Oxycodone ER

Generic Name: oxycodone hydrochloride

Dosage Form: tablet, film coated, extended release
OXYCODONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS, 80 mg CII

0033

Rx only

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 ER 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 ER - 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 ER

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 PHARMACOKINETICS AND 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

oxycodone and ibuprofen

eye-bue-PROE-fen, ox-i-KOE-done hye-droe-KLOR-ide

Oral route(Tablet)

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. Ibuprofen/oxycodone hydrochloride is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal adverse events especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal .

Commonly used brand name(s)

In the U.S.

• Combunox

Available Dosage Forms:

• Tablet

Therapeutic Class: Opioid/NSAID Combination

Pharmacologic Class: NSAID

Chemical Class: Propionic Acid (class)

Uses For oxycodone and ibuprofen

Ibuprofen and oxycodone combination is used to relieve acute, moderate to severe pain.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) used in this combination to relieve inflammation, swelling, and pain.

Oxycodone is a narcotic analgesic that acts in the central nervous system to relieve pain. If oxycodone is used for a long time, it may become habit-forming (causing mental or physical dependence). Physical dependence may lead to withdrawal side effects when you stop taking the medicine. Since ibuprofen and oxycodone combination is only used for short-term (7 days or less) relief of pain, physical dependence probably will not occur.

oxycodone and ibuprofen is available only with your doctor's prescription.

Before Using oxycodone and ibuprofen

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For oxycodone and ibuprofen, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to oxycodone and ibuprofen or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ibuprofen and oxycodone combination in children below 14 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oxycodone and ibuprofen combination in the elderly. However, elderly patients who may be more sensitive than younger adults to the effects of ibuprofen and oxycodone combination, are more likely to have kidney, lung, or stomach problems, which may require caution in patients receiving oxycodone and ibuprofen combination.

Pregnancy

	Pregnancy Category	Explanation
1st Trimester	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.
2nd Trimester	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.
3rd Trimester	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using oxycodone and ibuprofen.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking oxycodone and ibuprofen, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using oxycodone and ibuprofen with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Ketorolac


• Naltrexone


• Pentoxifylline

Using oxycodone and ibuprofen with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Acetophenazine


• Adinazolam


• Alfentanil


• Alprazolam


• Amobarbital


• Anileridine


• Aprobarbital


• Ardeparin


• Argatroban


• Atazanavir


• Beta Glucan


• Bivalirudin


• Brofaromine


• Bromazepam


• Brotizolam


• Buprenorphine


• Buspirone


• Butabarbital


• Butalbital


• Butorphanol


• Carisoprodol


• Certoparin


• Chloral Hydrate


• Chlordiazepoxide


• Chlorpromazine


• Chlorzoxazone


• Cilostazol


• Citalopram


• Clarithromycin


• Clobazam


• Clonazepam


• Clopidogrel


• Clorazepate


• Clorgyline


• Clovoxamine


• Codeine


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Dantrolene


• Desflurane


• Desirudin


• Dexmedetomidine


• Dezocine


• Diazepam


• Diphenhydramine


• Dipyridamole


• Doxylamine


• Enflurane


• Enoxaparin


• Erythromycin


• Escitalopram


• Estazolam


• Eszopiclone


• Ethchlorvynol


• Ethopropazine


• Femoxetine


• Fentanyl


• Flesinoxan


• Flumazenil


• Flunitrazepam


• Fluoxetine


• Fluphenazine


• Flurazepam


• Fluvoxamine


• Fondaparinux


• Fospropofol


• Furazolidone


• Ginkgo


• Halazepam


• Halothane


• Heparin


• Hydrocodone


• Hydromorphone


• Hydroxyzine


• Indinavir


• Iproniazid


• Isocarboxazid


• Isoflurane


• Itraconazole


• Ketamine


• Ketazolam


• Ketoconazole


• Lazabemide


• Lepirudin


• Levorphanol


• Linezolid


• Lorazepam


• Lormetazepam


• Medazepam


• Meperidine


• Mephenesin


• Mephobarbital


• Meprobamate


• Mesoridazine


• Metaxalone


• Methdilazine


• Methocarbamol


• Methohexital


• Methotrexate


• Midazolam


• Moclobemide


• Morphine


• Morphine Sulfate Liposome


• Nadroparin


• Nalbuphine


• Nefazodone


• Nelfinavir


• Nialamide


• Nitrazepam


• Nitrous Oxide


• Nordazepam


• Opium


• Oxazepam


• Oxycodone


• Oxymorphone


• Pargyline


• Parnaparin


• Paroxetine


• Pemetrexed


• Pentazocine


• Pentobarbital


• Perphenazine


• Phenelzine


• Phenobarbital


• Prazepam


• Procarbazine


• Prochlorperazine


• Promazine


• Promethazine


• Propiomazine


• Propofol


• Propoxyphene


• Protein C


• Quazepam


• Ramelteon


• Rasagiline


• Remifentanil


• Reviparin


• Ritonavir


• Rivaroxaban


• Saquinavir


• Secobarbital


• Selegiline


• Sertraline


• Sevoflurane


• Sibutramine


• Sodium Oxybate


• Sufentanil


• Tacrolimus


• Tapentadol


• Telithromycin


• Temazepam


• Thiethylperazine


• Thiopental


• Thioridazine


• Ticlopidine


• Tinzaparin


• Tirofiban


• Toloxatone


• Tranylcypromine


• Triazolam


• Trifluoperazine


• Triflupromazine


• Trimeprazine


• Vilazodone


• Zaleplon


• Zimeldine


• Zolpidem

Using oxycodone and ibuprofen with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Acetohexamide


• Alacepril


• Alprenolol


• Amikacin


• Amiloride


• Arotinolol


• Aspirin


• Atenolol


• Azilsartan Medoxomil


• Azosemide


• Befunolol


• Bemetizide


• Benazepril


• Bendroflumethiazide


• Benzthiazide


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Bucindolol


• Bumetanide


• Bupranolol


• Buthiazide


• Candesartan Cilexetil


• Canrenoate


• Captopril


• Carteolol


• Carvedilol


• Celiprolol


• Chlorothiazide


• Chlorpropamide


• Chlorthalidone


• Cilazapril


• Clopamide


• Cyclopenthiazide


• Cyclosporine


• Delapril


• Desipramine


• Desvenlafaxine


• Dilevalol


• Duloxetine


• Enalaprilat


• Enalapril Maleate


• Eprosartan


• Esmolol


• Ethacrynic Acid


• Fosinopril


• Furosemide


• Gliclazide


• Glimepiride


• Glipizide


• Gliquidone


• Glyburide


• Hydrochlorothiazide


• Hydroflumethiazide


• Imidapril


• Indapamide


• Irbesartan


• Labetalol


• Landiolol


• Levobetaxolol


• Levobunolol


• Lisinopril


• Lithium


• Losartan


• Mepindolol


• Methyclothiazide


• Metipranolol


• Metolazone


• Metoprolol


• Miconazole


• Milnacipran


• Moexipril


• Nadolol


• Nebivolol


• Nipradilol


• Olmesartan Medoxomil


• Oxprenolol


• Penbutolol


• Pentopril


• Perindopril


• Phenytoin


• Pindolol


• Piretanide


• Polythiazide


• Propranolol


• Quinapril


• Ramipril


• Rifampin


• Sotalol


• Spirapril


• Spironolactone


• St John's Wort


• Tacrine


• Talinolol


• Tasosartan


• Telmisartan


• Temocapril


• Tertatolol


• Timolol


• Tolazamide


• Tolbutamide


• Torsemide


• Trandolapril


• Triamterene


• Trichlormethiazide


• Valsartan


• Venlafaxine


• Voriconazole


• Xipamide


• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using oxycodone and ibuprofen with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use oxycodone and ibuprofen, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of oxycodone and ibuprofen. Make sure you tell your doctor if you have any other medical problems, especially:

• Addison's disease (adrenal gland problem) or


• Alcohol abuse, history of or


• Brain disease or


• Depression or


• Enlarged prostate (BPH, prostatic hypertrophy) or


• Head injury or


• Hypothyroidism (underactive thyroid) or


• Kidney disease, severe or


• Kyphoscoliosis (curvature of spine that can cause breathing problems) or


• Liver disease, severe or


• Lung disease, severe or


• Problems with urination or


• Psychosis (mental illness) or


• Seizure disorders or


• Systemic lupus erythematosus (SLE) or


• Weakened physical condition—Use with caution. May increase risk for more serious side effects.

• Anemia or


• Breathing problems (e.g., asthma, hypercapnia, hypoxia) or


• Bleeding problems or


• Dehydration or


• Edema (fluid retention) or


• Heart attack, history of or


• Heart disease (e.g., congestive heart failure) or


• Hypertension (high blood pressure) or


• Hypotension (low blood pressure) or


• Kidney disease or


• Liver disease or


• Lung disease (e.g., chronic obstructive pulmonary disease [COPD], cor pulmonale) or


• Pancreatitis (inflammation of the pancreas) or


• Shock or


• Stomach ulcers or bleeding, history of or


• Stroke, history of—Use with caution. May make these conditions worse.

• Aspirin-sensitive asthma or


• Aspirin sensitivity, history of or


• Bronchial asthma, acute or severe, or other chronic lung disease or


• Hypercarbia (large amount of carbon dioxide in the blood) or


• Paralytic ileus (bowel blockage) or


• Respiratory depression (troubled breathing)—Should not be used in patients with these conditions.

• Drug abuse or dependence, or history of—Dependence may be more likely to develop.

• Heart surgery (e.g., coronary artery bypass graft [CABG])—Should not be used to relieve pain right before or after the surgery.

Proper Use of oxycodone and ibuprofen

For safe and effective use of oxycodone and ibuprofen, do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Taking too much of oxycodone and ibuprofen may increase the chance of unwanted effects.

oxycodone and ibuprofen should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of oxycodone and ibuprofen will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of oxycodone and ibuprofen. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For pain:
    
    • Adults and teenagers 14 years of age and older—One tablet every 4 to 6 hours as needed. However, the dose is usually not more than 4 tablets per day, and should not be taken for longer than 7 days, unless directed by your doctor.
    
    
    • Children and teenagers younger than 14 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of oxycodone and ibuprofen, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using oxycodone and ibuprofen

It is very important that your doctor check your progress while you are taking oxycodone and ibuprofen. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

Your doctor will want to check your blood pressure at the beginning of treatment and monitor it throughout treatment with oxycodone and ibuprofen. If high blood pressure occurs or worsens while taking oxycodone and ibuprofen, it may lead to serious heart problems.

oxycodone and ibuprofen may increase your risk of having a heart attack or stroke. This is more likely to occur in people who already have heart disease. People who use oxycodone and ibuprofen for a long time might also have a higher risk. Some signs of serious heart problems are chest pain, tightness in the chest, fast or irregular heartbeat, or unusual flushing or warmth of the skin. Stop taking oxycodone and ibuprofen and check with your doctor right away if you notice any of these warning signs.

Ibuprofen and oxycodone combination will add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicines for hay fever, allergies, or colds; sedatives, tranquilizers, sleeping medicine, or other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Do not drink alcoholic beverages, and check with your medical doctor or dentist before taking any of the medicines listed above, while you are using oxycodone and ibuprofen.

oxycodone and ibuprofen may cause bleeding in your stomach or intestines. This is more likely to occur if you have had a stomach ulcer in the past, if you smoke or drink alcohol regularly, are over 60 years of age, are in poor health, or are using certain other medicines (such as steroids or a blood thinner). These problems can occur at any time with or without warning, and can be fatal. You should contact your doctor immediately if any of the following symptoms occur including black, tarry stools; bloody stools; vomiting of blood or material that looks like coffee grounds; severe or continuing stomach pain, cramping, or burning; trouble breathing; severe or continuing nausea, heartburn and/or indigestion.

Liver problems may occur while you are using oxycodone and ibuprofen. Stop using oxycodone and ibuprofen and check with your doctor right away if you have more than one of these symptoms: abdominal pain or tenderness; clay-colored stools; dark urine; decreased appetite; fever; headache; itching; loss of appetite; nausea and vomiting; skin rash; swelling of the feet or lower legs; unusual tiredness or weakness; or yellow eyes or skin.

oxycodone and ibuprofen may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using oxycodone and ibuprofen.

Serious skin reactions can occur with oxycodone and ibuprofen. Check with your doctor right away if you have blistering, peeling, or loosening of the skin; red skin lesions; a severe skin rash or acne; sores or ulcers on the skin; or fever or chills while you are using oxycodone and ibuprofen.

Using oxycodone and ibuprofen during late pregnancy can harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away. Do not use oxycodone and ibuprofen during the later part of a pregnancy unless your doctor tells you to.

oxycodone and ibuprofen may cause some people to become drowsy, dizzy, lightheaded, or to feel a false sense of well-being. Make sure you know how you react to oxycodone and ibuprofen before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert and clearheaded. If these reactions are especially bothersome, check with your doctor.

Dizziness, lightheadedness, or fainting may occur, especially when getting up suddenly from a lying or sitting position. Getting up slowly may lessen this problem.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking oxycodone and ibuprofen.

Ibuprofen and oxycodone combination may cause dryness of the mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if dry mouth continues for more than 2 weeks, check with your dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Call your doctor right away if you have confusion, drowsiness, fever, a general feeling of illness, a headache, loss of appetite, nausea, a stiff neck or back, or vomiting. These could be symptoms of a serious condition called meningitis.

If you have heart disease or congestive heart failure (CHF), tell your doctor if you have unexplained weight gain or edema (fluid retention or body swelling) with oxycodone and ibuprofen.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

oxycodone and ibuprofen Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common

• Feeling faint, dizzy, or lightheaded


• feeling of warmth or heat


• flushing or redness of the skin, especially on the face and neck


• headache


• sweating

Rare

• Abdominal or stomach pain


• blurred vision


• changes in skin color


• chest pain


• confusion


• convulsions


• decrease in frequency of urination


• decreased urine


• difficulty with breathing


• difficulty in passing urine (dribbling)


• dizziness


• dizziness, faintness, or lightheadedness when getting up from a lying position


• dry mouth


• excessive muscle tone


• fainting


• fast heartbeat


• fast, pounding, or irregular heartbeat or pulse


• increased need to urinate


• increased thirst


• loss of appetite


• mood changes


• muscle pain or cramps


• muscle stiffness


• muscle tension or tightness


• nausea or vomiting


• numbness or tingling in the hands, feet, or lips


• pain, tenderness, or swelling of the foot or leg


• painful urination


• pale skin


• passing urine more often


• severe constipation


• severe vomiting


• shortness of breath


• troubled breathing with exertion


• unusual bleeding or bruising


• unusual tiredness or weakness


• weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Change in consciousness


• chest pain or discomfort


• cold and clammy skin


• constricted pupils


• continuing ringing or buzzing or other unexplained noise in the ears


• decreased awareness or responsiveness


• difficult or troubled breathing


• difficulty with sleeping


• disorientation


• drowsiness to profound coma


• fainting


• hallucination


• hearing loss


• irregular, fast or slow, or shallow breathing


• lethargy


• loss of bladder control


• loss of consciousness


• muscle spasm or jerking of all extremities


• pale or blue lips, fingernails, or skin


• severe sleepiness


• skeletal muscle flaccidity


• sleepiness or unusual drowsiness


• sudden fainting


• sudden loss of consciousness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Acid or sour stomach


• belching


• bloated full feeling


• diarrhea


• difficulty having a bowel movement (stool)


• excess air or gas in the stomach or intestines


• fever


• heartburn


• indigestion


• lack or loss of strength


• passing gas


• stomach discomfort, upset, or pain

Rare

• Back pain


• body aches or pain


• bruising, large, flat, blue or purplish patches in the skin


• changes in vision


• chills


• congestion


• cough or hoarseness


• delusions


• dementia


• difficult urination


• difficulty with moving


• dryness or soreness of the throat


• enlarged abdomen or stomach


• false or unusual sense of well-being


• fear


• hoarseness


• impaired vision


• increase in body movements


• lower back or side pain


• nervousness


• pain, swelling, or redness in the joints


• rash


• runny nose


• sleeplessness


• swelling


• taste perversion


• tender, swollen glands in the neck


• trouble with sleeping


• trouble with swallowing


• unable to sleep


• voice changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: oxycodone and ibuprofen side effects (in more detail)

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Compare oxycodone and ibuprofen with other medications

• Pain

Oxycodone

Dosage Form: tablet
Oxycodone HYDROCHLORIDE TABLETS, USP


CII


Rx Only

DESCRIPTION

Oxycodone Hydrochloride Tablets, USP are an opioid analgesic.

Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg or 30 mg of Oxycodone hydrochloride, USP.

Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine.  Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7).

Chemically, Oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula:

The tablets contain the following inactive ingredients: Microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate.

The 5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg and 27 mg, respectively, of Oxycodone free base.

CLINICAL PHARMACOLOGY

Pharmacology:

The analgesic ingredient, Oxycodone, is a semi-synthetic narcotic with multiple actions qualitatively similar to those of morphine; the most prominent of these involves the central nervous system and organs composed of smooth muscle.

Oxycodone, as the hydrochloride salt, is a pure agonist opioid whose principal therapeutic action is analgesia and has been in clinical use since 1917. Like all pure opioid agonists, there is no ceiling effect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Based upon a single-dose, relative-potency study conducted in humans with cancer pain, 10 to 15 mg of Oxycodone given intramuscularly produced an analgesic effect similar to 10 mg of morphine given intramuscularly. Both drugs have a 3 to 4 hour duration of action. Oxycodone retains approximately one half of its analgesic activity when administered orally.

Effects on 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. A significant feature of opioid-induced analgesia is that it occurs without loss of consciousness. The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities, (e.g., touch, vibrations, vision, hearing, etc.) are not obtunded.

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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on Gastrointestinal Tract And Other Smooth Muscle: Oxycodone, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla. The frequency and severity of emesis gradually diminishes with time.

Oxycodone may cause a decrease in the secretion of hydrochloric acid in the stomach that reduces motility while increasing the tone of the antrum, stomach, and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on Cardiovascular System: Oxycodone, in therapeutic doses, produces peripheral vasodilatation (arteriolar and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Caution should be used in hypovolemic patients, such as those suffering acute myocardial infarction, because Oxycodone may cause or further aggravate their hypotension. Caution should also be used in patients with cor pulmonale who have received therapeutic doses of opioids.

Pharmacodynamics:

The relationship between the plasma level of Oxycodone and the analgesic response will depend on the patient's age, state of health, medical condition and extent of previous opioid treatment.

The minimum effective plasma concentration of Oxycodone to achieve analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. Thus, patients need to be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of Oxycodone for any individual patient may increase with repeated dosing due to an increase in pain and/or development of tolerance.

Pharmacokinetics:

The activity of Oxycodone Hydrochloride Tablets is primarily due to the parent drug Oxycodone. Oxycodone Hydrochloride Tablets are designed to provide immediate release of Oxycodone.

Table 1: Pharmacokinetic Parameters (Mean±SD)

DoseParameters	AUC (ngxhr/mL)	Cmax (ng/mL)	Tmax (hr)	Cmin (ng/mL)	Cavg (ng/mL)	Half-Life(hr)
Single Dose    Pharmacokinetics
Oxycodone HCl 5 mg tabs x 3	133.2±33	22.3±8.2	1.8±1.8	n/a	n/a	3.73±0.9
Oxycodone HCl 15 mg tab	128.2±35.1	22.2±7.6	1.4±0.7	n/a	n/a	3.55±1.0
Oxycodone HCl Liquid Concentrate 15 mg oral solution	130.6±34.7	21.1±6.1	1.9±1.5	n/a	n/a	3.71±0.8
Oxycodone HCl 30 mg tab	268.2±60.7	39.3±14.0	2.6±3.0	n/a	n/a	3.85±1.3
Food-Effect, Single Dose
Oxycodone HCl 10 mg/10 mL oral sol'n (fasted)	105±6.2	19.0±3.7	1.25±0.5	n/a	n/a	2.9±0.4
Oxycodone HCl 10 mg/10 mL oral sol'n (fed)	133±25.2	17.7±3.0	2.54±1.2	n/a	n/a	3.3±0.5
Multiple-Dose Studies	AUC (72-84)
Oxycodone HCl 5 mg tabs    q6h x 14 doses	113.3±24.0	15.7±3.2	1.3±0.3	7.4±1.8	9.4±2.0	n/a
Oxycodone HCl 3.33 mg (3.33 mL)    oral sol'n. q4h x 21 doses	99.0±24.8	12.9±3.1	1.0±0.3	7.2±2.3	9.7±2.6	n/a

Absorption: About 60% to 87% of an oral dose of Oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of Oxycodone. The relative oral bioavailability of Oxycodone Hydrochloride 15 mg and 30 mg Tablets compared to the 5 mg Oxycodone Hydrochloride Tablets is 96% and 101% respectively. Oxycodone Hydrochloride 15 mg Tablets and 30 mg Tablets are bioequivalent to the 5 mg Oxycodone Hydrochloride Tablets (see Table 1 for pharmacokinetic parameters). Dose proportionality of Oxycodone has been established using the Oxycodone Hydrochloride 5mg Tablets at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of Oxycodone with Oxycodone Hydrochloride Tablets.

Figure 1 – Oxycodone Hydrochloride Tablets, USP  Dose-Proportionality Study 5mg, 15mg, 30mg (single-dose)

Food Effect: A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of Oxycodone absorption from the oral solution (see Table 1). In addition, food caused a delay in Tmax (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets.

Distribution: Following intravenous administration, the volume of distribution (Vss) for Oxycodone was 2.6 L/kg. Plasma protein binding of Oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk (see PRECAUTIONS-Nursing Mothers.)

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. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present.

The formation of oxymorphone, but not norOxycodone, is mediated by CYP2D6 and as such its formation can, in theory, be affected by other drugs (see PRECAUTIONS-Drug Interactions.)

Elimination: 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. Apparent elimination half-life of Oxycodone following the administration of Oxycodone Hydrochloride Tablets was 3.5 to 4 hours.

Special Populations:

Geriatric: Population pharmacokinetic studies conducted with Oxycodone Hydrochloride Tablets indicated that the plasma concentrations of Oxycodone did not appear to be increased in patients over the age of 65.

Gender: Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of Oxycodone from Oxycodone Hydrochloride Tablets.

Race: Population pharmacokinetic analyses support the lack of race effect on Oxycodone pharmacokinetics after administration of Oxycodone Hydrochloride Tablets but these data should be interpreted conservatively, since the majority of patients enrolled into the studies were Caucasians (94%).

Renal Insufficiency: In a clinical trial supporting the development of Oxycodone Hydrochloride Tablets, too few patients with decreased renal function were evaluated to study these potential differences. In previous studies, patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations of Oxycodone in the plasma that were higher than in subjects with normal renal function. Based on information available on the metabolism and excretion of Oxycodone, dose initiation in patients with renal impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

Hepatic Failure: In a clinical trial supporting the development of Oxycodone Hydrochloride Tablets, too few patients with decreased hepatic function were evaluated to study these potential differences; however, since Oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

INDICATIONS AND USAGE

Oxycodone Hydrochloride Tablets, USP are an immediate-release oral formulation of Oxycodone hydrochloride indicated for the management of moderate to severe pain where the use of an opioid analgesic is appropriate.

CONTRAINDICATIONS

Oxycodone Hydrochloride 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 Tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.

WARNINGS

Respiratory Depression:

Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently 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 Hydrochloride Tablets should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Oxycodone Hydrochloride Tablets 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.

Hypotensive Effect:

Oxycodone Hydrochloride Tablets, like all opioid analgesics, may cause severe hypotension in an individual 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 Hydrochloride Tablets may produce orthostatic hypotension in ambulatory patients. Oxycodone Hydrochloride Tablets, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.

Head Injury and Increased Intracranial Pressure:

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

PRECAUTIONS

General:

Oxycodone Hydrochloride Tablets are intended for use in patients who require oral pain therapy with an opioid agonist. As with any opioid analgesic, it is critical to adjust the dosing regimen individually for each patient (see DOSAGE AND ADMINISTRATION).

Selection of patients for treatment with Oxycodone Hydrochloride Tablets should be governed by the same principles that apply to the use of other potent opioid analgesics. Opioid analgesics given on a fixed-dosage schedule have a narrow therapeutic index in certain patient populations, especially when combined with other 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. Physicians should individualize treatment in every case, using nonopioid analgesics, prn opioids and /or combination products, and chronic opioid therapy with drugs such as Oxycodone Hydrochloride Tablets in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Care Policy and Research, and the American Pain Society.

Use of Oxycodone Hydrochloride 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); convulsive disorders; 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 Hydrochloride Tablets, like all opioid analgesics, 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.

Tolerance and Physical Dependence:

Physical dependence and tolerance are not unusual during chronic opioid therapy. Significant tolerance should not occur in most patients treated with the lowest doses of Oxycodone.  It should be expected, however, that a fraction of patients will develop some degree of tolerance and require progressively higher dosages of Oxycodone Hydrochloride Tablets to maintain pain control during chronic treatment. The dosage should be selected according to the patient's individual analgesic response and ability to tolerate side effects. Tolerance to the analgesic effects of opioids is usually paralleled by tolerance to side effects except for constipation.

Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug or may be precipitated through the administration of drugs with opioid antagonist activity. If Oxycodone Hydrochloride Tablets are abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE).  If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of Oxycodone Hydrochloride Tablets combined with symptomatic support (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

Use In Pancreatic/Biliary Tract Disease:

Oxycodone Hydrochloride Tablets 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 Hydrochloride Tablets may cause increases in the serum amylase level.

Information for Patients/Caregivers:

If clinically advisable, patients (or their caregivers) receiving Oxycodone Hydrochloride Tablets should be given the following information by the physician, nurse, pharmacist or caregiver:

1. 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.


2. Patients should be advised not to adjust the dose of Oxycodone Hydrochloride Tablets without consulting the prescribing professional.


3. Patients should be advised that Oxycodone Hydrochloride Tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).


4. Patients should not combine Oxycodone Hydrochloride Tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.


5. 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.


6. Patients should be advised that Oxycodone Hydrochloride 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.


7. Patients should be advised that if they have been receiving treatment with Oxycodone Hydrochloride Tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Oxycodone Hydrochloride 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.

Drug Interactions:

Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent; however, clinicians should be aware of this possible interaction.

Neuromuscular Blocking Agents: Oxycodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

CNS Depressants: Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with Oxycodone Hydrochloride Tablets may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of Oxycodone Hydrochloride Tablets. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as Oxycodone Hydrochloride Tablets. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Oxycodone Hydrochloride Tablets and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs): MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of Oxycodone Hydrochloride Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term studies have not been performed in animals to evaluate the carcinogenic potential of Oxycodone Hydrochloride Tablets or Oxycodone. The possible effects on male or female fertility have not been studied in animals.

Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli ) or in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Pregnancy:

Teratogenic Effects:

Category B: Reproduction studies in Sprague-Dawley rats and New Zealand rabbits revealed that when Oxycodone was administered orally at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for adults on a mg/m2 basis) and 25 mg/kg (approximately 5 times the daily oral dose of 90 mg on a mg/m2 basis) respectively, was not teratogenic or embryo-fetal toxic. There are no adequate and well controlled studies of Oxycodone in pregnant women. Because animal reproductive studies are not always predictive of human responses, Oxycodone Hydrochloride Tablets should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects:

Neonates whose mothers have taken Oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.

Labor and Delivery:

Oxycodone Hydrochloride Tablets are not recommended for use in women during or immediately prior to labor. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. Neonates, whose mothers received opioid analgesics during labor, should be observed closely for signs of respiratory depression. A specific narcotic antagonist, naloxone, should be available for reversal of narcotic-induced respiratory depression in the neonate.

Nursing Mothers:

Oxycodone has been detected in breast milk. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving Oxycodone Hydrochloride Tablets since Oxycodone may be excreted in milk.

Pediatric Use:

The safety and efficacy of Oxycodone in pediatric patients have not been evaluated.

Geriatric Use:

Of the total number of subjects in clinical studies of Oxycodone Hydrochloride Tablets, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment:

Since Oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

Renal Impairment:

Published data reported that elimination of Oxycodone was impaired in end-stage renal failure. Mean elimination half-life was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Dose initiation should follow a conservative approach. Dosages should be adjusted according to the clinical situation.

Ambulatory Patients:

Oxycodone Hydrochloride Tablets may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.

ADVERSE REACTIONS

Oxycodone Hydrochloride Tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone Hydrochloride Tablets are associated with adverse experiences similar to those seen with other opioids.

Serious adverse reactions that may be associated with Oxycodone Hydrochloride Tablets therapy in clinical use are those observed with other opioid analgesics and include: Respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock (see OVERDOSE, WARNINGS).

The less severe adverse events seen on initiation of therapy with Oxycodone Hydrochloride Tablets are also typical opioid side effects. These events are dose dependent, and their frequency depends on 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 of these include nausea, constipation, vomiting, headache, and pruritus.

In many cases the frequency of adverse events during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse events will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.

In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving Oxycodone Hydrochloride Tablets, the following adverse events were recorded in Oxycodone Hydrochloride Tablets treated patients with an incidence ≥ 3%. In descending order of frequency they were: Nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

The following adverse experiences occurred in less than 3% of patients involved in clinical trials with Oxycodone:

Body as a Whole: Abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.

Cardiovascular: Deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.

Digestive: Anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.

Hemic and Lymphatic: Anemia and leukopenia.

Metabolic and Nutritional: Edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema.

Musculoskeletal: Arthralgia, arthritis, bone pain, myalgia and pathological fracture.

Nervous: Agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.

Respiratory: Bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.

Skin and Appendages: Herpes simplex, rash, sweating, and urticaria.

Special Senses: Amblyopia.

Urogenital: Urinary tract infection

DRUG ABUSE AND DEPENDENCE

Controlled Substance:

Oxycodone Hydrochloride Tablets contain Oxycodone, a mu-agonist opioid of the morphine type and is a Schedule II controlled substance. Oxycodone Hydrochloride Tablets, like other opioids used in analgesia, can be abused and are subject to criminal diversion.

Abuse:

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 addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Oxycodone Hydrochloride Tablets are intended for oral use only. Abuse of Oxycodone Hydrochloride Tablets poses a risk of overdose and death. The risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.

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.

OVERDOSAGE

Signs and Symptoms:

Acute overdose with Oxycodone Hydrochloride Tablets 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.

Treatment:

To treat Oxycodone Hydrochloride Tablets overdose, 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 narcotic antagonists, naloxone or nalmefene, are specific antidotes for opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to Oxycodone Hydrochloride Tablets overdose. If needed the appropriate dose of naloxone hydrochloride or nalmefene should be administered simultaneously with efforts at respiratory resuscitation (see package insert for each drug for the details). Since the duration of action of Oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Gastric emptying may be useful in removing unabsorbed drug.

Opioid antagonists should be administered cautiously to persons who are suspected to be physically dependent on any opioid agonist, including Oxycodone (see Opioid-Tolerant Individuals).

Opioid-Tolerant Individuals: In an individual physically dependent on opioids, administration of a usual dose of antagonist will precipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses.

DOSAGE AND ADMINISTRATION

Oxycodone Hydrochloride Tablets are intended for the management of moderate to severe pain in patients who require treatment with an oral opioid analgesic. The dose should be individually adjusted according to severity of pain, patient response and patient size. If the pain increases in severity, if analgesia is not adequate, or if tolerance occurs, a gradual increase in dosage may be required.

Patients who have not been receiving opioid analgesics should be started on Oxycodone Hydrochloride Tablets in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain. The dose should be titrated based upon the individual patient's response to their initial dose of Oxycodone Hydrochloride Tablets. Patients with chronic pain should have their dosage given on an around-the-clock basis to prevent the reoccurrence of pain rather than treating the pain after it has occurred. This dose can then be adjusted to an acceptable level of analgesia taking into account side effects experienced by the patient.

For control of severe chronic pain, Oxycodone Hydrochloride Tablets should be administered on a regularly scheduled basis, every 4-6 hours, at the lowest dosage level that will achieve adequate analgesia.

As with any potent opioid, it is critical to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. Although it is not possible to list every condition that is important to the selection of the initial dose of Oxycodone Hydrochloride Tablets, attention should be given to: 1) the daily dose, potency, and characteristics of a pure agonist or mixed agonist/antagonist the patient has been taking previously, 2)  the reliability of the relative potency estimate to calculate the dose of Oxycodone needed, 3)  the degree of opioid tolerance, 4)  the general condition and medical status of the patient, and 5) the balance between pain control and adverse experiences.

Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs:

When converting patients from fixed ratio opioid/non-opioid drug regimens a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of Oxycodone Hydrochloride Tablets in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose Oxycodone Hydrochloride Tablets should be based upon the most recent dose of opioid as a baseline for further titration of Oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia.

Patients Currently on Opioid Therapy:

If a patient has been receiving opioid-containing medications prior to taking Oxycodone Hydrochloride Tablets, the potency of the prior opioid relative to Oxycodone should be factored into the selection of the total daily dose (TDD) of Oxycodone.

In converting patients from other opioids to Oxycodone Hydrochloride Tablets close observation and adjustment of dosage based upon the patient's response to Oxycodone Hydrochloride Tablets is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of Oxycodone Hydrochloride Tablets may be necessary, especially in patients who have disease states that are changing rapidly.

Maintenance of Therapy:

Continual re-evaluation of the patient receiving Oxycodone Hydrochloride Tablets is important, with special attention to the maintenance of pain control and the relative incidence of side effects associated with therapy. If the level of pain increases, effort should be made to identify the source of increased pain, while adjusting the dose as described above to decrease the level of pain.

During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), the continued need for the use of opioid analgesics should be reassessed as appropriate.

Cessation of Therapy:

When a patient no longer requires therapy with Oxycodone Hydrochloride Tablets or other opioid analgesics for the treatment of their pain, it is important that therapy be gradually discontinued over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see Drug Abuse and Dependence section for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. It is not known at what dose of Oxycodone Hydrochloride Tablets that treatment may be discontinued without risk of the opioid abstinence syndrome.

HOW SUPPLIED

Oxycodone HYDROCHLORIDE TABLETS, USP are available as follows:

5 mg white to off-white round, biconvex tablets embossed with “R” above the bisect and “P” below on one side and “5” on the other side.

NDC 42858-001-10:  Unit Dose Packages of 100 (10X10)

NDC 42858-001-01:  Bottles of 100 tablets

10 mg white to off-white round, biconvex tablets embossed with “R” above the bisect and “P” below on one side and “10” on the other side

NDC 42858-002-10:  Unit Dose Packages of 100 (10X10)

NDC 42858-002-01:  Bottles of 100 tablets

15 mg white to off-white oval tablets embossed with “R” above the bisect and “P” below on one side and “15” on the other side.

NDC 42858-003-01:  Bottles of 100 tablets

20 mg white to off-white round, biconvex tablets embossed with “R” above the bisect and “P” below on one side and “20” on the other side

NDC 42858-004-01:  Bottles of 100 tablets

30 mg white to off-white round, biconvex tablets embossed with “R” above the bisect and “P” below on one side and “30” on the other side

NDC 42858-005-01:  Bottles of 100 tablets

Dispense in a tight, light-resistant container.

Protect from moisture.

DEA Order Form Required

Storage and Handling

Store at 25°C (77°F); excursions are permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]

Distributed by:

Rhodes Pharmaceuticals L.P.

Coventry, RI 02816

Manufactured by:

Purdue Pharmaceuticals L.P.

Wilson, NC 27893

Component No: 302427-0B

Rev. 11/2010

Package Label, Oxycodone Hydrochloride Tablets, USP – 5 mg Blister Card - 10 Tablets

Blister Card - 10 tablets                               NDC 42858-001-10

CII                                                                  Rx Only

Package Label, Oxycodone Hydrochloride Tablets, USP – 10 mg Blister Carton - 100 Tablets

Blister Carton - 100 tablets                         NDC 42858-002-10

CII                                                                  Rx Only

Package Label, Oxycodone Hydrochloride Tablets, USP – 15 mg– Bottle of 100 Tablets

Bottle of 100 tablets                                     NDC 42858-003-01

CII                                                                  Rx Only

Package Label, Oxycodone Hydrochloride Tablets, USP – 20 mg– Bottle of 100 Tablets

Bottle of 100 tablets                                     NDC 42858-004-01

CII                                                                  Rx Only

Package Label, Oxycodone Hydrochloride Tablets, USP – 30 mg– Bottle of 100 Tablets

Bottle of 100 tablets                                     NDC 42858-005-01

CII                                                                  Rx Only

Oxycodone HYDROCHLORIDE  Oxycodone hydrochloride  tablet