the broad range of plasma concentrations seen in clinical populations, the varying degrees of pain, and the development of tolerance, plasma oxycodone measurements are usually not helpful in clinical management. Plasma concentrations of the active drug substance may be of value in selected, unusual or complex cases.
Hepatic Impairment
A study of Oxycodone HCl Controlled-Release Tablets in patients with hepatic impairment indicates greater plasma concentrations than those with normal function. The initiation of therapy at 1/3 to 1/2 the usual doses and careful dose titration is warranted.
Renal Impairment
In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Dose initiation should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
Gender Differences
In pharmacokinetic studies, opioid-naive females demonstrate up to 25% higher average plasm
