2.1 Important Dosage and Administration Instructions

OXYCODONE HCl EXTENDED-RELEASE TABLETS should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
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. 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 consistent with individual patient treatment goals [see Warnings and Precautions (5.1)].
• Initiate the dosing regimen for each patient individually; taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with OXYCODONE HCl EXTENDEDRELEASE TABLETS and adjust the dosage accordingly [see Warnings and Precautions (5.3)].

Instruct patients to swallow OXYCODONE HCl EXTENDED-RELEASE TABLETS whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions (5.11)].
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 are administered orally every 12 hours.

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.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [ see Warnings and Precautions ( 5.3) ].

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
Discontinue all other around-the-clock opioid drugs when OXYCODONE HCl EXTENDEDRELEASE TABLETS therapy is initiated.
There are no established conversion ratios for conversion from other opioids to OXYCODONE HCl EXTENDED-RELEASE TABLETS defined by clinical trials. 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 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.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to OXYCODONE HCl EXTENDED-RELEASE TABLETS.

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
Treatment with OXYCODONE HCl EXTENDED-RELEASE TABLETS can be initiated after the transdermal fentanyl patch 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 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 EXTENDEDRELEASE TABLETS therapy is initiated.
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 OXYCODONE HCl EXTENDED-RELEASE TABLETS. 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 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.

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 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 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. [ 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 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 [ see Warnings and Precautions ( 5.1) ]. 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 adjustment 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, consider reducing the dosage. 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 one-third to one-half the recommended starting dosage of OXYCODONE HCl EXTENDED-RELEASE TABLETS, consider using a lower dosage of the concomitant CNS depressant, and monitor patients for signs of respiratory depression, sedation, and hypotension [ see Warnings and Precautions ( 5.6), Drug Interactions ( 7) ].

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 one-third to one-half 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 one-third to one-half the recommended starting dosage and titrate the dosage carefully. Monitor for signs of respiratory depression, sedation, and hypotension [ see Use in Specific Populations, ( 8.6), Clinical Pharmacology ( 12.3) ].

2.9 Safe Reduction or Discontinuation of OXYCODONE HCl EXTENDED-RELEASE TABLETS

Do not abruptly discontinue OXYCODONE HCl EXTENDED-RELEASE TABLETS in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS, there are a variety of factors that should be considered, including the dose of OXYCODONE HCl EXTENDEDRELEASE TABLETS 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS 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, monitor 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 a long duration 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 (5.14), Drug Abuse and Dependence (9.3)].

5.1 Addiction, Abuse, and Misuse

OXYCODONE HCl EXTENDED-RELEASE TABLETS contains oxycodone, a Schedule II controlled substance. As an opioid, OXYCODONE HCl EXTENDED-RELEASE TABLETS expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as OXYCODONE HCl EXTENDED-RELEASE TABLETS deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence ( 9) ].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OXYCODONE HCl EXTENDED-RELEASE TABLETS. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OXYCODONE HCl EXTENDED-RELEASE TABLETS, and monitor all patients receiving OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 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) ].
Opioids 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 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

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.

5.3 Life-Threatening Respiratory Depression

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 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 dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of OXYCODONE HCl EXTENDED-RELEASE TABLETS.

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 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

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 (2.5)].

5.4 Neonatal Opioid Withdrawal Syndrome

Prolonged use of OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [ see Use in Specific Populations ( 8.1), Patient Counseling Information ( 17) ].

5.5 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 ( 5.3) ], particularly when an inhibitor is added after a stable dose of OXYCODONE HCl EXTENDED-RELEASE TABLETS is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OXYCODONE HCl EXTENDED-RELEASE TABLETS-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using OXYCODONE HCl EXTENDED-RELEASE TABLETS with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OXYCODONE HCl EXTENDED-RELEASE TABLETS-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of OXYCODONE HCl EXTENDED-RELEASE TABLETS until stable drug effects are achieved [ see Drug Interactions ( 7) ].
Concomitant use of OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely 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) ].

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result if OXYCODONE HCl EXTENDED-RELEASE TABLETS are used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., non-benzodiazepines sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when OXYCODONE HCl EXTENDED-RELEASE TABLETS 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), Patient Counseling Information ( 17) ].

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of OXYCODONE HCl EXTENDED-RELEASE TABLETS 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: OXYCODONE HCl EXTENDED-RELEASE TABLETS-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 OXYCODONE HCl EXTENDED-RELEASE TABLETS [ see Warnings and Precautions ( 5.3) ].
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 ( 5.3) ].
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 ( 5.3, 5.6) ]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Adrenal Insufficiency

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.

5.9 Severe Hypotension

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

5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OXYCODONE HCl EXTENDED-RELEASE TABLETS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OXYCODONE HCl EXTENDED-RELEASE TABLETS.
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.

5.11 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.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

OXYCODONE HCl EXTENDED-RELEASE TABLETS are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The oxycodone in OXYCODONE HCl EXTENDED-RELEASE TABLETS may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The oxycodone in OXYCODONE HCl EXTENDED-RELEASE TABLETS 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. Monitor patients with a history of seizure disorders for worsened seizure control during OXYCODONE HCl EXTENDED-RELEASE TABLETS therapy.

5.14 Withdrawal

Do not abruptly discontinue OXYCODONE HCl EXTENDED-RELEASE TABLETS in a patient physically dependent on opioids. When discontinuing OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 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.

5.15 Risks of 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 [ see Patient Counseling Information ( 17) ].

5.16 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.

6.1 Clinical Trial Experience

Adult Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 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:

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.

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, 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

6.2 Postmarketing Experience

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 OXYCODONE HCl EXTENDED-RELEASE TABLETS.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology ( 12.2) ].

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions ( 5.4) ]. There are no available data with OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 estimated 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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

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) ].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. OXYCODONE HCl EXTENDED-RELEASE TABLETS 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS, 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.

Data

Animal Data

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/m2 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, respective, based on a mg/m2 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/m2 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/m2 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/m2 basis).

8.2 Lactation

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 OXYCODONE HCl EXTENDED-RELEASE TABLETS, 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS.
Clinical Considerations
Infants exposed to OXYCODONE HCl EXTENDED-RELEASE TABLETS through breast milk should be monitored 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.

8.3 Females and Males of Reproductive Potential

Infertility
Chronic use of opioids 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) ].

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, 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 OXYCODONE HCl EXTENDED-RELEASE TABLETS slowly in these patients and monitor closely for signs of central nervous system and respiratory depression. [ see Warnings and Precautions ( 5.7) ].
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 monitor renal function.

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 [ see Clinical Pharmacology ( 12.3) ]. Therefore, a dosage reduction is recommended for these patients [ see Dosage and Administration ( 2.8) ]. Monitor closely for signs of respiratory depression, sedation, and hypotension.

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

8.8 Sex 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.

9.1 Controlled Substance

OXYCODONE HCl EXTENDED-RELEASE TABLETS contains oxycodone, a Schedule II controlled substance.

9.2 Abuse

OXYCODONE HCl EXTENDED-RELEASE TABLETS contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. OXYCODONE HCl EXTENDED-RELEASE TABLETS can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions ( 5.1) ].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

OXYCODONE HCl EXTENDED-RELEASE TABLETS, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of OXYCODONE HCl EXTENDED-RELEASE TABLETS

OXYCODONE HCl EXTENDED-RELEASE TABLETS are for oral use only. Abuse of OXYCODONE HCl EXTENDED-RELEASE TABLETS poses a risk of overdose and death. The risk is increased with concurrent use of OXYCODONE HCl EXTENDED-RELEASE TABLETS with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved OXYCODONE HCl EXTENDED-RELEASE TABLETS enhances drug release and increases the risk of overdose and death.

With parenteral abuse, the inactive ingredients in OXYCODONE HCl EXTENDED-RELEASE TABLETS can be expected to result in local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, valvular heart injury, embolism, and death. Cases of thrombotic microangiopathy (a condition characterized clinically by thrombocytopenia and microangiopathic hemolytic anemia) associated with parenteral abuse have been reported.

Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV.

Abuse Deterrence Studies

OXYCODONE HCl EXTENDED-RELEASE TABLETS are formulated with inactive ingredients intended to make the tablet more difficult to manipulate for misuse and abuse. For the purposes of describing the results of studies of the abuse-deterrent characteristics of OXYCODONE HCl EXTENDED-RELEASE TABLETS resulting from a change in formulation, in this section, the original formulation of OXYCODONE HCl EXTENDED-RELEASE TABLETS, which is no longer marketed, will be referred to as “original OxyContin” and the reformulated, currently marketed product will be referred to as “OXYCODONE HCl EXTENDED-RELEASE TABLETS”.

In Vitro Testing
In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the extended-release formulation. Results support that, relative to original OxyContin, there is an increase in the ability of OXYCODONE HCl EXTENDED-RELEASE TABLETS to resist crushing, breaking, and dissolution using a variety of tools and solvents. The results of these studies also support this finding for OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to an immediate-release oxycodone. When subjected to an aqueous environment, OXYCODONE HCl EXTENDED-RELEASE TABLETS gradually forms a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a needle.

Clinical Studies
In a randomized, double-blind, placebo-controlled 5-period crossover pharmacodynamic study, 30 recreational opioid users with a history of intranasal drug abuse received intranasally administered active and placebo drug treatments. The five treatment arms were finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS 30 mg tablets, coarsely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS 30 mg tablets, finely crushed original OxyContin 30 mg tablets, powdered oxycodone HCl 30 mg, and placebo. Data for finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS, finely crushed original OxyContin, and powdered oxycodone HCl are described below.

Drug liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”).

Twenty-seven of the subjects completed the study. Incomplete dosing due to granules falling from the subjects’ nostrils occurred in 34% (n = 10) of subjects with finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS, compared with 7% (n = 2) of subjects with finely crushed original OxyContin and no subjects with powdered oxycodone HCl.

The intranasal administration of finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS was associated with a numerically lower mean and median drug liking score and a lower mean and median score for take drug again, compared to finely crushed original OxyContin or powdered oxycodone HCl as summarized in Table 5.

Figure 1 demonstrates a comparison of drug liking for finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS compared to powdered oxycodone HCl in subjects who received both treatments. The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for OXYCODONE HCl EXTENDED-RELEASE TABLETS vs. oxycodone HCl powder greater than or equal to the value on the X-axis. Approximately 44% (n = 12) had no reduction in liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to oxycodone HCl. Approximately 56% (n = 15) of subjects had some reduction in drug liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to oxycodone HCl. Thirty-three percent (n = 9) of subjects had a reduction of at least 30% in drug liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS compared to oxycodone HCl, and approximately 22% (n = 6) of subjects had a reduction of at least 50% in drug liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS compared to oxycodone HCl.

The results of a similar analysis of drug liking for finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to finely crushed original OxyContin were comparable to the results of finely crushed OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to powdered oxycodone HCl. Approximately 43% (n = 12) of subjects had no reduction in liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS relative to original OxyContin. Approximately 57% (n = 16) of subjects had some reduction in drug liking, 36% (n = 10) of subjects had a reduction of at least 30% in drug liking, and approximately 29% (n = 8) of subjects had a reduction of at least 50% in drug liking with OXYCODONE HCl EXTENDED-RELEASE TABLETS compared to original OxyContin.

Summary

The in vitro data demonstrate that OXYCODONE HCl EXTENDED-RELEASE TABLETS have physicochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from the in vitro data, also indicate that OXYCODONE HCl EXTENDED-RELEASE TABLETS have physicochemical properties that are expected to reduce abuse via the intranasal route. However, abuse of OXYCODONE HCl EXTENDED-RELEASE TABLETS by these routes, as well as by the oral route, is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of OXYCODONE HCl EXTENDED-RELEASE TABLETS on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

OXYCODONE HCl EXTENDED-RELEASE TABLETS contain oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. OXYCODONE HCl EXTENDED-RELEASE TABLETS can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions ( 5.1) and Drug Abuse and Dependence ( 9.1) ].

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue OXYCODONE HCl EXTENDED-RELEASE TABLETS in a patient physically dependent on opioids. Rapid tapering of OXYCODONE HCl EXTENDEDRELEASE TABLETS in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing OXYCODONE HCl EXTENDED-RELEASE TABLETS, gradually taper the dosage using a patient specific plan that considers the following: the dose of OXYCODONE HCl EXTENDED-RELEASE TABLETS the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.14)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Effects on the Central Nervous System

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) ].

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 biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

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.

Effects on the Endocrine System

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.

Chronic use of opioids 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) ].

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. 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) ].

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

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, 20 mg, and 40 mg tablet strengths for both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 6). 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.

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 ( 8.4) ].

Elimination

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) ].

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 (a- 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.

Specific Populations

Age: Geriatric Population

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

Age: Pediatric Population

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.

Sex

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) ].

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.

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.

Drug Interaction Studies

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)].

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) ].

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) ].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted.
Mutagenesis
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.
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 (up to 8 mg/kg/day), up to 1.3 times a human dose of 60 mg/day.