ged opioid effects. these effects could be more pronounced with concomitant use of cyp2d6 and 3a4 inhibitors. if co-administration with oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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)]. 7.3 mixed agonist/antagonist and partial agonists 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 oxycodone hcl extended-release tablets. 7.4 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 oxycodone hcl extended-release tablets for signs of respiratory depression that may be greater than otherwise expected. 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 oxycodone hcl extended-release tablets are used concurrently with anticholinergic drugs.

not indicated as an as-needed (prn) analgesic.

he 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 oxycodone hcl extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of oxycodone hcl extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse. abuse, or misuse of oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets. 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 (co2) 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 oxycodone hcl extended-release tablets, the risk is greatest during the initiation of therapy or following a dose increase. closely monitor patients for respiratory depression when initiating therapy with oxycodone hcl extended-release tablets and following dose increases. to reduce the risk of respiratory depression, proper dosing and titration of oxycodone hcl extended-release tablets are essential [see dosage and administration (2)]. overestimating the oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets, 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 oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets are used concomitantly with other central nervous system (cns) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). when considering the use of oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets therapy is made, start with 1/3 to 1/2 the usual dose of oxycodone hcl extended-release tablets, 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 (2.6)]. 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 oxycodone hcl extended-release tablets and when oxycodone hcl extended-release tablets are 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 oxycodone hcl extended-release tablets, as in these patients, even usual therapeutic doses of oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets. in patients with circulatory shock, oxycodone hcl extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. avoid the use of oxycodone hcl extended-release tablets in patients with circulatory shock. 5.8 use in patients with head injury or increased intracranial pressure monitor patients taking oxycodone hcl extended-release tablets who may be susceptible to the intracranial effects of co2 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 oxycodone hcl extended-release tablets. oxycodone hcl extended-release tablets may reduce respiratory drive, and the resultant co2 retention can further increase intracranial pressure. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets. these reports included choking, gagging, regurgitation and tablets stuck in the throat. instruct patients not to pre-soak, lick or otherwise wet oxycodone hcl extended-release 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 oxycodone hcl extended-release tablets are contraindicated in patients with gi obstruction, including paralytic ileus. the oxycodone in oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets. in these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. when discontinuing oxycodone hcl extended-release tablets, gradually taper the dose [see dosage and administration (2.9)]. do not abruptly discontinue oxycodone hcl extended-release tablets. 5.13 driving and operating machinery oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets, 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 oxycodone hcl extended-release tablets 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(7.2) 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.

s (5.9)].cutting, breaking, crushing, chewing, or dissolving oxycodone hcl extended-release tablets will result in uncontrolled delivery of oxycodone and can lead to overdose or death [see warnings and precautions (5.1)]. oxycodone hcl extended-release tablets 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. 2.2 initial dosage in adults who are not opioid-tolerant the starting dosage for patients who are not opioid tolerant is oxycodone hcl extended-release tablets 10 mg orally every 12 hours. adult 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 [see warnings and precautions (5.2)]. 2.3 conversion from opioids to oxycodone hcl extended-release tablets in adults conversion from other oral oxycodone formulations to oxycodone hcl extended-release tablets if switching from other oral oxycodone formulations to oxycodone hcl extended-release tablets, administer one half of the patient's total daily oral oxycodone dose as oxycodone hcl extended-release tablets every 12 hours. conversion from other opioids to oxycodone hcl extended-release tablets there are no established conversion ratios for conversion from other opioids to oxycodone hcl extended-release tablets defined by clinical trials. discontinue all other around-the-clock opioid drugs when oxycodone hcl extended-release tablets therapy is initiated and initiate dosing using oxycodone hcl extended-release tablets 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 opioids. conversion from methadone to oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets if switching from transdermal fentanyl patch to oxycodone hcl extended-release tablets, ensure that the patch has been removed for at least 18 hours prior to starting oxycodone hci extended-release tablets. although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of oxycodone hci extended-release tablets every 12 hours for each 25 mcg per hour fentanyl transdermal patch. follow the patient closely during conversion from transdermal fentanyl to oxycodone hcl extended-release tablets, as there is limited documented experience with this conversion. 2.4 initial dosage in pediatric patients 11 years and older the following dosing information is for use only in pediatric patients 11 years and older already receiving and tolerating opioids for at least five consecutive days. for the two days immediately preceding dosing with oxycodone hcl extended-release tablets, patients must be taking a minimum of 20 mg per day of oxycodone or its equivalent. oxycodone hcl extended-release tablets is not appropriate for use in pediatric patients requiring less than a 20 mg total daily dose. table 1, based on clinical trial experience, displays the conversion factor when switching pediatric patients 11 years and older (under the conditions described above) from opioids to oxycodone hcl extended-release tablets. discontinue all other around-the-clock opioid drugs when oxycodone hcl extended-release tablets therapy is initiated. although tables of oral and parenteral equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and formulations. as such, it is preferable 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 and manage an adverse reaction. consider the following when using the information in table 1. this is not a table of equianalgesic doses. the conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to oxycodone hcl extended-release tablets. the table cannot be used to convert from oxycodone hcl extended-release tablets to another opioid. doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose. the formula for conversion from prior opioids, including oral oxycodone, to the daily dose of oxycodone hcl extended-release tablets is mg per day of prior opioid x factor = mg per day of oxycodone hcl extended-release tablets. divide the calculated total daily dose by 2 to get the every-12-hour oxycodone hcl extended-release tablets dose. if rounding is necessary, always round the dose down to the nearest oxycodone hcl extended-release tablet strength available. table 1: conversion factors when switching pediatric patients 11 years and older to oxycodone hcl extended-release tablets * for patients receiving high-dose parenteral opioids, a more conservative conversion is warranted. for example, for high-dose parenteral morphine, use 1.5 instead of 3 as a multiplication factor. prior opioid conversion factor oral parenteral* oxycodone 1 - hydrocodone 0.9 - hydromorphone 4 20 morphine 0.5 3 tramadol 0.17 0.2 step #1: to calculate the estimated total oxycodone hcl extended-release tablets daily dosage using table 1: for pediatric patients taking a single opioid, sum the current total daily dosage of the opioid and then multiply the total daily dosage by the approximate conversion factor to calculate the approximate oxycodone hcl extended-release tablets daily dosage. for pediatric patients on a regimen of more than one opioid, calculate the approximate oxycodone dose for each opioid and sum the totals to obtain the approximate oxycodone hcl extended-release tablets daily dosage. for pediatric patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion. step #2: if rounding is necessary, always round the dosage down to the nearest oxycodone hcl extended-release tablet strength available and initiate oxycodone hcl extended-release tablets therapy with that dose. if the calculated oxycodone hcl extended-release tablets total daily dosage is less than 20 mg, there is no safe strength for conversion and do not initiate oxycodone hcl extended-release tablets. example conversion from a single opioid (e.g., hydrocodone) to oxycodone hcl extended-release tablets: using theconversion factor of 0.9 for oral hydrocodone in table 1, a total daily hydrocodone dosage of 50 mg is converted to 45 mg of oxycodone per day or 22.5 mg of oxycodone hcl extended-release tablets every 12 hours. after rounding down to the nearest strength available, the recommended oxycodone hcl extended-release tablets starting dosage is 20 mg every 12 hours. step #3: close observation and titration are warranted until pain management is stable on the new opioid. monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to oxycodone hcl extended-release tablets. [seedosage and administration (2.5)] for important instructions on titration and maintenance of therapy. there is limited experience with conversion from transdermal fentanyl to oxycodone hcl extended-release tablets in pediatric patients 11 years and older. if switching from transdermal fentanyl patch to oxycodone hcl extended-release tablets, ensure that the patch has been removed for at least 18 hours prior to starting oxycodone hcl extended-release tablets. although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of oxycodone hcl extended-release tablets every 12 hours for each 25 mcg per hour fentanyl transdermal patch. follow the patient closely during conversion from transdermal fentanyl to oxycodone hcl extended-release tablets. if using asymmetric dosing, instruct patients to take the higher dose in the morning and the lower dose in the evening. 2.5 titration and maintenance of therapy in adults and pediatric patients 11 years and older individually titrate oxycodone hcl extended-release tablets to a dosage that provides adequate analgesia and minimizes adverse reactions. continually reevaluate patients receiving oxycodone hcl extended-release tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and 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 dosage increase of oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets dosage. because steady-state plasma concentrations are approximated in 1 day, oxycodone hcl extended-release tablets 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 dosage 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 for pediatric patients 11 years and older, the total daily oxycodone dosage usually can be increased by 25% of the current total daily dosage. as a guideline for adults, the total daily oxycodone dosage usually can be increased by 25% to 50% of the current total daily dosage, each time an increase is clinically indicated. 2.6 dosage modifications with concomitant use of central nervous system depressants if the patient is currently taking a central nervous system (cns) depressant and the decision is made to begin oxycodone hcl extended-release tablets, start with 1/3 to 1/2 the recommended starting dosage of oxycodone hcl extended-release tablets and monitor patients for signs of respiratory depression, sedation, and hypotension [see warnings and precautions (5.4), drug interactions (7.1)]. 2.7 dosage modifications in geriatric patients who are debilitated and not opioid-tolerant for geriatric patients who are debilitated and not opioid tolerant, start dosing patients at 1/3 to 1/2 the recommended starting dosage and titrate the dosage cautiously [see use in specific populations (8.5)]. 2.8 dosage modifications in patients with hepatic impairment for patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the recommended starting dosage followed by careful dosage titration [see clinical pharmacology (12.3)]. 2.9 discontinuation of oxycodone hcl extended-release tablets when the patient no longer requires therapy with oxycodone hcl extended-release tablets, gradually titrate the dosage downward to prevent signs and symptoms of withdrawal in the physically dependent patient. do not abruptly discontinue oxycodone hcl extended-release tablets.

713 patients with moderate to severe pain of various etiologies. in open-label studies of cancer pain, 187 patients received oxycodone hcl extended-release tablets in total daily doses ranging from 20 mg to 640 mg per day. the average total daily dose was approximately 105 mg per day. oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets with placebo are shown in table 2 below: table 2: common adverse reactions (>5%) adverse reaction oxycodone hcl extended-release tablets (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 oxycodone hcl extended-release tablets 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, hypoesthesia, 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 clinical trial experience in pediatric patients 11 years and older the safety of oxycodone hcl extended-release tablets has been evaluated in one clinical trial with 140 patients 11 to 16 years of age. the median duration of treatment was approximately three weeks. the most frequently reported adverse events were vomiting, nausea, headache, pyrexia, and constipation. table 3 includes a summary of the incidence of treatment emergent adverse events reported in ≥5% of patients. table 3: incidence of adverse reactions reported in ≥ 5.0% patients 11 to 16 years system organ class preferred term 11 to 16 years (n=140) n (%) any adverse event >= 5% 71 (51) gastrointestinal disorders 56 (40) vomiting 30 (21) nausea 21 (15) constipation 13 (9) diarrhea 8 (6) general disorders and administration site conditions 32 (23) pyrexia 15 (11) metabolism and nutrition disorders 9 (6) decreased appetite 7 (5) nervous system disorders 23 (16) pruritus 8 (6) the following adverse reactions occurred in a clinical trial of oxycodone hcl extended-release tablets in patients 11 to 16 years of age with an incidence between ≥1.0% and < 5.0%. events are listed within each system/organ class. blood and lymphatic system disorders: febrile neutropenia, neutropenia cardiac disorders: tachycardia gastrointestinal disorders: abdominal pain, gastroesophageal reflux disease general disorders and administration site conditions: fatigue, pain, chills, asthenia injury, poisoning, and procedural complications: procedural pain, seroma investigations: oxygen saturation decreased, alanine aminotransferase increased, hemoglobin decreased, platelet count decreased, neutrophil count decreased, red blood cell count decreased, weight decreased metabolic and nutrition disorders: hypochloremia, hyponatraemia musculoskeletal and connective tissue disorders: pain in extremity, musculoskeletal pain nervous system disorders: somnolence, hypoesthesia, lethargy, paresthesia psychiatric disorders: insomnia, anxiety, depression, agitation renal and urinary disorders: dysuria, urinary retention respiratory, thoracic, and mediastinal disorders: oropharyngeal pain skin and subcutaneous tissue disorders: hyperhidrosis, rash 6.2 postmarketing experience the following adverse reactions have been identified during post-approval use of controlled-release oxycodone: abuse, addiction, aggression, amenorrhea, cholestasis, completed suicide, death, dental caries, increased hepatic enzymes, hyperalgesia, hypogonadism, hyponatremia, ileus, intentional overdose, mood altered, muscular hypertonia, overdose, palpitations (in the context of withdrawal), seizures, suicidal attempt, suicidal ideation, syndrome of inappropriate antidiuretic hormone secretion, and urticaria. anaphylaxis has been reported with ingredients contained in oxycodone hcl extended-release tablets. 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.

ged opioid effects. these effects could be more pronounced with concomitant use of cyp2d6 and 3a4 inhibitors. if co-administration with oxycodone hcl extended-release tablets 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 oxycodone hcl extended-release tablets 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)]. 7.3 mixed agonist/antagonist and partial agonists 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 oxycodone hcl extended-release tablets. 7.4 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 oxycodone hcl extended-release tablets for signs of respiratory depression that may be greater than otherwise expected. 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 oxycodone hcl extended-release tablets are used concurrently with anticholinergic drugs.

mg/day, respectively on a mg/m2 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/m2 basis). however, body weight of these pups recovered. 8.2 labor and delivery opioids cross the placenta and may produce respiratory depression in neonates. oxycodone hcl extended-release tablets are not recommended for use in women immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. opioid analgesics can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. however this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. 8.3 nursing mothers oxycodone has been detected in breast milk. instruct patients not to undertake nursing while receiving oxycodone hcl extended-release tablets. do not initiate oxycodone hcl extended-release tablets 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. 8.4 pediatric use the safety and efficacy of oxycodone hcl extended-release tablets have been established in pediatric patients ages 11 to 16 years. use of oxycodone hcl extended-release tablets is supported by evidence from adequate and well-controlled trials with oxycodone hcl extended-release tablets in adults as well as an open-label study in pediatric patients ages 6 to 16 years. however, there were insufficient numbers of patients less than 11 years of age enrolled in this study to establish the safety of the product in this age group. the safety of oxycodone hcl extended-release tablets in pediatric patients was evaluated in 155 patients previously receiving and tolerating opioids for at least 5 consecutive days with a minimum of 20 mg per day of oxycodone or its equivalent on the two days immediately preceding dosing with oxycodone hcl extended-release tablets. patients were started on a total daily dose ranging between 20 mg and 100 mg depending on prior opioid dose. the most frequent adverse events observed in pediatric patients were vomiting, nausea, headache, pyrexia, and constipation [see dosage and administration (2.4), adverse reactions (6.1), clinical pharmacology (12.3) and clinical trials (14)]. 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 oxycodone hcl extended-release tablets cautiously in these patients. 8.6 hepatic impairment a study of oxycodone hcl extended-release tablets in patients with hepatic impairment demonstrated greater plasma concentrations than those seen at equivalent doses in persons with normal hepatic function. therefore, in the setting of 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)]. 8.7 renal impairment in patients with renal impairment, as evidenced by decreased creatinine clearance (<60 ml/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. follow a conservative approach to dose initiation and adjust according to the clinical situation [see clinical pharmacology (12.3)]. 8.8 gender differences in pharmacokinetic studies with oxycodone hcl extended-release tablets, opioid-naïve females demonstrate up to 25% higher average plasma concentrations and greater frequency of typical opioid adverse events than males, even after adjustment for body weight. the clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages, and there was no male/female difference detected for efficacy or adverse events in clinical trials.

ng 182 patients with moderate to severe pain. oxycodone hcl extended-release tablets doses of 20 mg and 30 mg produced statistically significant pain reduction compared to placebo. effects on the central nervous system 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 co2 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 overdose [seeoverdosage (10)]. effects on the 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. effects on the 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. effects on the endocrine system opioids inhibit the secretion of acth, cortisol, testosterone, and luteinizing hormone (lh) in humans. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon. effects on the immune system opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. the clinical significance of these findings is unknown. overall, the effects of opioids appear to be modestly immunosuppressive. 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 subjective “drug effect”, analgesia and feelings of relaxation. the minimum effective analgesic concentration 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 reaction relationships there is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, cns effects, and respiratory depression. in opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related side effects. the dose of oxycodone hcl extended-release tablets must be individualized because the effective analgesic dose for some patients will be too high to be tolerated by other patients [see dosage and administration (2.1)]. 12.3 pharmacokinetics the activity of oxycodone hcl extended-release tablets is primarily due to the parent drug oxycodone. oxycodone hcl extended-release tablets are designed to provide delivery of oxycodone over 12 hours. cutting, breaking, chewing, crushing or dissolving oxycodone hcl extended-release tablets impairs the controlled-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone. oxycodone release from oxycodone hcl extended-release tablets is ph independent. the oral bioavailability of oxycodone is 60% to 87%. the relative oral bioavailability of oxycodone from oxycodone hcl extended-release tablets to that from immediate-release oral dosage forms is 100%. upon repeated dosing with oxycodone hcl extended-release tablets in healthy subjects in pharmacokinetic studies, steady-state levels were achieved within 24-36 hours. oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. the apparent elimination half-life (t½) of oxycodone following the administration of oxycodone hcl 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. plasma oxycodone concentration over time dose proportionality has been established for oxycodone hcl extended-release tablets 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg tablet strengths for both peak plasma concentrations (cmax) and extent of absorption (auc) (see table 5). given the short elimination t½ of oxycodone, steady-state plasma concentrations of oxycodone are achieved within 24-36 hours of initiation of dosing with oxycodone hcl extended-release tablets. in a study comparing 10 mg of oxycodone hcl 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. table 5 mean [% coefficient of variation] regimen dosage form auc (ng∙hr/ml)* cmax (ng/ml) tmax (hr) * for single-dose auc = auc 0-inf † data obtained while subjects received naltrexone, which can enhance absorption single dose† 10 mg 136 [27] 11.5 [27] 5.11 [21] 15 mg 196 [28] 16.8 [29] 4.59 [19] 20 mg 248 [25] 22.7 [25] 4.63 [22] 30 mg 377 [24] 34.6 [21] 4.61 [19] 40 mg 497 [27] 47.4 [30] 4.40 [22] 60 mg 705 [22] 64.6 [24] 4.15 [26] 80 mg 908 [21] 87.1 [29] 4.27 [26] food effects food has no significant effect on the extent of absorption of oxycodone from oxycodone hcl extended-release tablets. distribution following intravenous administration, the steady-state 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 use in specific populations (8.3)]. metabolism oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated. noroxycodone and noroxymorphone are the major circulating metabolites. cyp3a mediated n-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from cyp2d6 mediated o-demethylation to oxymorphone. therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see drug interactions (7.3)]. noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone, however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. oxymorphone is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. oxymorphone has been shown to be active and possessing analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant. other metabolites (α- and ß-oxycodol, noroxycodol and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. the enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established. excretion oxycodone and its metabolites are excreted primarily via the kidney. the amounts measured in the urine have been reported as follows: free and conjugated oxycodone 8.9%, free noroxycodone 23%, free oxymorphone less than 1%, conjugated oxymorphone 10%, free and conjugated noroxymorphone 14%, reduced free and conjugated metabolites up to 18%. the total plasma clearance was approximately 1.4 l/min in adults. special populations geriatric use the plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects (age 21-45). gender across individual pharmacokinetic studies, average plasma oxycodone concentrations for female subjects were up to 25% higher than for male subjects on a body weight-adjusted basis. the reason for this difference is unknown [see use in specific populations (8.8)]. renal impairment data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 ml/min) showed 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 was 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 mean elimination t½ for oxycodone of 1 hour. 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 healthy 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 mean elimination t½ for oxycodone increased by 2.3 hours. pediatric use in the pediatric age group of 11 years of age and older, systemic exposure of oxycodone is expected to be similar to adults at any given dose of oxycodone hcl extended-release tablets. drug-drug interactions cyp3a4 inhibitors cyp3a4 is the major isoenzyme involved in noroxycodone formation. co-administration of oxycodone hcl extended-release tablets (10 mg single dose) and the cyp3a4 inhibitor ketoconazole (200 mg bid) increased oxycodone auc and cmax by 170% and 100%, respectively [see drug interactions (7.2)]. cyp3a4 inducers a published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone auc and cmax values by 86% and 63%, respectively [see drug interactions (7.2)]. cyp2d6 inhibitors oxycodone is metabolized in part to oxymorphone via cyp2d6. while this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade has not been shown to be of clinical significance with oxycodone hcl extended-release tablets [see drug interactions (7.2)].

tivation at concentrations up to 5000 µg/plate, chromosomal aberration test in human lymphocytes (in the absence of metabolic activation) at concentrations up to 1500 µg/ml, and with activation after 48 hours of exposure at concentrations up to 5000 µg/ml, and in the in vivo bone marrow micronucleus assay in mice (at plasma levels up to 48 µg/ml). impairment of fertility in a study of reproductive performance, rats were administered a once daily gavage dose of the vehicle or oxycodone hydrochloride (0.5, 2, and 8 mg/kg/day). male rats were dosed for 28 days before cohabitation with females, during the cohabitation and until necropsy (2-3 weeks post-cohabitation). females were dosed for 14 days before cohabitation with males, during cohabitation and up to gestation day 6. oxycodone hydrochloride did not affect reproductive function in male or female rats at any dose tested (≤ 8 mg/kg/day).

the clinical trial to provide meaningful safety data in this age group.

ease tablets 30 mg are film-coated, round, brown-colored, bi-convex tablets debossed with op on one side and 30 on the other and are supplied as child-resistant closure, opaque plastic bottles of 100 (ndc 0115-1559-01) oxycodone hcl extended-release tablets (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 100 (ndc 0115-1560-01) oxycodone hcl extended-release tablets (oxycodone hydrochloride) extended-release tablets 60 mg are film-coated, round, red-colored, bi-convex tablets debossed with op on one side and 60 on the other and are supplied as child-resistant closure, opaque plastic bottles of 100 (ndc 0115-1561-01) oxycodone hcl extended-release tablets (oxycodone hydrochloride) extended-release tablets 80 mg are film-coated, round, green-colored, bi-convex tablets debossed with op on one side and 80 on the other and are supplied as child-resistant closure, opaque plastic bottles of 100 (ndc 0115-1562-01) 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