HEALTHCARE PROFESSIONALS

CONTRAINDICATIONS

HYSINGLA ER is contraindicated in patients with:

• Significant respiratory depression;
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment;
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity to hydrocodone or any component of HYSINGLA ER.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse

HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of opioid addiction, abuse, and misuse. Because extended-release products such as HYSINGLA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of hydrocodone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed HYSINGLA ER. 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 HYSINGLA ER, and monitor all patients receiving HYSINGLA ER 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 HYSINGLA ER, but use in such patients necessitates intensive counseling about the risks and proper use of HYSINGLA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose.

Abuse or misuse of HYSINGLA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing HYSINGLA ER. 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.

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/​O​p​i​o​i​d​A​n​a​l​g​e​s​i​c​R​E​MSPCG.
• 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/​O​p​i​o​i​d​A​n​a​l​g​e​s​i​c​R​E​M​S​B​l​u​e​print

Life‐Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of HYSINGLA ER, 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 HYSINGLA ER.

To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential. Overestimating the HYSINGLA ER 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 HYSINGLA ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.

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.

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of HYSINGLA ER 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.

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

Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics, azole-antifungal agents, and protease inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved, and discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in HYSINGLA ER treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.  When using HYSINGLA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in HYSINGLA ER treated patients, monitor patients closely at frequent intervals and consider dosage reduction of HYSINGLA ER until stable drug effects are achieved..

Concomitant use of HYSINGLA ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone.  When using HYSINGLA ER 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.

Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of HYSINGLA ER with benzodiazepines or CNS depressants (e.g., non-benzodiazepine 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.

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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

Advise both patients and caregivers about the risks of respiratory depression and sedation when HYSINGLA ER 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.

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

The use of HYSINGLA ER 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: HYSINGLA ER-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 HYSINGLA ER.

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.

Monitor such patients closely, particularly when initiating and titrating HYSINGLA ER and when HYSINGLA ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

Adrenal Insufficiency

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

Severe Hypotension

HYSINGLA ER 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 depressants drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of HYSINGLA ER. In patients with circulatory shock, HYSINGLA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYSINGLA ER in patients with circulatory shock.

QTc Interval Prolongation

QTc prolongation has been observed with HYSINGLA ER following doses of 160 mg. This observation should be considered in making decisions regarding patient monitoring when prescribing HYSINGLA ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong QTc interval.

HYSINGLA ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33–50%, or changing to an alternate analgesic.

Risk 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), HYSINGLA ER may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor those patients for signs of sedation and respiratory depression, particularly when initiating therapy with HYSINGLA ER.

Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of HYSINGLA ER in patients with impaired consciousness or coma.

Gastrointestinal Obstruction, Dysphagia, and Choking

In the clinical studies with specific instructions to take HYSINGLA ER with water to swallow the tablets, 11 out of 2476 subjects reported difficulty swallowing HYSINGLA ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet.

Instruct patients not to pre-soak, lick or otherwise wet HYSINGLA ER 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.

Patients with underlying gastrointestinal 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 gastrointestinal disorders resulting in a small gastrointestinal lumen.

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER.

Risks of Use in Patients with Gastrointestinal Conditions

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

The hydrocodone in HYSINGLA ER 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.

Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in HYSINGLA ER 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 HYSINGLA ER therapy.

Withdrawal

Do not abruptly discontinue HYSINGLA ER in a patient physically dependent on opioids. When discontinuing HYSINGLA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including HYSINGLA ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Risks of Driving and Operating Machinery

HYSINGLA ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14–16 hours (range 6–30 hours) after initial dosing of HYSINGLA ER. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of HYSINGLA ER and know how they will react to the medication.

ADVERSE REACTIONS

The most common adverse reactions (≥5%) reported by patients treated with HYSINGLA ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.

DRUG INTERACTIONS

Clinically significant drug interactions with HYSINGLA ER include:

CYP3A4 Inhibitors: The concomitant use of HYSINGLA ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of HYSINGLA ER and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

CYP3A4 Inducers:

The concomitant use of HYSINGLA ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression..

Benzodiazepines and Other Central Nervous System (CNS) Depressants: concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms.

Muscle Relaxants: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Strong Laxatives: Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels. 

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation:  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.

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.  HYSINGLA ER is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.

Lactation studies have not been conducted with HYSINGLA, 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 HYSINGLA ER.

Females and Males of Reproductive Potential: 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.

Pediatric Use: The safety and effectiveness of HYSINGLA ER in pediatric patients have not been established.

Geriatric Use: 

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of HYSINGLA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

Hydrocodone 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.

Hepatic Impairment: No adjustment in starting dose with HYSINGLA ER is required in patients with mild or moderate hepatic impairment.  Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function. Therefore, a dosage reduction is recommended for these patients. Monitor closely for respiratory depression, sedation, and hypotension.

Renal Impairment:  No dose adjustment is needed in patients with mild renal impairment.  Patients with moderate or severe renal impairment or end stage renal disease have higher plasma concentrations than those with normal renal function.  Therefore, a dosage reduction is recommended for these patients. Monitor closely for respiratory depression, sedation, and hypotension.

DRUG ABUSE AND DEPENDENCE

HYSINGLA ER contains hydrocodone, a Schedule II controlled substance with a high potential for abuse similar to other opioids, including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol.  HYSINGLA ER can be abused and is subject to misuse, addiction, and criminal diversion.

Please read Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1‑888‑726‑7535, option 2, or FDA
at 1‑800‑FDA‑1088 or www​.fda​.gov/​s​a​f​e​t​y​/​m​e​d​watch.

Intended for healthcare professionals of the United States of America only.

CONTRAINDICATIONS
OXYCONTIN is contraindicated in patients with:

• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity (e.g., anaphylaxis) to oxycodone.

WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse

OXYCONTIN contains oxycodone, a Schedule II controlled substance. OXYCONTIN exposes users to the risks of opioid addiction, abuse, and misuse. Because extended-release products such as OXYCONTIN deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OXYCONTIN. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OXYCONTIN, and monitor all patients receiving OXYCONTIN for the development of these behaviors 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 intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose.

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.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OXYCONTIN. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.

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: fda​.gov/​O​p​i​o​i​d​A​n​a​l​g​e​s​i​c​R​E​MSPCG .
• 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/​O​p​i​o​i​d​A​n​a​l​g​e​s​i​c​R​E​M​S​B​l​u​e​print

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. 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 OXYCONTIN, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of OXYCONTIN.

To reduce the risk of respiratory depression, proper dosing and titration of OXYCONTIN are essential. 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.

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose: Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with OXYCONTIN. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of OXYCONTIN 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.

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

Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics, azole-antifungal agents, and protease inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved, and discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of OXYCONTIN until stable drug effects are achieved.

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. 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.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OXYCONTIN with benzodiazepines or 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.

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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

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.

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

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.

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.

Monitor such patients closely, particularly when initiating and titrating OXYCONTIN and when OXYCONTIN is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

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.

Severe Hypotension

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 depressants drugs (eg, phenothiazines or general anesthetics). Monitor 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.

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), OXYCONTIN may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor those patients for signs of sedation and respiratory depression, particularly when initiating therapy with OXYCONTIN.

Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of OXYCONTIN in patients with impaired consciousness or coma.

Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen

There have been post-marketing reports of difficulty swallowing OXYCONTIN tablets. These reports include 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.

Risks of Use in Patients with Gastrointestinal Conditions

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. Monitor patients with biliary tract disease, including acute pancreatitis.

Increased Risk of Seizures in Patients with Seizure Disorders

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. Monitor patients with a history of seizure disorders for worsened seizure control during OXYCONTIN therapy.

Withdrawal

Do not 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

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. When discontinuing OXYCONTIN, gradually taper the dosage. Do not abruptly discontinue OXYCONTIN.

Risks of Driving and Operating Machinery

OXYCONTIN may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OXYCONTIN and know how they will react to the medication.

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.

ADVERSE REACTIONS

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.

The most common adverse reactions (≥5%) reported by adult patients in clinical trials comparing OXYCONTIN with placebo are constipation, nausea, somnolence, dizziness, pruritus, vomiting, headache, dry mouth, asthenia, and sweating.

DRUG INTERACTIONS

Significant Drug Interactions with OXYCONTIN INCLUDE:

Inhibitors of CYP3A4 and CYP2D6: The concomitant use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.

CYP3A4 Inducers: The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms.

Muscle Relaxants: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

USE IN SPECIFIC POPULATIONS

Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome.  There are no available data with OXYCONTIN in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Use of OXYCONTIN during pregnancy may cause fetal harm.

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 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.

Females and Males of Reproductive Potential: 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.

Pediatric Use: 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.

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%.  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.

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 these patients and monitor closely for signs of central nervous system and respiratory depression.

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.

Hepatic Impairment: 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.  Therefore, a dosage reduction is recommended for these patients. Monitor closely for signs of respiratory depression, sedation, and hypotension.

 Renal Impairment: In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function.

Follow a conservative approach to dose initiation and adjust according to the clinical situation.

Sex Differences: 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.

DRUG ABUSE AND DEPENDENCE

OXYCONTIN contains oxycodone, a Schedule II controlled substance.  OXYCONTIN contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol.  OXYCONTIN can be abused and is subject to misuse, addiction, and criminal diversion.

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

Risks Specific to Abuse of OXYCONTIN

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

Please read Full Prescribing Information, including Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1‑888‑726‑7535, option 2, or FDA
at 1‑800‑FDA‑1088 or www​.fda​.gov/​s​a​f​e​t​y​/​m​e​d​watch.

Intended for healthcare professionals of the United States of America only.