Oxycodone extended-release tablets
 Oxycodone Acetaminophen

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Oxycodone


Generic Name: Oxycodone hydrochloride
Dosage Form: Extended-release tablets

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

Warning

Oxycodone hydrochloride extended-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 hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Oxycodone hydrochloride extended-release tablets are an extended-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 hydrochloride extended-release tablets are NOT intended for use as a prn analgesic.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets ARE FOR USE IN OPIOID TOLERANT PATIENTS ONLY. This tablet strength may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

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

Oxycodone Description

Oxycodone Hydrochloride Extended-Release Tablets are an opioid analgesic supplied in 80 mg tablet strength for oral administration. The tablet strength describes the amount of Oxycodone per tablet as the hydrochloride salt. The structural formula for Oxycodone hydrochloride is as follows:

C18H21NO4•HCl M.W. 351.82

The chemical formula is 4,5-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). Each tablet contains 80 mg of Oxycodone hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C blue #2 indigo carmine lake, hypromellose (2208, 100M), iron oxide yellow, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide and triacetin.

Oxycodone - 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 hydrochloride extended-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 hydrochloride extended-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 hydrochloride extended-release tablets is primarily due to the parent drug Oxycodone. Oxycodone hydrochloride extended-release tablets are designed to provide extended delivery of Oxycodone over 12 hours.

Breaking, chewing or crushing Oxycodone hydrochloride extended-release tablets eliminates the extended delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of Oxycodone.

Oxycodone release from Oxycodone hydrochloride extended-release tablets is pH independent. Oxycodone is well absorbed from Oxycodone hydrochloride extended-release tablets with an oral bioavailability of 60% to 87%. The relative oral bioavailability of Oxycodone hydrochloride extended-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 to 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 hydrochloride extended-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 hydrochloride extended-release tablets exhibit a biphasic absorption pattern with two apparent absorption half-times of 0.6 and 6.9 hours, which describes the initial release of Oxycodone from the tablet followed by a prolonged release.

Dose proportionality has been established for the 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg tablet strengths for both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 1 below). Given the short half-life of elimination of Oxycodone from Oxycodone hydrochloride extended-release tablets, steady-state plasma concentrations of Oxycodone are achieved within 24 to 36 hours of initiation of dosing with Oxycodone hydrochloride extended-release tablets. In a study comparing 10 mg of Oxycodone hydrochloride extended-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. There was less fluctuation in plasma concentrations for the Oxycodone hydrochloride extended-release tablets than for the immediate-release formulation.

Table 1: Mean [% coefficient variation]

for single-dose AUC=AUC 0-inf; for multiple-dose AUC=AUC 0-T

* data obtained while volunteers received naltrexone which can enhance absorption

Regimen Dosage Form AUC (ng·hr/mL) Cmax (ng/mL) Tmax (hrs) Trough Conc. (ng/mL)
Single Dose 10 mg Oxycodone hydrochloride extended-release tablets 100.7 [26.6] 10.6 [20.1] 2.7 [44.1] n.a.
20 mg Oxycodone hydrochloride extended-release tablets 207.5 [35.9] 21.4 [36.6] 3.2 [57.9] n.a.
40 mg Oxycodone hydrochloride extended-release tablets 423.1 [33.3] 39.3 [34.0] 3.1 [77.4] n.a.
80 mg Oxycodone hydrochloride extended-release tablets* 1085.5 [32.3] 98.5 [32.1] 2.1 [52.3] n.a.
Multiple Dose 10 mg Oxycodone hydrochloride extended-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]

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

* data obtained while volunteers received naltrexone which can enhance absorption

Regimen Dosage Form AUC4 (ng·hr/mL) Cmax (ng/mL) Tmax (hrs) Trough Conc. (ng/mL)
Single Dose 4 × 40 mg Oxycodone hydrochloride extended-release tablets* 1935.3 [34.7] 152.0 [28.9] 2.56 [42.3] n.a.
2 × 80 mg Oxycodone hydrochloride extended-release tablets* 1859.3 [30.1] 153.4 [25.1] 2.78 [69.3] n.a.
1 × 160 mg Oxycodone hydrochloride extended-release tablets* 1856.4 [30.5] 156.4 [24.8] 2.54 [36.4] n.a.

Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE NOT INDICATED FOR RECTAL ADMINISTRATION. Data from a study involving 21 normal volunteers show that Oxycodone hydrochloride extended-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 hydrochloride extended-release tablets.

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 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)

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.

Indications and Usage for Oxycodone

Oxycodone hydrochloride extended-release tablets are an extended-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 hydrochloride extended-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 Health 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 hydrochloride extended-release tablets are not indicated for pain in the immediate post-operative period (the first 12 to 24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. Oxycodone hydrochloride extended-release tablets are only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative 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 hydrochloride extended-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 hydrochloride extended-release tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.

Warnings

Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR CRUSHED. TAKING BROKEN, CHEWED OR CRUSHED Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS COULD LEAD TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF Oxycodone.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets ARE FOR USE IN OPIOID-TOLERANT PATIENTS ONLY. This tablet strength may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

Oxycodone Hydrochloride Extended-Release 80 mg Tablets are for use only in opioid tolerant patients requiring daily Oxycodone equivalent dosages of 160 mg or more. Care should be taken in the prescribing of this tablet strength. 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 hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Oxycodone hydrochloride extended-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. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

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 hydrochloride extended-release tablets are a mu-agonist opioid with an abuse liability similar to morphine and are 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. 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 hydrochloride extended-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 hydrochloride extended-release tablets are 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 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 hydrochloride extended-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 hydrochloride extended-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 hydrochloride extended-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 hydrochloride extended-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 hydrochloride extended-release tablets.

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) 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 Post-Operative Use

Oxycodone hydrochloride extended-release tablets are not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).

Oxycodone hydrochloride extended-release tablets are not indicated for pain in the immediate post-operative 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 hydrochloride extended-release tablets are not indicated for pain in the post-operative period if the pain is mild or not expected to persist for an extended period of time.

Oxycodone hydrochloride extended-release tablets are only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative 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 hydrochloride extended-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 (see DOSAGE AND ADMINISTRATION).

Oxycodone hydrochloride extended-release tablets and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative 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 (see PATIENT INFORMATION at the end of the package insert)

If clinically advisable, patients receiving Oxycodone hydrochloride extended-release tablets or their caregivers should be given the following information by the physician, nurse, pharmacist, or caregiver:

  1. Patients should be aware that Oxycodone hydrochloride extended-release tablets contain Oxycodone, which is a morphine-like substance.
  2. Patients should be advised that Oxycodone hydrochloride extended-release tablets were designed to work properly only if swallowed whole. Oxycodone hydrochloride extended-release tablets will release all their contents at once if broken, chewed or crushed, resulting in a risk of fatal overdose.
  3. 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.
  4. Patients should be advised not to adjust the dose of Oxycodone hydrochloride extended-release tablets without consulting the prescribing professional.
  5. Patients should be advised that Oxycodone hydrochloride extended-release tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
  6. Patients should not combine Oxycodone hydrochloride extended-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.
  7. 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.
  8. Patients should be advised that Oxycodone hydrochloride extended-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.
  9. Patients should be advised that if they have been receiving treatment with Oxycodone hydrochloride extended-release tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Oxycodone hydrochloride extended-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.
  10. Patients should be instructed to keep Oxycodone hydrochloride extended-release tablets in a secure place out of the reach of children. When Oxycodone hydrochloride extended-release tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.

Use in Drug and Alcohol Addiction

Oxycodone hydrochloride extended-release tablets are an opioid with no approved use in the management of addictive disorders. Their 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 hydrochloride extended-release tablets, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

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 hydrochloride extended-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 mcg, chromosomal aberration test in human lymphocytes in the absence of metabolic activation at doses of up to 1500 mcg/mL and with activation 48 hours after exposure at doses of up to 5000 mcg/mL, and in the in vivo bone marrow micronucleus test in mice (at plasma levels of up to 48 mcg/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 mcg/mL) at 24 but not 48 hours of exposure and in the mouse lymphoma assay at doses of 50 mcg/mL or greater with metabolic activation and at 400 mcg/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 hydrochloride extended-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 hydrochloride extended-release tablets because of the possibility of sedation and/or respiratory depression in the infant.

Pediatric Use

Safety and effectiveness of Oxycodone hydrochloride extended-release tablets have not been established in pediatric patients below the age of 18. It must be remembered that Oxycodone hydrochloride extended-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 PHARMACOKINETICSAND METABOLISM). Of the total number of subjects (445) in clinical studies of Oxycodone hydrochloride extended-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 hydrochloride extended-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 hydrochloride extended-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 plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials.

Adverse Reactions

The safety of Oxycodone hydrochloride extended-release tablets was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received Oxycodone hydrochloride extended-release tablets in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day.

Serious adverse reactions which may be associated with Oxycodone hydrochloride extended-release tablet therapy in clinical use are those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, and (to an even lesser degree) circulatory depression, hypotension, or shock (see OVERDOSAGE).

The non-serious adverse events seen on initiation of therapy with Oxycodone hydrochloride extended-release tablets are typical opioid side effects. These events are dose-dependent, and their frequency depends upon the dose, the clinical setting, the patient"s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent (>5%) include: constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, sweating, and asthenia.

In many cases the frequency of these events during initiation of therapy may be minimized by careful individualization of starting dosage, slow titration, and the avoidance of large swings in the plasma concentrations of the opioid. Many of these adverse events will cease or decrease in intensity as Oxycodone hydrochloride extended-release tablets therapy is continued and some degree of tolerance is developed.

Clinical trials comparing Oxycodone hydrochloride extended-release tablets with immediate-release Oxycodone and placebo, revealed a similar adverse event profile between Oxycodone hydrochloride extended-release tablets and immediate-release Oxycodone. The most common adverse events (>5%) reported by patients at least once during therapy were:

Table 3
Oxycodone Hydrochloride Extended-Release Tablets (n=227) Oxycodone Hydrochloride Immediate-Release Tablets (n=225) Placebo (n=45)
(%) (%) (%)
Constipation 23 26 7
Nausea 23 27 11
Somnolence 23 24 4
Dizziness 13 16 9
Pruritus 13 12 2
Vomiting 12 14 7
Headache 7 8 7
Dry Mouth 6 7 2
Asthenia 6 7 --
Sweating 5 6 2

The following adverse experiences were reported in Oxycodone hydrochloride extended-release tablets treated patients with an incidence between 1% and 5%. In descending order of frequency they were anorexia, nervousness, insomnia, fever, confusion, diarrhea, abdominal pain, dyspepsia, rash, anxiety, euphoria, dyspnea, postural hypotension, chills, twitching, gastritis, abnormal dreams, thought abnormalities, and hiccups.

The following adverse reactions occurred in less than 1% of patients involved in clinical trials or were reported in post marketing experience:

General: accidental injury, chest pain, facial edema, malaise, neck pain, pain, and symptoms associated with either an anaphylactic or anaphylactoid reaction

Cardiovascular: migraine, syncope, vasodilation, ST depression

Digestive: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, nausea and vomiting, stomatitis, ileus

Hemic and Lymphatic: lymphadenopathy

Metabolic and Nutritional: dehydration, edema, hyponatremia, peripheral edema, syndrome of inappropriate antidiuretic hormone secretion, thirst

Nervous: abnormal gait, agitation, amnesia, depersonalization, depression, emotional lability, hallucination, hyperkinesia, hypesthesia, hypotonia, malaise, paresthesia, seizures, speech disorder, stupor, tinnitus, tremor, vertigo, withdrawal syndrome with or without seizures

Respiratory: cough increased, pharyngitis, voice alteration

Skin: dry skin, exfoliative dermatitis, urticaria

Special Senses: abnormal vision, taste perversion

Urogenital: amenorrhea, decreased libido, dysuria, hematuria, impotence, polyuria, urinary retention, urination impaired

Overdosage

Acute overdosage with Oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.

Deaths due to overdose have been reported with abuse and misuse of Oxycodone hydrochloride extended-release tablets, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when Oxycodone hydrochloride extended-release tablets are abused concurrently with alcohol or other CNS depressants, including other opioids.

In the treatment of Oxycodone overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

The pure opioid antagonists such as naloxone or nalmefene are specific antidotes against respiratory depression from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Oxycodone overdose. In patients who are physically dependent on any opioid agonist including Oxycodone hydrochloride extended-release tablets, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

Oxycodone Dosage and Administration

General Principles

Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE AN OPIOID AGONIST AND A SCHEDULE II CONTROLLED SUBSTANCE WITH AN ABUSE LIABILITY SIMILAR TO MORPHINE.

Oxycodone, LIKE MORPHINE AND OTHER OPIOIDS USED IN ANALGESIA, CAN BE ABUSED AND IS SUBJECT TO CRIMINAL DIVERSION.

Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS ARE TO BE SWALLOWED WHOLE, AND ARE NOT TO BE BROKEN, CHEWED OR CRUSHED. TAKING BROKEN, CHEWED OR CRUSHED Oxycodone HYDROCHLORIDE EXTENDED-RELEASE TABLETS LEADS TO THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF Oxycodone.

In treating pain it is vital to assess the patient regularly and systematically. Therapy should also be regularly reviewed and adjusted based upon the patient"s own reports of pain and side effects and the health professional"s clinical judgment.

Oxycodone hydrochloride extended-release tablets are indicated for the management of moderate to severe pain requiring treatment with a strong opioid for continuous, around-the-clock analgesia for an extended period of time. The extended-release nature of the formulation allows the Oxycodone hydrochloride extended-release tablets to be effectively administered every 12 hours (see CLINICAL PHARMACOLOGY; PHARMACOKINETICS ANDMETABOLISM). While symmetric (same dose AM and PM), around-the-clock, q12h dosing is appropriate for the majority of patients, some patients may benefit from asymmetric (different dose given in AM than in PM) dosing, tailored to their pain pattern. It is usually appropriate to treat a patient with only one opioid for around-the-clock therapy.

Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Guidelines. Health care professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring [See BOXEDWARNINGS].

Initiation of Therapy

It is critical to initiate the dosing regimen for each patient individually, taking into account the patient"s prior opioid and non-opioid analgesic treatment. Attention should be given to:

  1. the general condition and medical status of the patient;
  2. the daily dose, potency and kind of the analgesic(s) the patient has been taking;
  3. the reliability of the conversion estimate used to calculate the dose of Oxycodone;
  4. the patient"s opioid exposure and opioid tolerance (if any);
  5. special safety issues associated with conversion to Oxycodone hydrochloride extended-release tablets doses at or exceeding 160 mg q12h (see Special instructions for Oxycodone Hydrochloride Extended-Release Tablets, 80 mg); and
  6. the balance between pain control and adverse experiences.

Care should be taken to use low initial doses of Oxycodone hydrochloride extended-release tablets in patients who are not already opioid-tolerant, especially those who are receiving concurrent treatment with muscle relaxants, sedatives, or other CNS active medications (see PRECAUTIONS: Drug-Drug Interactions).

For initiation of Oxycodone hydrochloride extended-release tablets therapy for patients previously taking opioids, the conversion ratios from Foley, KM. [NEJM, 1985; 313:84-95], found below, are a reasonable starting point, although not verified in well-controlled, multiple-dose trials.

Oxycodone hydrochloride extended-release tablets should be individually titrated to a dose that provides adequate analgesia and minimizes side effects.

  1. Using standard conversion ratio estimates (see Table 4 below), multiply the mg/day of the previous opioids by the appropriate multiplication factors to obtain the equivalent total daily dose of oral Oxycodone.
  2. When converting from Oxycodone, divide this 24-hour Oxycodone dose in half to obtain the twice a day (q12h) dose of Oxycodone hydrochloride extended-release tablets.
  3. Round down to a dose which is appropriate for the tablet strength available (80 mg tablets).
  4. Discontinue all other around-the-clock opioid drugs when Oxycodone hydrochloride extended-release tablets therapy is initiated.
  5. No fixed conversion ratio is likely to be satisfactory in all patients, especially patients receiving large opioid doses. The recommended doses shown in Table 4 are only a starting point, and close observation and frequent titration are indicated until patients are stable on the new therapy.
Table 4: Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Daily Dose of Oral Oxycodone* (Mg/Day Prior Opioid × Factor = Mg/Day Oral Oxycodone)
Oral Prior Opioid Parenteral Prior Opioid
Oxycodone 1 --
Codeine 0.15 --
Hydrocodone 0.9 --
Hydromorphone 4 20
Levorphanol 7.5 15
Meperidine 0.1 0.4
Methadone 1.5 3
Morphine 0.5 3

* To be used only for conversion to oral Oxycodone. For patients receiving high-dose parenteral opioids, a more conservative conversion is warranted. For example, for high-dose parenteral morphine, use 1.5 instead of 3 as a multiplication factor.

In all cases, supplemental analgesia (see below) should be made available in the form of a suitable short-acting analgesic.

Oxycodone hydrochloride extended-release tablets can be safely used concomitantly with usual doses of non-opioid analgesics and analgesic adjuvants, provided care is taken to select a proper initial dose (see PRECAUTIONS).

Conversion from Transdermal Fentanyl to Oxycodone Hydrochloride Extended-Release Tablets

Eighteen hours following the removal of the transdermal fentanyl patch, Oxycodone hydrochloride extended-release tablets treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative Oxycodone dose, approximately 10 mg q12h of Oxycodone hydrochloride extended release tablets should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. The patient should be followed closely for early titration, as there is very limited clinical experience with this conversion.

Managing Expected Opioid Adverse Experiences

Most patients receiving opioids, especially those who are opioid-naive, will experience side effects. Frequently the side effects from Oxycodone hydrochloride extended-release tablets are transient, but may require evaluation and management. Adverse events such as constipation should be anticipated and treated aggressively and prophylactically with a stimulant laxative and/or stool softener. Patients do not usually become tolerant to the constipating effects of opioids.

Other opioid-related side effects such as sedation and nausea are usually self-limited and often do not persist beyond the first few days. If nausea persists and is unacceptable to the patient, treatment with anti-emetics or other modalities may relieve these symptoms and should be considered.

Individualization of Dosage

Once therapy is initiated, pain relief and other opioid effects should be frequently assessed. Patients should be titrated to adequate effect (generally mild or no pain with the regular use of no more than two doses of supplemental analgesia per 24 hours). Patients who experience breakthrough pain may require dosage adjustment or rescue medication. Because steady-state plasma concentrations are approximated within 24 to 36 hours, dosage adjustment may be carried out every 1 to 2 days. It is most appropriate to increase the q12h dose, not the dosing frequency. There is no clinical information on dosing intervals shorter than q12h. As a guideline, except for the increase from 10 mg to 20 mg q12h, the total daily Oxycodone dose usually can be increased by 25% to 50% of the current dose at each increase.

If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. If this adjustment leads to inadequate analgesia, a supplemental dose of immediate-release Oxycodone may be given. Alternatively, non-opioid analgesic adjuvants may be employed. Dose adjustments should be made to obtain an appropriate balance between pain relief and opioid-related adverse experiences.

If significant adverse events occur before the therapeutic goal of mild or n



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