oxycodone HCl 40 MG 12 HR Extended Release Oral Tablet, Abuse Deterrent

DRUG INTERACTIONS

7 Mixed agonist/antagonist and partial agonist opioid analgesics: Avoid use with OXYCONTIN because they may reduce analgesic effect of OXYCONTIN or precipitate withdrawal symptoms. ( 7.4) 7.1 CNS Depressants The concomitant use of OXYCONTIN and other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma, or death. Monitor patients receiving CNS depressants and OXYCONTIN for signs of respiratory depression, sedation, and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration ( 2.2) and Warnings and Precautions ( 5.4)] . 7.2 Muscle Relaxants Oxycodone may enhance the neuromuscular blocking action of true skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and OXYCONTIN for signs of respiratory depression that may be greater than otherwise expected. 7.3 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 and 2D6 Because the CYP3A4 isoenzyme plays a major role in the metabolism of oxycodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations and result in increased or prolonged opioid effects. These effects could me more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If co-administration with OXYCONTIN is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology ( 12.3)]. Inducers of CYP3A4 CYP450 3A4 inducers may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with OXYCONTIN is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved. After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression [see Clinical Pharmacology ( 12.3)] . 7.4 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of oxycodone or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving OXYCONTIN. 7.5 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with enlarged prostates. 7.6 Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concurrently with anticholinergic drugs.

OVERDOSAGE

10 Clinical Presentation Acute overdosage with OXYCONTIN can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on OXYCONTIN. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in OXYCONTIN, carefully monitor the patient until spontaneous respiration is reliably reestablished. OXYCONTIN will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made 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 of the antagonist.

DESCRIPTION

11 OXYCONTIN (oxycodone hydrochloride extended-release tablets) is an opioid analgesic supplied in 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration. The tablet strengths describe the amount of oxycodone per tablet as the hydrochloride salt. The structural formula for oxycodone hydrochloride is as follows: The chemical name is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. Oxycodone is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL). It is slightly soluble in alcohol (octanol water partition coefficient 0.7). The 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg and 80 mg tablets contain the following inactive ingredients: butylated hydroxytoluene (BHT), hypromellose, polyethylene glycol 400, polyethylene oxide, magnesium stearate, titanium dioxide. The 10 mg tablets also contain hydroxypropyl cellulose. The 15 mg tablets also contain black iron oxide, yellow iron oxide, and red iron oxide. The 20 mg tablets also contain polysorbate 80 and red iron oxide. The 30 mg tablets also contain polysorbate 80, red iron oxide, yellow iron oxide, and black iron oxide. The 40 mg tablets also contain polysorbate 80 and yellow iron oxide. The 60 mg tablets also contain polysorbate 80, red iron oxide and black iron oxide. The 80 mg tablets also contain hydroxypropyl cellulose, yellow iron oxide and FD&C Blue #2/Indigo Carmine Aluminum Lake. OXYCONTIN Structure

CLINICAL STUDIES

14 A double-blind, placebo-controlled, fixed-dose, parallel group, two-week study was conducted in 133 patients with persistent, moderate to severe pain, who were judged as having inadequate pain control with their current therapy. In this study, OXYCONTIN 20 mg, but not 10 mg, was statistically significant in pain reduction compared with placebo.

HOW SUPPLIED

16 /STORAGE AND HANDLING OXYCONTIN (oxycodone hydrochloride extended-release tablets) 40 mg are film-coated, round, yellow-colored, bi-convex tablets debossed with OP on one side and 40 on the other and are supplied as child-resistant closure, opaque plastic bottles of 30. Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). Dispense in tight, light-resistant container. CAUTION DEA FORM REQUIRED

RECENT MAJOR CHANGES

Boxed Warning 04/2014 Indications and Usage ( 1) 04/2014 Dosage and Administration ( 2) 04/2014 Warnings and Precautions ( 5) 04/2014

GERIATRIC USE

8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology ( 12.3)] . Of the total number of subjects (445) in clinical studies of oxycodone hydrochloride controlled-release tablets, 148 (33.3%) were age 65 and older (including those age 75 and older) while 40 (9.0%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone hydrochloride controlled-release tablets. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. However, reduce the starting dose to 1/3 to 1/2 the usual dosage in debilitated, non-opioid-tolerant patients. Respiratory depression is the chief risk in elderly or debilitated patients, usually the result of large initial doses in patients who are not tolerant to opioids, or when opioids are given in conjunction with other agents that depress respiration. Titrate the dose of OXYCONTIN cautiously in these patients.

DOSAGE FORMS AND STRENGTHS

3 10 mg film-coated extended-release tablets (round, white-colored, bi-convex tablets debossed with OP on one side and 10 on the other) 15 mg film-coated extended-release tablets (round, gray-colored, bi-convex tablets debossed with OP on one side and 15 on the other) 20 mg film-coated extended-release tablets (round, pink-colored, bi-convex tablets debossed with OP on one side and 20 on the other) 30 mg film-coated extended-release tablets (round, brown-colored, bi-convex tablets debossed with OP on one side and 30 on the other) 40 mg film-coated extended-release tablets (round, yellow-colored, bi-convex tablets debossed with OP on one side and 40 on the other) 60 mg film-coated extended-release tablets* (round, red-colored, bi-convex tablets debossed with OP on one side and 60 on the other) 80 mg film-coated extended-release tablets* (round, green-colored, bi-convex tablets debossed with OP on one side and 80 on the other) * 60 mg and 80 mg tablets for use in opioid-tolerant patients only Extended-release tablets: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg ( 3)

INDICATIONS AND USAGE

1 OXYCONTIN is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve OXYCONTIN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve OXYCONTIN for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. OXYCONTIN is not indicated as an as-needed (prn) analgesicOXYCONTIN is not indicated as an as-needed (prn) analgesic OXYCONTIN is an opioid agonist product indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. ( 1) Limitations of Use Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release formulations, reserve OXYCONTIN for use in patients for whom alternative treatment options (e.g. non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1) OXYCONTIN is not indicated as an as-needed (prn) analgesic. ( 1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of OXYCONTIN in pediatric patients below the age of 18 years have not been established.

PREGNANCY

8.1 Pregnancy Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions ( 5.3)] . Teratogenic Effects – Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. OXYCONTIN should be used during pregnancy only if the potential benefit justifies the risk to the fetus. The effect of oxycodone in human reproduction has not been adequately studied. Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 0.5 and 15 times an adult human dose of 160 mg/day, respectively on a mg/m 2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups [see Nonclinical Toxicology ( 13.1)]. Non-Teratogenic Effects Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.4-times an adult human dose of 160 mg/day, on a mg/m 2 basis). However, body weight of these pups recovered.

NUSRING MOTHERS

8.3 Nursing Mothers Oxycodone has been detected in breast milk. Instruct patients not to undertake nursing while receiving OXYCONTIN. Do not initiate OXYCONTIN therapy while nursing because of the possibility of sedation or respiratory depression in the infant. Withdrawal signs can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

BOXED WARNING

WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse OXYCONTIN ® exposes patients and other users to the risks of opioid addiction , abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OXYCONTIN and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions ( 5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of OXYCONTIN. Monitor for respiratory depression, especially during initiation of OXYCONTIN or following a dose increase. Instruct patients to swallow OXYCONTIN tablets whole; crushing, chewing, or dissolving OXYCONTIN tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions ( 5.2)] . Accidental Ingestion Accidental ingestion of even one dose of OXYCONTIN, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions ( 5.2)] . Neonatal Opioid Withdrawal Syndrome Prolonged use of OXYCONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions ( 5.3)] . Cytochrome P450 3A4 Interaction The concomitant use of OXYCONTIN with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OXYCONTIN and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.14) and Clinical Pharmacology ( 12.3)] . WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION See full prescribing information for complete boxed warning. OXYCONTIN exposes users to risks of addictions, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing and monitor regularly for development of these behaviors and conditions. ( 5.1) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow OXYCONTIN tablets whole to avoid exposure to a potentially fatal dose of oxycodone. ( 5.2) Accidental ingestion of OXYCONTIN, especially in children, can result in a fatal overdose of oxycodone. ( 5.2) Prolonged use of OXYCONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.3) Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from OXYCONTIN. ( 5.14)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression and death. If coadminstration is required, consider dose reduction of one or both drugs. ( 5.4) Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. ( 5.5, 5.6) Hypotensive effects: Monitor during dose initiation and titration. ( 5.7) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of OXYCONTIN in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8) Use with caution in patients who have difficulty swallowing or have underlying GI disorders that may predispose them to obstruction. ( 5.9) Concomitant use of CYP3A4 inhibitors may increase opioid effects. ( 5.14) 5.1 Addiction, Abuse, and Misuse OXYCONTIN contains oxycodone, a Schedule II controlled substance. As an opioid, OXYCONTIN exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9)]. As modified-release products such as OXYCONTIN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence ( 9)] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OXYCONTIN. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse or misuse prior to prescribing OXYCONTIN, and monitor all patients receiving OXYCONTIN for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as OXYCONTIN, but use in such patients necessitates intensive counseling about the risks and proper use of OXYCONTIN along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse, or misuse of OXYCONTIN by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of oxycodone and can result in overdose and death [see Overdosage ( 10)]. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OXYCONTIN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information ( 17)] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10)] . Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OXYCONTIN, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OXYCONTIN and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of OXYCONTIN are essential [see Dosage and Administration ( 2)] . Overestimating the OXYCONTIN dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of OXYCONTIN, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of OXYCONTIN during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension and profound sedation, coma, or respiratory depression may result if OXYCONTIN is used concomitantly with other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of OXYCONTIN in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin OXYCONTIN therapy is made, start with 1/3 to 1/2 the usual dose of OXYCONTIN, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions ( 7.1) and Dosage and Administration ( 2.2)] . 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating OXYCONTIN and when OXYCONTIN is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2)] . 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with OXYCONTIN, as in these patients, even usual therapeutic doses of OXYCONTIN may decrease respiratory drive to the point of apnea [see Warnings and Precautions ( 5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Hypotensive Effects OXYCONTIN may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7.1)] . Monitor these patients for signs of hypotension after initiating or titrating the dose of OXYCONTIN. In patients with circulatory shock, OXYCONTIN may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OXYCONTIN in patients with circulatory shock. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking OXYCONTIN who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with OXYCONTIN. OXYCONTIN may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OXYCONTIN in patients with impaired consciousness or coma. 5.9 Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen There have been post-marketing reports of difficulty in swallowing OXYCONTIN tablets. These reports included choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet OXYCONTIN tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth. There have been rare post-marketing reports of cases of intestinal obstruction, and exacerbation of diverticulitis, some of which have required medical intervention to remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen. 5.10 Use in Patients with Gastrointestinal Conditions OXYCONTIN is contraindicated in patients with GI obstruction, including paralytic ileus. The oxycodone in OXYCONTIN may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase. 5.11 Use in Patients with Convulsive or Seizure Disorders The oxycodone in OXYCONTIN may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OXYCONTIN therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including OXYCONTIN. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing OXYCONTIN, gradually taper the dose [see Dosage and Administration ( 2.4)] . Do not abruptly discontinue OXYCONTIN. 5.13 Driving and Operating Machinery OXYCONTIN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OXYCONTIN and know how they will react to the medication. 5.14 Cytochrome P450 3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of OXYCONTIN, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations. Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid effects. CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If co-administration is necessary, caution is advised when initiating OXYCONTIN treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions ( 7.3) and Clinical Pharmacology ( 12.3)]. 5.15 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse and Misuse Inform patients that the use of OXYCONTIN, even when taken as recommended can result in addiction, abuse and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1)]. Instruct patients not to share OXYCONTIN with others and to take steps to protect OXYCONTIN from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression including information that the risk is greatest when starting OXYCONTIN or when the dose is increased and that it can occur even at recommended doses [see Warnings and Precautions ( 5.2)] . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions ( 5.2)] . Instruct patients to take steps to store OXYCONTIN securely and to dispose of unused OXYCONTIN by flushing the tablets down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of OXYCONTIN during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.3)]. Interactions with Alcohol and other CNS Depressants Inform patients that potentially serious additive effects may occur if OXYCONTIN is used with other CNS depressants, and not to use such drugs unless supervised by a health care provider. Important Administration Instructions Instruct patients how to properly take OXYCONTIN, including the following: OXYCONTIN is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved OXYCONTIN tablets can result in a fatal overdose. OXYCONTIN tablets should be taken one tablet at a time. Do not pre-soak, lick or otherwise wet the tablet prior to placing in the mouth. Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth. Hypotension Inform patients that OXYCONTIN may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Driving or Operating Heavy Machinery Inform patients that OXYCONTIN may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in OXYCONTIN. Advise patients how to recognize such a reaction and when to seek medical attention. Pregnancy Advise female patients that OXYCONTIN can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant. Disposal of Unused OXYCONTIN Advise patients to flush the unused tablets down the toilet when OXYCONTIN is no longer needed. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Purdue Pharma L.P. Stamford, CT 06901-3431 ©2014, Purdue Pharma L.P. U.S. Patent Numbers 6,488,963; 7,129,248; 7,674,799; 7,674,800; 7,683,072; 7,776,314; 8,114,383; 8,309,060; and 8,337,888.

DOSAGE AND ADMINISTRATION

2 OXYCONTIN 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. ( 2.1) For opioid-naïve and opioid non-tolerant patients, initiate with 10 mg tablets orally every 12 hours. ( 2.1) Do not abruptly discontinue OXYCONTIN in a physically dependent patient. ( 2.4) Tablets must be swallowed intact and are not to be cut, broken, chewed, crushed, or dissolved (risk of potentially fatal dose). ( 2.5, 5.1) OXYCONTIN tablets should be taken one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. ( 2.5, 5.9, 17) 2.1 Initial Dosing OXYCONTIN should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. OXYCONTIN 60 mg and 80 mg tablets, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients considered opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid. Initiate the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1)] . Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with OXYCONTIN [see Warnings and Precautions ( 5.2)]. OXYCONTIN tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information ( 17)] . Crushing, chewing, or dissolving OXYCONTIN tablets will result in uncontrolled delivery of oxycodone and can lead to overdose or death [see Warnings and Precautions ( 5.1)] . Use of OXYCONTIN as the First Opioid Analgesic Initiate treatment with OXYCONTIN with one 10 mg tablet orally every 12 hours. Use of OXYCONTIN in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is OXYCONTIN 10 mg orally every 12 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression. Conversion from other Oral Oxycodone Formulations to OXYCONTIN Patients receiving other oral oxycodone formulations may be converted to OXYCONTIN by administering one-half of the patient’s total daily oral oxycodone dose as OXYCONTIN every 12 hours.Patients receiving other oral oxycodone formulations may be converted to OXYCONTIN by administering one-half of the patient’s total daily oral oxycodone dose as OXYCONTIN every 12 hours. Conversion from other Opioids to OXYCONTIN Discontinue all other around-the-clock opioid drugs when OXYCONTIN therapy is initiated. There are no established conversion ratios for conversion from other opioids to OXYCONTIN defined by clinical trials. Discontinue all other around-the-clock opioid drugs when OXYCONTIN therapy is initiated and initiate dosing using OXYCONTIN 10 mg orally every 12 hours. It is safer to underestimate a patient’s 24-hour oral oxycodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone requirements which could result in adverse reactions. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. Conversion from Methadone to OXYCONTIN Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma. Conversion from Transdermal Fentanyl to OXYCONTIN Eighteen hours following the removal of the transdermal fentanyl patch, OXYCONTIN treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 10 mg every 12 hours of OXYCONTIN, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OXYCONTIN, as there is limited documented experience with this conversion.Eighteen hours following the removal of the transdermal fentanyl patch, OXYCONTIN treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 10 mg every 12 hours of OXYCONTIN, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OXYCONTIN, as there is limited documented experience with this conversion. 2.2 Titration and Maintenance of Therapy Individually titrate OXYCONTIN to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OXYCONTIN to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse and misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics. Patients who experience breakthrough pain may require a dose increase of OXYCONTIN or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the OXYCONTIN dose. Because steady-state plasma concentrations are approximated in 1 day, OXYCONTIN dosage may be adjusted every 1 to 2 days. If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. There are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours. As a guideline, the total daily oxycodone dose usually can be increased by 25% to 50% of the current dose, each time an increase is clinically indicated.There are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours. As a guideline, the total daily oxycodone dose usually can be increased by 25% to 50% of the current dose, each time an increase is clinically indicated. 2.3 Patients with Hepatic Impairment For patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration [see Clinical Pharmacology ( 12.3)] . 2.4 Discontinuation of OXYCONTIN When the patient no longer requires therapy with OXYCONTIN tablets, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically dependent patient. Do not abruptly discontinue OXYCONTIN. 2.5 Administration of OXYCONTIN Instruct patients to swallow OXYCONTIN tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions ( 5.1)] . Instruct patients to take OXYCONTIN one tablet at a time and with enough water to ensure complete swallowing immediately after placing in the mouth [see Warnings and Precautions ( 5.9) and Patient Counseling Information ( 17)].