• BOXED WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    X

    Important Safety Information and Indication

    WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    Addiction, Abuse, and Misuse
    HYSINGLA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing HYSINGLA ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)].

    Accidental Ingestion
    Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    Cytochrome P450 3A4 Interaction
    The concomitant use of HYSINGLA ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

    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 paralytic ileus and gastrointestinal obstruction, hypersensitivity to any component of Hysingla ER or the active ingredient, hydrocodone bitartrate.

    WARNINGS AND PRECAUTIONS

    Addiction, Abuse, and Misuse

    • Hysingla ER contains hydrocodone, a Schedule II controlled substance. Hysingla ER exposes users to the risks of opioid addiction, abuse, and misuse. As 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 and in those who obtain the drug illicitly. 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 or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.

    • 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.

    • Opioid agonists such as Hysingla ER 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.

    Life‐Threatening Respiratory Depression

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended, 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 dose increase. Closely monitor patients for respiratory depression when initiating therapy with Hysingla ER and following dose increases.

    • To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dose when converting patients from another opioid product can result in 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.

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use of Hysingla ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    Interactions with Central Nervous System Depressants

    • Hypotension, profound sedation, coma, respiratory depression, and death may result if Hysingla ER is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of Hysingla ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Hysingla ER therapy is made, start with a lower Hysingla ER dose than usual (i.e., 20-30% less), monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    Use in Elderly, Cachectic, and Debilitated Patients

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating Hysingla ER and when given concomitantly with other drugs that depress respiration.

    Use in Patients with Chronic Pulmonary Disease

    • When initiating therapy and titrating with Hysingla ER, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre‐existing respiratory depression. In these patients, even usual therapeutic doses of Hysingla ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non‐opioid analgesics in these patients if possible.

    Use in Patients with Head Injury and Increased Intracranial Pressure

    • In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

    • Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or impaired consciousness). 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.

    Hypotensive Effect

    • 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 been compromised by a depleted blood volume or after concurrent administration with drugs (e.g., phenothiazines or other agents which compromise vasomotor tone). Monitor these patients for signs of hypotension after initiating or titrating the dose 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.

    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.

    Decreased Bowel Motility

    • Hysingla ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of Hysingla ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.

    Cytochrome P450 3A4 Inhibitors and Inducers

    • The clinical results with CYP3A4 inhibitors show an increase in hydrocodone plasma concentrations and possibly increased or prolonged opioid effects, which could be more pronounced with concomitant use of CYP3A4 inhibitors. The expected clinical result with CYP3A4 inducers is a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone.

    • If co-administration is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.

    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.

    Interaction with Mixed Agonist/Antagonist Opioid Analgesics

    • Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including Hysingla ER. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

    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.

    ADVERSE REACTIONS

    • 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.

    INDICATIONS AND USAGE

    Hysingla® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Hysingla ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

    • Hysingla ER is not indicated as an as-needed analgesic.

    Please read the Full Prescribing Information, including Boxed Warning.

    Introducing

    Find Out More

    Please read the Full Prescribing Information, including Boxed Warning

    Now Approved Available February 2015

  • BOXED WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME

    X

    Important Safety Information and Indication

    WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME

    Addiction, Abuse, and Misuse
    Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

    Accidental Exposure
    Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    CONTRAINDICATIONS

    • Butrans 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 paralytic ileus; hypersensitivity (eg, anaphylaxis) to buprenorphine.

    WARNINGS AND PRECAUTIONS

    Addiction, Abuse, and Misuse

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

    • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butrans and in those who obtain the drug illicitly. 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 Butrans, and monitor all patients receiving Butrans for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Butrans, but use in such patients necessitates intensive counseling about the risks and proper use of Butrans, along with intensive monitoring for signs of addiction, abuse, or misuse.

    • Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

    • Opioid agonists such as Butrans are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Butrans. 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.

    Life-Threatening Respiratory Depression

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended, 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 Butrans, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with Butrans and following dose increases.

    • To reduce the risk of respiratory depression, proper dosing and titration of Butrans are essential. Overestimating the Butrans dose when converting patients from another opioid product can result in fatal overdose with the first dose.

    • Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use of Butrans during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    Interactions with Central Nervous System Depressants

    • Hypotension, profound sedation, coma, respiratory depression, and death may result if Butrans is used concomitantly with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of Butrans in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Butrans therapy is made, start with Butrans 5 mcg/hour patch, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    Use in Elderly, Cachectic and Debilitated Patients

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating Butrans and when given concomitantly with other drugs that depress respiration.

    Use in Patients With Chronic Pulmonary Disease

    • When initiating therapy and titrating with Butrans, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In these patients, even usual therapeutic doses of Butrans may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

    QTc Prolongation

    • A positive-controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval.

    • Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (eg, quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (eg, sotalol, amiodarone, dofetilide).

    Hypotensive Effects

    • Butrans 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 been compromised by a reduced blood volume or concurrent administration with certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of Butrans.

    Use in Patients With Head Injury or Increased Intracranial Pressure

    • Monitor patients taking Butrans who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with Butrans. Butrans may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butrans in patients with impaired consciousness or coma.

    Hepatotoxicity

    • Although not observed in Butrans chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. For patients at increased risk of hepatotoxicity, obtain baseline liver enzyme levels and monitor periodically and during treatment with Butrans.

    Application Site Skin Reactions

    • In rare cases, severe application site skin reactions with signs of marked inflammation including "burn," "discharge," and "vesicles" have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

    Anaphylactic/Allergic Reactions

    • Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans.

    Application of External Heat

    • Advise patients and their caregivers to avoid exposing the Butrans application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur. Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

    Patients With Fever

    • Monitor patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the Butrans dose if signs of respiratory or central nervous system depression occur.

    Use in Patients With Gastrointestinal Conditions

    • Butrans is contraindicated in patients with paralytic ileus. Avoid the use of Butrans in patients with other GI obstruction. Butrans may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

    Use in Patients With Convulsive or Seizure Disorders

    • Butrans may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during Butrans therapy.

    Driving and Operating Machinery

    • Butrans may impair the mental and 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 Butrans and know how they will react to the medication.

    Use in Addiction Treatment

    • Butrans has not been studied and is not approved for use in the management of addictive disorders.

    ADVERSE REACTIONS

    • Most common adverse reactions (≥5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

    INDICATIONS AND USAGE

    Butrans® (buprenorphine) Transdermal System is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butrans is not indicated as an as-needed (prn) analgesic.

    Please read the Full Prescribing Information, including Boxed Warning.

    Find Out More

    Please read the Full Prescribing Information, including Boxed Warning

  • BOXED WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    X

    Important Safety Information and Indication

    WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    Addiction, Abuse, and Misuse
    OxyContin® exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing OxyContin and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of OxyContin. Monitor for respiratory depression, especially during initiation of OxyContin or following a dose increase. Instruct patients to swallow OxyContin tablets whole; crushing, chewing, or dissolving OxyContin tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)].

    Accidental Ingestion
    Accidental ingestion of even one dose of OxyContin, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of OxyContin during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    Cytochrome P450 3A4 Interaction
    The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OxyContin and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)].

    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 paralytic ileus and gastrointestinal obstruction

    • Hypersensitivity (e.g., anaphylaxis) to oxycodone

    Warnings and Precautions

    • OxyContin contains oxycodone, a Schedule II controlled substance. OxyContin exposes users to the risks of opioid addiction, abuse, and misuse. As modified-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 or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as 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.

      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.

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

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release 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 OxyContin, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OxyContin and following dose increases.

      To reduce the risk of respiratory depression, proper dosing and titration of OxyContin are essential. Overestimating the OxyContin dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

      Accidental ingestion of even one dose of OxyContin, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

    • Prolonged use of OxyContin during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    • Hypotension and profound sedation, coma, respiratory depression or death may result if OxyContin is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

      When considering the use of OxyContin in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin OxyContin therapy is made, start with 1/3 to 1/2 the usual dose of OxyContin, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating OxyContin and when given concomitantly with other drugs that depress respiration.

    • When initiating or titrating OxyContin, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression. In these patients, even usual therapeutic doses of OxyContin may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

    • OxyContin may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose 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.

    • Monitor patients taking OxyContin who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with OxyContin. OxyContin may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OxyContin in patients with impaired consciousness or coma.

    • 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 exacerbations of diverticulitis, some of which have required medical intervention to remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen.

    • OxyContin is contraindicated in patients with GI obstruction, including paralytic ileus. OxyContin may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

    • OxyContin may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OxyContin therapy.

    • Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including 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 dose. Do not abruptly discontinue OxyContin.

    • 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.

    • Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase concentrations of oxycodone and prolong opioid effects. CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone.

      If co-administration is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.

    • 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 were constipation, nausea, somnolence, dizziness, pruritus, vomiting, headache, dry mouth, asthenia, and sweating.

    Adult Indications and Usage

    OxyContin is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve OxyContin for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain

    • OxyContin is not indicated as an as-needed (prn) analgesic

    Please read the Full Prescribing Information, including Boxed Warning.

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    Please read the Full Prescribing Information, including Boxed Warning

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  • IMPORTANT SAFETY INFORMATION AND INDICATION
    Please read the Full Prescribing Information, including Boxed Warning.

    WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    Addiction, Abuse, and Misuse
    HYSINGLA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing HYSINGLA ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)].

    Accidental Ingestion
    Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    Cytochrome P450 3A4 Interaction
    The concomitant use of HYSINGLA ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

    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 paralytic ileus and gastrointestinal obstruction, hypersensitivity to any component of Hysingla ER or the active ingredient, hydrocodone bitartrate.

    WARNINGS AND PRECAUTIONS

    Addiction, Abuse, and Misuse

    • Hysingla ER contains hydrocodone, a Schedule II controlled substance. Hysingla ER exposes users to the risks of opioid addiction, abuse, and misuse. As 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 and in those who obtain the drug illicitly. 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 or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.

    • 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.

    • Opioid agonists such as Hysingla ER 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.

    Life‐Threatening Respiratory Depression

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended, 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 dose increase. Closely monitor patients for respiratory depression when initiating therapy with Hysingla ER and following dose increases.

    • To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dose when converting patients from another opioid product can result in 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.

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use of Hysingla ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    Interactions with Central Nervous System Depressants

    • Hypotension, profound sedation, coma, respiratory depression, and death may result if Hysingla ER is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of Hysingla ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Hysingla ER therapy is made, start with a lower Hysingla ER dose than usual (i.e., 20-30% less), monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    Use in Elderly, Cachectic, and Debilitated Patients

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating Hysingla ER and when given concomitantly with other drugs that depress respiration.

    Use in Patients with Chronic Pulmonary Disease

    • When initiating therapy and titrating with Hysingla ER, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre‐existing respiratory depression. In these patients, even usual therapeutic doses of Hysingla ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non‐opioid analgesics in these patients if possible.

    Use in Patients with Head Injury and Increased Intracranial Pressure

    • In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

    • Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or impaired consciousness). 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.

    Hypotensive Effect

    • 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 been compromised by a depleted blood volume or after concurrent administration with drugs (e.g., phenothiazines or other agents which compromise vasomotor tone). Monitor these patients for signs of hypotension after initiating or titrating the dose 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.

    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.

    Decreased Bowel Motility

    • Hysingla ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of Hysingla ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.

    Cytochrome P450 3A4 Inhibitors and Inducers

    • The clinical results with CYP3A4 inhibitors show an increase in hydrocodone plasma concentrations and possibly increased or prolonged opioid effects, which could be more pronounced with concomitant use of CYP3A4 inhibitors. The expected clinical result with CYP3A4 inducers is a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone.

    • If co-administration is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.

    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.

    Interaction with Mixed Agonist/Antagonist Opioid Analgesics

    • Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including Hysingla ER. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

    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.

    ADVERSE REACTIONS

    • 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.

    INDICATIONS AND USAGE

    Hysingla® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Hysingla ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

    • Hysingla ER is not indicated as an as-needed analgesic.

  • IMPORTANT SAFETY INFORMATION AND INDICATION
    Please read the Full Prescribing Information, including Boxed Warning.

    WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME

    Addiction, Abuse, and Misuse
    Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].

    Accidental Exposure
    Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    CONTRAINDICATIONS

    • Butrans 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 paralytic ileus; hypersensitivity (eg, anaphylaxis) to buprenorphine.

    WARNINGS AND PRECAUTIONS

    Addiction, Abuse, and Misuse

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

    • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butrans and in those who obtain the drug illicitly. 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 Butrans, and monitor all patients receiving Butrans for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Butrans, but use in such patients necessitates intensive counseling about the risks and proper use of Butrans, along with intensive monitoring for signs of addiction, abuse, or misuse.

    • Abuse or misuse of Butrans by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death.

    • Opioid agonists such as Butrans are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Butrans. 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.

    Life-Threatening Respiratory Depression

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended, 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 Butrans, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with Butrans and following dose increases.

    • To reduce the risk of respiratory depression, proper dosing and titration of Butrans are essential. Overestimating the Butrans dose when converting patients from another opioid product can result in fatal overdose with the first dose.

    • Accidental exposure to Butrans, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

    Neonatal Opioid Withdrawal Syndrome

    • Prolonged use of Butrans during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    Interactions with Central Nervous System Depressants

    • Hypotension, profound sedation, coma, respiratory depression, and death may result if Butrans is used concomitantly with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of Butrans in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Butrans therapy is made, start with Butrans 5 mcg/hour patch, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    Use in Elderly, Cachectic and Debilitated Patients

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating Butrans and when given concomitantly with other drugs that depress respiration.

    Use in Patients With Chronic Pulmonary Disease

    • When initiating therapy and titrating with Butrans, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In these patients, even usual therapeutic doses of Butrans may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

    QTc Prolongation

    • A positive-controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval.

    • Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (eg, quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (eg, sotalol, amiodarone, dofetilide).

    Hypotensive Effects

    • Butrans 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 been compromised by a reduced blood volume or concurrent administration with certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of Butrans.

    Use in Patients With Head Injury or Increased Intracranial Pressure

    • Monitor patients taking Butrans who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with Butrans. Butrans may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butrans in patients with impaired consciousness or coma.

    Hepatotoxicity

    • Although not observed in Butrans chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. For patients at increased risk of hepatotoxicity, obtain baseline liver enzyme levels and monitor periodically and during treatment with Butrans.

    Application Site Skin Reactions

    • In rare cases, severe application site skin reactions with signs of marked inflammation including "burn," "discharge," and "vesicles" have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

    Anaphylactic/Allergic Reactions

    • Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans.

    Application of External Heat

    • Advise patients and their caregivers to avoid exposing the Butrans application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur. Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

    Patients With Fever

    • Monitor patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the Butrans dose if signs of respiratory or central nervous system depression occur.

    Use in Patients With Gastrointestinal Conditions

    • Butrans is contraindicated in patients with paralytic ileus. Avoid the use of Butrans in patients with other GI obstruction. Butrans may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

    Use in Patients With Convulsive or Seizure Disorders

    • Butrans may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during Butrans therapy.

    Driving and Operating Machinery

    • Butrans may impair the mental and 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 Butrans and know how they will react to the medication.

    Use in Addiction Treatment

    • Butrans has not been studied and is not approved for use in the management of addictive disorders.

    ADVERSE REACTIONS

    • Most common adverse reactions (≥5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

    INDICATIONS AND USAGE

    Butrans® (buprenorphine) Transdermal System is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations, reserve Butrans for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butrans is not indicated as an as-needed (prn) analgesic.

  • IMPORTANT SAFETY INFORMATION AND INDICATION
    Please read the Full Prescribing Information, including Boxed Warning.

    WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION

    Addiction, Abuse, and Misuse
    OxyContin® exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing OxyContin and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

    Life-Threatening Respiratory Depression
    Serious, life-threatening, or fatal respiratory depression may occur with use of OxyContin. Monitor for respiratory depression, especially during initiation of OxyContin or following a dose increase. Instruct patients to swallow OxyContin tablets whole; crushing, chewing, or dissolving OxyContin tablets can cause rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.2)].

    Accidental Ingestion
    Accidental ingestion of even one dose of OxyContin, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)].

    Neonatal Opioid Withdrawal Syndrome
    Prolonged use of OxyContin during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

    Cytochrome P450 3A4 Interaction
    The concomitant use of OxyContin with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OxyContin and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.14) and Clinical Pharmacology (12.3)].

    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 paralytic ileus and gastrointestinal obstruction

    • Hypersensitivity (e.g., anaphylaxis) to oxycodone

    Warnings and Precautions

    • OxyContin contains oxycodone, a Schedule II controlled substance. OxyContin exposes users to the risks of opioid addiction, abuse, and misuse. As modified-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 or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as 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.

      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.

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

    • Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release 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 OxyContin, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OxyContin and following dose increases.

      To reduce the risk of respiratory depression, proper dosing and titration of OxyContin are essential. Overestimating the OxyContin dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

      Accidental ingestion of even one dose of OxyContin, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

    • Prolonged use of OxyContin during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

    • Hypotension and profound sedation, coma, respiratory depression or death may result if OxyContin is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

      When considering the use of OxyContin in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that can cause CNS depression. If the decision to begin OxyContin therapy is made, start with 1/3 to 1/2 the usual dose of OxyContin, monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

    • Closely monitor elderly, cachectic, and debilitated patients, since life-threatening respiratory depression is more likely to occur due to altered pharmacokinetics or clearance, particularly when initiating and titrating OxyContin and when given concomitantly with other drugs that depress respiration.

    • When initiating or titrating OxyContin, monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression. In these patients, even usual therapeutic doses of OxyContin may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

    • OxyContin may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose 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.

    • Monitor patients taking OxyContin who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with OxyContin. OxyContin may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OxyContin in patients with impaired consciousness or coma.

    • 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 exacerbations of diverticulitis, some of which have required medical intervention to remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen.

    • OxyContin is contraindicated in patients with GI obstruction, including paralytic ileus. OxyContin may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

    • OxyContin may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OxyContin therapy.

    • Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including 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 dose. Do not abruptly discontinue OxyContin.

    • 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.

    • Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase concentrations of oxycodone and prolong opioid effects. CYP450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone.

      If co-administration is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved.

    • 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 were constipation, nausea, somnolence, dizziness, pruritus, vomiting, headache, dry mouth, asthenia, and sweating.

    Adult Indications and Usage

    OxyContin is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

    Limitations of Use

    • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve OxyContin for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain

    • OxyContin is not indicated as an as-needed (prn) analgesic

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