Nucynta Er

• NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing and reassess regularly for development of these behaviors or conditions. (

  5.1 Addiction, Abuse, and Misuse

  NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present

  [see Drug Abuse and Dependence (9)]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA ER, and reassess all patients receiving NUCYNTA 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 prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

  .

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

  [see Overdosage (10)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  )
• Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (

  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.

  ,

  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status

  [see Overdosage (10)]

  .

  Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential

  [see Dosage and Administration (2)]

  . Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

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

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

  .

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

  [see Dosage and Administration (2.6)].

  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 NUCYNTA 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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

  )
• Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (

  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status

  [see Overdosage (10)]

  .

  Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential

  [see Dosage and Administration (2)]

  . Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

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

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

  .

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

  [see Dosage and Administration (2.6)].

  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 NUCYNTA 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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

  )
• Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol

  [see Clinical Pharmacology (12.3)]

  .

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

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

  [see Drug Interactions (7)]

  .

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

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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA 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 depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)]

  .

  )
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol

  [see Clinical Pharmacology (12.3)]

  .

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

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

  [see Drug Interactions (7)]

  .

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

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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA 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 depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)]

  .

  ,

  7 DRUG INTERACTIONS

  Table 3 includes clinically significant drug interactions with NUCYNTA ER.

  Table 3. Clinically Significant Drug Interactions with NUCYNTA ER

  Alcohol
  Clinical Impact:	Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol.
  Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non- prescription products containing alcohol while on NUCYNTA ER therapy [see Warnings and Precautions (5.3)] .
  Benzodiazepines and Other Central Nervous System (CNS) Depressants
  Clinical Impact:	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 [see Warnings and Precautions (5.3)] .
  Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)].
  Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol
  Serotonergic Drugs
  Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.7)].
  Intervention:	If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue NUCYNTA ER if serotonin syndrome is suspected.
  Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
  Monoamine Oxidase Inhibitors (MAOIs)
  Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
  Intervention:	Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment
  Examples:	phenelzine, tranylcypromine, linezolid
  Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
  Clinical Impact:	May reduce the analgesic effect of NUCYNTA ER and/or precipitate withdrawal symptoms.
  Intervention:	Avoid concomitant use.
  Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
  Muscle Relaxants
  Clinical Impact:	Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
  Intervention:	Because respiratory depression may be greater than otherwise expected, decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)]
  Examples:	cyclobenzaprine, metaxalone
  Diuretics
  Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
  Intervention:	Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
  Anticholinergic Drugs
  Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
  Intervention:	Evaluate patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs.

  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
    : Avoid use with NUCYNTA ER because they may reduce analgesic effect of NUCYNTA ER or precipitate withdrawal symptoms.

  )
• If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of NUCYNTA ER for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.

  Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations (8.1)]

  .

  )
• Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (

  5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

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

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

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

  )

• Severe and persistent pain in adults that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.
• Severe and persistent neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

• NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.
  )
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks (
  2.5 Dosage Modification in Patients with Hepatic Impairment

  The use of NUCYNTA ER in patients with severe hepatic impairment (Child-Pugh Score 10-15) is not recommended

  [see Warnings and Precautions (5.16)]

  .

  In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate treatment using 50 mg NUCYNTA ER, administer no more frequently than once every 24 hours, and regularly evaluate for respiratory and central nervous system depression, particularly during initiation and titration of NUCYNTA ER. The maximum recommended dose for patients with moderate hepatic impairment is 100 mg of NUCYNTA ER per day. Regularly evaluate patients for respiratory and central nervous system depression

  [see Clinical Pharmacology (12.2)]

  .

  No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6)

  [see Warnings and Precautions (5.16), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
  ).
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment, and response, and risk factors for addiction, abuse, and misuse. (
  5.1 Addiction, Abuse, and Misuse

  NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present

  [see Drug Abuse and Dependence (9)]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA ER, and reassess all patients receiving NUCYNTA 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 prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

  .

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

  [see Overdosage (10)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  )
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments. (
  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.
  ,
  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status

  [see Overdosage (10)]

  .

  Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential

  [see Dosage and Administration (2)]

  . Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

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

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

  .

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

  [see Dosage and Administration (2.6)].

  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 NUCYNTA 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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
  )
• Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with NUCYNTA ER. Consider prescribing naloxone based on the patient's risk factors for overdose. (
  2.2 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 NUCYNTA ER

  [see Warnings and Precautions (5.2)].

  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).

  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

  [see Warnings and Precautions (5.1, 5.2, 5.3)].

  Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.
  ,
  5.1 Addiction, Abuse, and Misuse

  NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present

  [see Drug Abuse and Dependence (9)]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA ER, and reassess all patients receiving NUCYNTA 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 prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

  .

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

  [see Overdosage (10)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  ,
  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status

  [see Overdosage (10)]

  .

  Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential

  [see Dosage and Administration (2)]

  . Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

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

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

  .

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

  [see Dosage and Administration (2.6)].

  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 NUCYNTA 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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
  ,
  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol

  [see Clinical Pharmacology (12.3)]

  .

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

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

  [see Drug Interactions (7)]

  .

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

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

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA 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 depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)]

  .
  )
• Instruct patients to swallow NUCYNTA ER tablets intact, and not to cut, break, chew, crush, or dissolve the tablets (risk of potentially fatal overdose). (
  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.
  ,
  5.1 Addiction, Abuse, and Misuse

  NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA 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 tapentadol present

  [see Drug Abuse and Dependence (9)]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA ER, and reassess all patients receiving NUCYNTA 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 prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

  [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

  .

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

  [see Overdosage (10)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  )
• Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in mouth. (
  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.
  )
• Do not exceed a total daily dose of NUCYNTA ER of 500 mg. (
  2.1 Important Dosage and Administration Instructions

  • NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
  • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

    [see Warnings and Precautions (5)]

    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

    [see Warnings and Precautions (5.1)]
  • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5.2)]

    .
  • Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death

    [see Warnings and Precautions (5.1)].
  • Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER

    [see Warnings and Precautions (5.7)]

    .
  • Although the maximum approved total daily dose of NUCYNTA immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA ER is 500 mg. Do not exceed a total daily dose of NUCYNTA ER of 500 mg.
  )
• For opioid-naïve and opioid non-tolerant patients, initiate treatment with 50 mg tablet orally twice daily (approximately every 12 hours). See full prescribing information for instructions on conversion, titration, and maintenance of therapy. (
  2.3 Initial Dosage

  Use of NUCYNTA ER as the First Opioid Analgesic (opioid-naïve patients)

  Initiate treatment with NUCYNTA ER with the 50 mg tablet orally twice daily (approximately every 12 hours).

  Use of NUCYNTA ER in Patients who are not Opioid Tolerant

  The starting dose for patients who are not opioid tolerant is NUCYNTA ER 50 mg orally twice daily (approximately every 12 hours). Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

  Conversion from NUCYNTA to NUCYNTA ER

  Patients can be converted from NUCYNTA to NUCYNTA ER using the equivalent total daily dose of NUCYNTA and dividing it into two equal doses of NUCYNTA ER separated by approximately 12-hour intervals. As an example, a patient receiving 50 mg of NUCYNTA four times per day (200 mg/day) may be converted to 100 mg NUCYNTA ER twice a day.

  Conversion from Other Opioids to NUCYNTA ER

  When NUCYNTA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. There are no established conversion ratios for conversion from other opioids to NUCYNTA ER defined by clinical trials. Initiate dosing using NUCYNTA ER 50 mg orally every 12 hours.

  It is safer to underestimate a patient's 24-hour oral tapentadol dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral tapentadol requirements which could result in an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations.

  Close observation and frequent titration are warranted until pain management is stable on the new opioid. Frequently evaluate patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to NUCYNTA ER.

  Conversion from Methadone to NUCYNTA ER

  Frequent evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.
  ,
  2.4 Titration and Maintenance of Therapy

  Individually titrate NUCYNTA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving NUCYNTA ER to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions (5.1, 5.14)]

  . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  Patients who experience breakthrough pain may require a dosage adjustment of NUCYNTA ER or may need rescue medication with an appropriate dose of an immediate-release analgesic.

  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the NUCYNTA ER dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

  [see Warnings and Precautions (5)]

  . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

  Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily every three days. In clinical studies, efficacy with NUCYNTA ER was demonstrated relative to placebo in the dosage range of 100 mg to 250 mg twice daily

  [see Clinical Studies (14)]

  .
  )
• Titrate patients with dose increases of 50 mg no more than twice daily every three days. (
  2.4 Titration and Maintenance of Therapy

  Individually titrate NUCYNTA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving NUCYNTA ER to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions (5.1, 5.14)]

  . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  Patients who experience breakthrough pain may require a dosage adjustment of NUCYNTA ER or may need rescue medication with an appropriate dose of an immediate-release analgesic.

  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the NUCYNTA ER dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

  [see Warnings and Precautions (5)]

  . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

  Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily every three days. In clinical studies, efficacy with NUCYNTA ER was demonstrated relative to placebo in the dosage range of 100 mg to 250 mg twice daily

  [see Clinical Studies (14)]

  .
  )
• Moderate Hepatic Impairment: Initiate treatment with 50 mg NUCYNTA ER no more than every 24 hours. Do not exceed 100 mg per day. Regularly evaluate for respiratory and central nervous system depression (
  2.5 Dosage Modification in Patients with Hepatic Impairment

  The use of NUCYNTA ER in patients with severe hepatic impairment (Child-Pugh Score 10-15) is not recommended

  [see Warnings and Precautions (5.16)]

  .

  In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate treatment using 50 mg NUCYNTA ER, administer no more frequently than once every 24 hours, and regularly evaluate for respiratory and central nervous system depression, particularly during initiation and titration of NUCYNTA ER. The maximum recommended dose for patients with moderate hepatic impairment is 100 mg of NUCYNTA ER per day. Regularly evaluate patients for respiratory and central nervous system depression

  [see Clinical Pharmacology (12.2)]

  .

  No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6)

  [see Warnings and Precautions (5.16), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
  )
• Do not abruptly discontinue NUCYNTA ER in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.6 Safe Reduction or Discontinuation of NUCYNTA ER

  Do not abruptly discontinue NUCYNTA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

  Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

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

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

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

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

  [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].
  )

NUCYNTA ER 50 mg, 100 mg, 150 mg, 200 mg and 250 mg extended-release tablets are available in the following colors and prints:

• 50 mg extended-release tablets are white oblong-shaped with a black print "OMJ 50" on one side
• 100 mg extended-release tablets are light-blue oblong-shaped with a black print "OMJ 100" on one side
• 150 mg extended-release tablets are blue-green oblong-shaped with a black print "OMJ 150" on one side
• 200 mg extended-release tablets are blue oblong-shaped with a depression in the middle running lengthwise on each side and a black print "OMJ 200" on one side
• 250 mg extended-release tablets are dark blue oblong-shaped with a depression in the middle running lengthwise on each side and a white print "OMJ 250" on one side.

• Pregnancy
  : Based on animal data, may cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome

  [see Warnings and Precautions (5.4)].

  Available data with NUCYNTA ER are insufficient to inform a drug- associated risk for major birth defects and miscarriage or adverse maternal outcomes. In animal reproduction studies, embryofetal mortality and structural malformations were observed with subcutaneous administration of tapentadol during organogenesis to rabbits and delays in skeletal maturation were observed in rats at exposures equivalent to and less than the maximum recommended human dose (MRHD), respectively. When administered to pregnant rats during organogenesis and through lactation, increased pup mortality was noted following oral tapentadol exposures to doses equivalent to the MRHD

  [see

  Data

  ]

  . Based on animal data, advise pregnant women of the potential risk to a fetus.

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

  Clinical Considerations

  Fetal/neonatal adverse reactions

  Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

  [see Warnings and Precautions (5.4)].

  Labor or Delivery

  Opioids cross the placenta and may produce respiratory depression and psychophysiological effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including NUCYNTA ER, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

  Data

  Animal Data

  Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1.36 times the plasma exposure at the maximum recommended human dose (MRHD) of 500 mg/day for NUCYNTA ER based on an area under the time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of embryofetal toxicity included transient delays in skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.3, 0.8, and 2.5 times the plasma exposure at the MRHD based on an AUC comparison, respectively] revealed embryofetal toxicity at doses ≥10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses ≥10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day.

  Embryofetal toxicity, including malformations, may be secondary to the significant maternal toxicity observed in the study.

  In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early postnatal period [resulting in up to 2.28 times the plasma exposure at the MRHD on an AUC basis] did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. At maternal tapentadol doses ≥150 mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4. Treatment-related developmental delay was observed in the dead pups, including incomplete ossification. In addition, significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above) were seen throughout lactation.
  )
• Lactation:
  Not recommended. (
  8.2 Lactation

  Risk Summary

  There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded.

  Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER.

  Clinical Considerations

  Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
  )
• Severe Hepatic or Renal Impairment:
  Use not recommended. (
  8.6 Hepatic Impairment

  Use of NUCYNTA ER in patients with severe hepatic impairment (Child-Pugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended

  [see Dosage and Administration (2.5)].

  No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6)

  [see Warnings and Precautions (5.16), Clinical Pharmacology (12.3)]

  .
  ,
  8.7 Renal Impairment

  Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. No dosage adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30-90 mL/minute)

  [see Warnings and Precautions (5.17), Clinical Pharmacology (12.3)]

  .
  )