Get your patient on Oxycontin (Oxycodone Hydrochloride)

• OXYCONTIN should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
• 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. 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, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OXYCONTIN for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OXYCONTIN. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2) ].
• OXYCONTIN is administered orally every 12 hours.
• Instruct patients to swallow OXYCONTIN tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions (5.12) ] . Cutting, breaking, 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) ] .

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1 , 5.2 , 5.3) ].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2) ] .

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

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 dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioids. Frequently reevaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to OXYCONTIN.

The starting dosage for adults who are not opioid tolerant is OXYCONTIN 10 mg orally every 12 hours. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.2) ].

If switching from other oral oxycodone formulations to OXYCONTIN, administer one half of the patient's total daily oral oxycodone dose as OXYCONTIN every 12 hours.

Regular evaluation 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.

Treatment with OXYCONTIN can be initiated after the fentanyl transdermal system has been removed for at least 18 hours. Although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of OXYCONTIN every 12 hours for each 25 mcg per hour fentanyl transdermal system. Follow the patient closely during conversion from fentanyl transdermal system to OXYCONTIN, as there is limited documented experience with this conversion.

When OXYCONTIN therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to OXYCONTIN defined by clinical trials. Initiate dosing using OXYCONTIN 10 mg orally every 12 hours.

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 OXYCONTIN, patients must be taking a minimum of 20 mg per day of oxycodone or its equivalent. OXYCONTIN 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 OXYCONTIN.

When OXYCONTIN therapy is initiated, discontinue all opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There is substantial inter-patient variability in the relative potency of different opioid drugs and formulations. Therefore, a conservative approach is advised when determining the total daily dosage of OXYCONTIN. 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 and manage an adverse reaction due to an overdose.

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 OXYCONTIN.
• The table cannot be used to convert from OXYCONTIN to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in a fatal overdose.
• The formula for conversion from prior opioids, including oral oxycodone, to the daily dose of OXYCONTIN is mg per day of prior opioid x factor = mg per day of OXYCONTIN. Divide the calculated total daily dose by 2 to get the every-12-hour OXYCONTIN dose. If rounding is necessary, always round the dose down to the nearest OXYCONTIN tablet strength available.

Step #1 : To calculate the estimated total OXYCONTIN 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 OXYCONTIN 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 OXYCONTIN 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 OXYCONTIN tablet strength available and initiate OXYCONTIN therapy with that dose. If the calculated OXYCONTIN total daily dosage is less than 20 mg, there is no safe strength for conversion and do not initiate OXYCONTIN.

• Example conversion from a single opioid (e.g., hydrocodone) to OXYCONTIN: Using the conversion 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 OXYCONTIN every 12 hours. After rounding down to the nearest strength available, the recommended OXYCONTIN 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 OXYCONTIN [see Dosage and Administration (2.5) ] for important instructions on titration and maintenance of therapy.

There is limited experience with conversion from transdermal fentanyl to OXYCONTIN in pediatric patients 11 years and older. If switching from transdermal fentanyl patch to OXYCONTIN, ensure that the patch has been removed for at least 18 hours prior to starting OXYCONTIN. Although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg of OXYCONTIN every 12 hours for each 25 mcg per hour fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to OXYCONTIN.

If using asymmetric dosing, instruct patients to take the higher dose in the morning and the lower dose in the evening.

Individually titrate OXYCONTIN to a dosage that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OXYCONTIN to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse and misuse [see Warnings and Precautions (5.1 , 5.15) ] . 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 use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment 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 dosage. Because steady-state plasma concentrations are approximated in 1 day, OXYCONTIN dosage may be adjusted every 1 to 2 days.

If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . 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.

If the patient is currently taking a central nervous system (CNS) depressant and the decision is made to begin OXYCONTIN, start with one-third to one-half the recommended starting dosage of OXYCONTIN, consider using a lower dosage of the concomitant CNS depressant, and regularly evaluate patients for signs of respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.3) , Drug Interactions (7) ] .

For geriatric patients who are debilitated and not opioid-tolerant, start dosing patients at one-third to one-half the recommended starting dosage and titrate the dosage cautiously. Regularly evaluate for signs of respiratory depression, sedation, and hypotension [see Use in Specific Populations (8.5) ] .

For patients with hepatic impairment, start dosing patients at one-third to one-half the recommended starting dosage and titrate the dosage carefully. Regularly evaluate for signs of respiratory depression, sedation, and hypotension [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

Do not rapidly reduce or abruptly discontinue OXYCONTIN in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking OXYCONTIN, there are a variety of factors that should be considered, including the total daily dose of opioid (including OXYCONTIN) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on OXYCONTIN who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.15) , Drug Abuse and Dependence (9.3) ].

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] . There are no available data with OXYCONTIN in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 60 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] .

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. OXYCONTIN is 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, including OXYCONTIN, 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. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Pregnant rats were treated with 0.5, 2, 4, and 8 mg/kg oxycodone hydrochloride (0.08, 0.3, 0.7, and 1.3 times the human daily dose of 60 mg/day, respectively based on a mg/m ² basis) during the period of organogenesis. Oxycodone did not cause adverse effects to the fetus at exposures up to 1.3 times the human dose of 60 mg/day. The high dose produced maternal toxicity characterized by excessive gnawing on forelimbs and decreased body weight gain.

Pregnant rabbits were treated with 1, 5, 25, and 125 mg/kg oxycodone hydrochloride (0.3, 2, 8, and 40 times the human daily dose of 60 mg/day, respectively, based on a mg/m ² basis) during the period of organogenesis. Oxycodone did not cause adverse effects to the fetus at exposures up to 40 times the human dose of 60 mg/day. The 25 mg/kg and 125 mg/kg doses high doses produced maternal toxicity characterized by decreased food consumption and body weight gain.

Pregnant rats were treated with 0.5, 2, and 6 mg/kg oxycodone hydrochloride (0.08, 0.32, and 1 times the human daily dose of 60 mg/kg, respectively, based on a mg/m ² basis) during the period of organogenesis through lactation. 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 an adult human dose of 60 mg/day, on a mg/m ² basis). However, body weight of these pups recovered.

In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3 times an adult human oral dose of 60 mg/day on a mg/m ² basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m ² basis).

Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with extended–release oxycodone, including OXYCONTIN, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with OXYCONTIN.

Monitor infants exposed to OXYCONTIN through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) , Nonclinical Toxicology (13.1) ] .

The safety and efficacy of OXYCONTIN have been established in pediatric patients ages 11 to 16 years. Use of OXYCONTIN is supported by evidence from adequate and well-controlled trials with OXYCONTIN 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 OXYCONTIN 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 OXYCONTIN. 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) , Clinical Studies (14) ] .

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, a dosage reduction in debilitated, non-opioid-tolerant patients is recommended [see Dosage and Administration (2.7) ] .

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who are not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OXYCONTIN slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8) ] .

Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

A study of OXYCONTIN in patients with hepatic impairment demonstrated greater plasma concentrations than those seen at equivalent doses in persons with normal hepatic function [see Clinical Pharmacology (12.3) ] . Therefore, a dosage reduction is recommended for these patients [see Dosage and Administration (2.8) ]. Regularly evaluate closely for signs of respiratory depression, sedation, and hypotension.

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 [see Clinical Pharmacology (12.3) ] . Follow a conservative approach to dose initiation and adjust according to the clinical situation.

In pharmacokinetic studies with OXYCONTIN, 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.

OXYCONTIN contains oxycodone, a Schedule II controlled substance. As an opioid, OXYCONTIN exposes users to the risks of addiction, abuse, and misuse.

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. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2) ] .

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing OXYCONTIN, and reassess all patients receiving OXYCONTIN for the development of these behaviors and 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 opioids such as OXYCONTIN but use in such patients necessitates intensive counseling about the risks and proper use of OXYCONTIN along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] .

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) ].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of 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 overdose reversal agents, 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 dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of OXYCONTIN are essential [see Dosage and Administration (2) ] . Overestimating the OXYCONTIN dosage 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.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9) ] .

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1 , 5.3) ].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.3) , Overdosage (10) ].

Profound sedation, respiratory depression, coma, and death may result from concomitant use of OXYCONTIN with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ] .

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) , Overdosage (10) ] .

Advise both patients and caregivers about the risks of respiratory depression and sedation when OXYCONTIN is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) ] .

Use of OXYCONTIN for an extended period of time during pregnancy can result in withdrawal 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) ] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link:
  www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Concomitant use of OXYCONTIN with a CYP3A4 inhibitor, 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 adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2) ] , particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OXYCONTIN-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using OXYCONTIN with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OXYCONTIN-treated patients, evaluate patients at frequent intervals and consider dosage reduction of OXYCONTIN until stable drug effects are achieved [see Drug Interactions (7) ].

Concomitant use of OXYCONTIN with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using OXYCONTIN with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7) ].

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3) ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.9) , Warnings and Precautions (5.15) ] .

The use of OXYCONTIN in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease : OXYCONTIN-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OXYCONTIN [see Warnings and Precautions (5.2) ].

Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2) ].

Regularly evaluate patients, particularly when initiating and titrating OXYCONTIN and when OXYCONTIN is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2 , 5.3) , Drug Interactions (7) ] . Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

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) ] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage 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.

In patients who may be susceptible to the intracranial effects of CO ₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OXYCONTIN may reduce respiratory drive, and the resultant CO ₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OXYCONTIN.

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.

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.

OXYCONTIN is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The oxycodone in OXYCONTIN may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2) ] .

The oxycodone in OXYCONTIN may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during OXYCONTIN therapy.

Do not rapidly reduce or abruptly discontinue OXYCONTIN in a patient physically dependent on opioids. When discontinuing OXYCONTIN in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.9) , Drug Abuse and Dependence (9.3) ].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving 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.

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.

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.

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 2 below:

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, 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

The safety of OXYCONTIN 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.

The following adverse reactions occurred in a clinical trial of OXYCONTIN 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, hyponatremia

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

The following adverse reactions have been identified during post-approval use of extended-release oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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.

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.

Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis : Anaphylaxis has been reported with ingredients contained in OXYCONTIN.

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ].

Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7) ].

Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.13) ] .

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [ defined in Drug Abuse and Dependence (9.2) ], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.

Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

Oxycodone is a full opioid agonist and is relatively selective for the mu receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO ₂ tension and electrical stimulation.

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 overdose situations [see Overdosage (10) ] .

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 biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED).

Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] .

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.

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 opioid agonists. 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 [see Dosage and Administration (2.1 , 2.5) ] .

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 adverse reactions [see Dosage and Administration (2.1 , 2.5) ] .

The activity of OXYCONTIN is primarily due to the parent drug oxycodone. OXYCONTIN is designed to provide delivery of oxycodone over 12 hours.

Cutting, breaking, chewing, crushing or dissolving OXYCONTIN impairs the controlled-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Oxycodone release from OXYCONTIN is pH independent. The oral bioavailability of oxycodone is 60% to 87%. The relative oral bioavailability of oxycodone from OXYCONTIN to that from immediate-release oral dosage forms is 100%. Upon repeated dosing with OXYCONTIN 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 (t _½ ) of oxycodone following the administration of OXYCONTIN was 4.5 hours compared to 3.2 hours for immediate-release oxycodone.

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.

Dose proportionality has been established for OXYCONTIN 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg tablet strengths for both peak plasma concentrations (C _max ) and extent of absorption (AUC) (see Table 6 ) . Given the short elimination t _½ of oxycodone, steady-state plasma concentrations of oxycodone are achieved within 24-36 hours of initiation of dosing with OXYCONTIN. In a study comparing 10 mg of OXYCONTIN every 12 hours to 5 mg of immediate-release oxycodone every 6 hours, the two treatments were found to be equivalent for AUC and C _max , and similar for C _min (trough) concentrations.

Food has no significant effect on the extent of absorption of oxycodone from OXYCONTIN.

Following intravenous administration, the steady-state volume of distribution (V _ss ) 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 (8.2) ] .

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) ] .

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.

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.

The plasma concentrations of oxycodone are only nominally affected by age, being 15% greater in elderly as compared to young subjects (age 21-45).

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 OXYCONTIN.

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) ] .

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 t _½ for oxycodone increased by 2.3 hours.

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 t _½ for oxycodone of 1 hour.

CYP3A4 is the major isoenzyme involved in noroxycodone formation. Co-administration of OXYCONTIN (10 mg single dose) and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and C _max by 170% and 100%, respectively [see Drug Interactions (7) ].

A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C _max values by 86% and 63%, respectively [see Drug Interactions (7) ].

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 OXYCONTIN [see Drug Interactions (7) ].

Carcinogenic potential of oxycodone was evaluated in a 2-year oral gavage study in Sprague-Dawley rats. Oxycodone did not increase the incidence of tumors in male and female rats at doses up to 6 mg/kg/day (approximately 0.1 times and 0.5 times for males and females, respectively, a human oxycodone dose of 60 mg/day based on AUC comparison).

Oxycodone was genotoxic in the in vitro mouse lymphoma assay. Oxycodone was negative when tested at appropriate concentrations in the in vitro chromosomal aberration assay, the in vitro bacterial reverse mutation assay (Ames test), and the in vivo bone marrow micronucleus assay in mice.

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 (up to 8 mg/kg/day), up to 1.3 times a human dose of 60 mg/day.

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

Store OXYCONTIN securely and dispose of properly [see Patient Counseling Information (17) ] .

Dispense in tight, light-resistant container.