Medication

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION 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 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.3 )] Interactions with Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Hypotensive Effects [see Warnings and Precautions ( 5.7 )] Gastrointestinal Effects [see Warnings and Precautions ( 5.9 , 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (>5%) are constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, asthenia, and sweating. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OXYCONTIN was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OXYCONTIN in total daily doses ranging from 20 mg to 640 mg per day. The average total daily dose was approximately 105 mg per day. OXYCONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage ( 10 )] . The most common adverse reactions (>5%) reported by patients in clinical trials comparing OXYCONTIN with placebo are shown in Table 1 below: TABLE 1: Common Adverse Reactions (>5%) Adverse Reaction OXYCONTIN (n=227) Placebo (n=45) (%) (%) Constipation (23) (7) Nausea (23) (11) Somnolence (23) (4) Dizziness (13) (9) Pruritus (13) (2) Vomiting (12) (7) Headache (7) (7) Dry Mouth (6) (2) Asthenia (6) - Sweating (5) (2) In clinical trials, the following adverse reactions were reported in patients treated with OXYCONTIN with an incidence between 1% and 5%: Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, gastritis General disorders and administration site conditions: chills, fever Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: twitching Psychiatric disorders: abnormal dreams, anxiety, confusion, dysphoria, euphoria, insomnia, nervousness, thought abnormalities Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups Skin and subcutaneous tissue disorders: rash Vascular disorders: postural hypotension The following adverse reactions occurred in less than 1% of patients involved in clinical trials: Blood and lymphatic system disorders: lymphadenopathy Ear and labyrinth disorders: tinnitus Eye disorders: abnormal vision Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, stomatitis General disorders and administration site conditions: withdrawal syndrome (with and without seizures), edema, peripheral edema, thirst, malaise, chest pain, facial edema Injury, poisoning and procedural complications: accidental injury Investigations: ST depression Metabolism and nutrition disorders: dehydration Nervous system disorders: syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypesthesia, hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, taste perversion Psychiatric disorders: depression, agitation, depersonalization, emotional lability, hallucination Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention Reproductive system and breast disorders: impotence Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of controlled-release oxycodone: abuse, addiction, amenorrhea, cholestasis, death, dental caries, increased hepatic enzymes, hyperalgesia, hypogonadism, hyponatremia, ileus, muscular hypertonia, overdose, palpitations (in the context of withdrawal), seizures, syndrome of inappropriate antidiuretic hormone secretion, and urticaria. Anaphylaxis has been reported with ingredients contained in OXYCONTIN. Advise patients how to recognize such a reaction and when to seek medical attention. In addition to the events listed above, the following have also been reported, potentially due to the swelling and hydrogelling property of the tablet: choking, gagging, regurgitation, tablets stuck in the throat and difficulty swallowing the tablet.

7 DRUG INTERACTIONS 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.