Nucynta

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF NUCYNTA TABLETS

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

  5.1 ADDICTION, ABUSE, AND MISUSE

  NUCYNTA tablets contain tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA tablets exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence (9)]

  .

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

  Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA tablets and reassess all patients receiving NUCYNTA tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA tablets but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA tablets 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)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA tablets. 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 on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  )
• Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA tablets are essential. (

  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 tablets, 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 tablets are essential

  [see Dosage and Administration (2.3)]

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

  Accidental ingestion of even one dose of NUCYNTA tablets, 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 tablets. 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)].

  )
• 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

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA tablets 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 tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)].

  ,

  7 DRUG INTERACTIONS

  Table 2 includes clinically significant drug interactions with NUCYNTA tablets.

  Table 2. Clinically Significant Drug Interactions with NUCYNTA Tablets

  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, increases the risk of respiratory depression, profound sedation, coma, and death [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 tablets 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 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 (5.3)]
  Intervention:	Do not use NUCYNTA tablets in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
  Examples:	phenelzine, tranylcypromine, linezolid
  Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
  Clinical Impact:	May reduce the analgesic effect of NUCYNTA tablets 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 tablets 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 tablets is used concomitantly with anticholinergic drugs.
  Alcohol, Other Opioids, and Drugs of Abuse
  Clinical Impact:	Due to its mu-opioid agonist activity, NUCYNTA tablets may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death [see Warnings and Precautions (5.16)] .
  Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non- prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA tablets therapy.
  Examples:	Alcohol, other opioids, illicit drugs

  • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:
    Avoid use with NUCYNTA tablets because they reduce analgesic effect of NUCYNTA tablets or precipitate withdrawal symptoms. .
  )
• Accidental ingestion of NUCYNTA tablets, especially by children, can result in a 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 tablets, 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 tablets are essential

  [see Dosage and Administration (2.3)]

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

  Accidental ingestion of even one dose of NUCYNTA tablets, 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 tablets. 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)].

  )
• 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 tablets 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.

  )

• NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see Clinical Pharmacology (12.3)].
  )
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of NUCYNTA tablets 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. (
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see Clinical Pharmacology (12.3)].
  ,
  5 WARNINGS AND PRECAUTIONS

  • Opioid-Induced Hyperalgesia and Allodynia
    : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
    : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue NUCYNTA tablets if serotonin syndrome is suspected.
  • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
    : Regularly evaluate, particularly during initiation and titration.
  • Adrenal Insufficiency
    : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • Severe Hypotension
    : Regularly evaluate during dosage initiation and titration. Avoid use of NUCYNTA tablets in patients with circulatory shock.
  • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
    : Monitor for sedation and respiratory depression. Avoid use of NUCYNTA tablets in patients with impaired consciousness or coma.

  5.1 ADDICTION, ABUSE, AND MISUSE

  NUCYNTA tablets contain tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA tablets exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence (9)]

  .

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

  Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA tablets and reassess all patients receiving NUCYNTA tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA tablets but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA tablets 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)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA tablets. 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 on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

  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 tablets, 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 tablets are essential

  [see Dosage and Administration (2.3)]

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

  Accidental ingestion of even one dose of NUCYNTA tablets, 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 tablets. 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

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA tablets 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 tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)].

  5.4 NEONATAL OPIOID WITHDRAWAL SYNDROME

  Use of NUCYNTA tablets 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)]

  .

  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.

  5.6 OPIOID-INDUCED HYPERALGESIA AND ALLODYNIA

  Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

  [see Dependence (9.3)]

  . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

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

  [see Dosage and Administration (2.7); Warnings and Precautions (5.13)].

  5.7 SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS

  Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)

  [see Drug Interactions (7)]

  . This may occur within the recommended dosage range.

  Serotonin syndrome symptoms may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue NUCYNTA tablets if serotonin syndrome is suspected.

  5.8 LIFE-THREATENING RESPIRATORY DEPRESSION IN PATIENTS WITH CHRONIC PULMONARY DISEASE OR IN ELDERLY, CACHECTIC, OR DEBILITATED PATIENTS

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

  Patients with Chronic Pulmonary Disease:

  NUCYNTA tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA tablets

  [see Warnings and Precautions (5.2)].

  Elderly, Cachectic, or Debilitated Patients:

  Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

  [see Warnings and Precautions (5.2)]

  .

  Regularly evaluate such patients closely, particularly when initiating and titrating NUCYNTA tablets and when NUCYNTA tablets are given concomitantly with other drugs that depress respiration

  [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)]

  . Alternatively, consider the use of non-opioid analgesics in these patients.

  5.9 ADRENAL INSUFFICIENCY

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

  5.10 SEVERE HYPOTENSION

  NUCYNTA tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

  [see Drug Interactions (7)].

  Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA tablets. In patients with circulatory shock, NUCYNTA tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA tablets in patients with circulatory shock.

  5.11 RISKS OF USE IN PATIENTS WITH INCREASED INTRACRANIAL PRESSURE, BRAIN TUMORS, HEAD INJURY, OR IMPAIRED CONSCIOUSNESS

  In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

  Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA tablets.

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

  5.12 RISKS OF USE IN PATIENTS WITH GASTROINTESTINAL CONDITIONS

  NUCYNTA tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

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

  5.13 INCREASED RISK OF SEIZURES IN PATIENTS WITH SEIZURE DISORDERS

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

  5.14 WITHDRAWAL

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

  [see Dosage and Administration (2.7), Drug Abuse and Dependence (9.3)]

  .

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

  [see Drug Interactions (7)]

  .

  5.15 RISKS OF DRIVING AND OPERATING MACHINERY

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

  5.16 INTERACTIONS WITH ALCOHOL, OTHER OPIOIDS, AND DRUGS OF ABUSE

  Due to its mu-opioid agonist activity, NUCYNTA tablets may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death

  [see Drug Interactions (7)]

  . Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on NUCYNTA tablets therapy

  [see Drug Interactions (7)]

  .

  5.17 RISK OF TOXICITY IN PATIENTS WITH HEPATIC IMPAIRMENT

  A study with NUCYNTA tablets in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA tablets in patients with severe hepatic impairment. Reduce the dose of NUCYNTA tablets in patients with moderate hepatic impairment

  [see Dosage and Administration (2.4)

  and

  Clinical Pharmacology (12.3)]

  . Regularly evaluate patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA tablets.

  5.18 RISK OF TOXICITY IN PATIENTS WITH RENAL IMPAIRMENT

  Use of NUCYNTA tablets in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known

  [see Clinical Pharmacology (12.3)]

  .
  )
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see 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. (
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see Clinical Pharmacology (12.3)].
  ,
  5.1 ADDICTION, ABUSE, AND MISUSE

  NUCYNTA tablets contain tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA tablets exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence (9)]

  .

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

  Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA tablets and reassess all patients receiving NUCYNTA tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA tablets but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA tablets 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)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA tablets. 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 on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  )
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA. Consider this risk when selecting an initial dose and when making dose adjustments.(
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see Clinical Pharmacology (12.3)].
  ,
  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 tablets, 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 tablets are essential

  [see Dosage and Administration (2.3)]

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

  Accidental ingestion of even one dose of NUCYNTA tablets, 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 tablets. 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)].
  )
• Nucynta tablets can be taken with or without food (
  2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS

  • NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of 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 tablets 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.
  • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
  • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. 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 tablets. Consider this risk when selecting an initial dose and when making dose adjustments

    [see Warnings and Precautions (5)]

    .
  • NUCYNTA tablets can be taken with or without food

    [

    see Clinical Pharmacology (12.3)].
  ).
• 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 tablets. 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 tablets

  [see Warnings and Precautions (5.3)].

  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 tablets contain tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA tablets exposes users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence (9)]

  .

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

  Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA tablets and reassess all patients receiving NUCYNTA tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA tablets but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA tablets 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)]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA tablets. 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 on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
  ,
  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 tablets, 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 tablets are essential

  [see Dosage and Administration (2.3)]

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

  Accidental ingestion of even one dose of NUCYNTA tablets, 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 tablets. 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

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA tablets 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 tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

  [see Drug Interactions (7)].
  )
• .
  Dosing in adults:
  See full prescribing information for detailed dosing instructions. (
  2.3 INITIAL DOSAGE IN ADULTS

  Initiating Treatment with NUCYNTA Tablets

  Initiate treatment with NUCYNTA tablets in a dosing range of 50 mg to 100 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of NUCYNTA tablets.

  On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability.

  Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended.

  NUCYNTA tablets may be given with or without food

  [see Clinical Pharmacology (12.3)].

  Conversion from NUCYNTA Tablets to NUCYNTA ER

  Patients can be converted from NUCYNTA tablets to NUCYNTA ER using the equivalent total daily dose of NUCYNTA tablets 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 tablets four times per day (200 mg/day) may be converted to 100 mg NUCYNTA ER twice a day. Conversion to NUCYNTA ER may lead to increased risk of excessive sedation and respiratory depression.
  )
• Dosing in Pediatric Patients aged 6 years and older with a body weight of at least 40 kg and who are able to swallow tablets:
  See full prescribing information for detailed dosing instructions. (
  2.4 DOSAGE IN PEDIATRIC PATIENTS 6 YEARS AND OLDER WITH BODY WEIGHT OF AT LEAST 40 KG

  Pediatric patients who are at least 6 years old, weigh at least 40 kg, and are able to swallow oral tablets:

  For patients weighing 40 to 59 kg, administer 50 mg every 4 hours. Do not exceed a maximum single dose of 50 mg. If adequate analgesia is not achieved with a 50 mg NUCYNTA tablet every 4 hours, do not increase to a 75 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing 60 to 79 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 75 mg. If adequate analgesia is not achieved with a 75 mg NUCYNTA tablet every 4 hours, do not increase to a 100 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing greater than or equal to 80 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. If adequate pain relief is not attained with a 75 mg NUCYNTA tablet every 4 hours, increase the dose to 100 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 100 mg.

  The maximum daily dose is 7.5 mg/kg/day (i.e., six 1.25 mg/kg doses over 24 hours).

  Daily doses greater than 600 mg have not been studied in pediatric patients and are not recommended.

  In pediatric patients with high body mass index (BMI), the maximum daily dose must not exceed the calculated maximum dose for a body weight at the 97th percentile for a given age.

  The efficacy and safety of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight (maximum single dose of 100 mg) have not been studied; therefore, the use of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight is not recommended

  [see Clinical Studies (14.2)]

  .

  Dose reductions may be considered over time as acute pain decreases.

  NUCYNTA tablets are not recommended for use in pediatric patients who weigh less than 40 kg as the recommended dose cannot be achieved with available tablet strengths. Consider use of another NUCYNTA product, such as NUCYNTA oral solution, in patients who cannot swallow oral tablets or who weigh less than 40 kg

  [see Pediatric Use (8.4)]

  .

  Duration of Treatment

  NUCYNTA (tapentadol) tablets are intended for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. In pediatric patients, the duration of treatment should not exceed 3 days as the safety and effectiveness of longer treatment have not been established.

  Hepatic or Renal Impairment

  NUCYNTA (tapentadol) tablets have not been studied in pediatric patients with hepatic or renal impairment; therefore, use in these populations is not recommended

  [see Pediatric Use (8.4)]

  .
  )
• Moderate Hepatic Impairment in Adult Patients:
  Initiate treatment with 50 mg no more than once every 8 hours (maximum of three doses in 24 hours). Regularly evaluate for respiratory and central nervous system depression. (
  2.4 DOSAGE IN PEDIATRIC PATIENTS 6 YEARS AND OLDER WITH BODY WEIGHT OF AT LEAST 40 KG

  Pediatric patients who are at least 6 years old, weigh at least 40 kg, and are able to swallow oral tablets:

  For patients weighing 40 to 59 kg, administer 50 mg every 4 hours. Do not exceed a maximum single dose of 50 mg. If adequate analgesia is not achieved with a 50 mg NUCYNTA tablet every 4 hours, do not increase to a 75 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing 60 to 79 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 75 mg. If adequate analgesia is not achieved with a 75 mg NUCYNTA tablet every 4 hours, do not increase to a 100 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing greater than or equal to 80 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. If adequate pain relief is not attained with a 75 mg NUCYNTA tablet every 4 hours, increase the dose to 100 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 100 mg.

  The maximum daily dose is 7.5 mg/kg/day (i.e., six 1.25 mg/kg doses over 24 hours).

  Daily doses greater than 600 mg have not been studied in pediatric patients and are not recommended.

  In pediatric patients with high body mass index (BMI), the maximum daily dose must not exceed the calculated maximum dose for a body weight at the 97th percentile for a given age.

  The efficacy and safety of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight (maximum single dose of 100 mg) have not been studied; therefore, the use of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight is not recommended

  [see Clinical Studies (14.2)]

  .

  Dose reductions may be considered over time as acute pain decreases.

  NUCYNTA tablets are not recommended for use in pediatric patients who weigh less than 40 kg as the recommended dose cannot be achieved with available tablet strengths. Consider use of another NUCYNTA product, such as NUCYNTA oral solution, in patients who cannot swallow oral tablets or who weigh less than 40 kg

  [see Pediatric Use (8.4)]

  .

  Duration of Treatment

  NUCYNTA (tapentadol) tablets are intended for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. In pediatric patients, the duration of treatment should not exceed 3 days as the safety and effectiveness of longer treatment have not been established.

  Hepatic or Renal Impairment

  NUCYNTA (tapentadol) tablets have not been studied in pediatric patients with hepatic or renal impairment; therefore, use in these populations is not recommended

  [see Pediatric Use (8.4)]

  .
  )
• Do not abruptly discontinue NUCYNTA tablets in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.6 TITRATION AND MAINTENANCE OF THERAPY

  Individually titrate NUCYNTA tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving NUCYNTA tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as 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.

  If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the NUCYNTA tablets dosage. If after increase the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
  ,
  5.14 WITHDRAWAL

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

  [see Dosage and Administration (2.7), Drug Abuse and Dependence (9.3)]

  .

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

  [see Drug Interactions (7)]

  .
  )

Tablets: 50 mg, 75 mg, 100 mg.

50 mg: round, biconvex and film-coated yellow tablets with "O-M" on one side and "50" on the other side.

75 mg: round, biconvex and film-coated yellow-orange tablets with "O-M" on one side and "75" on the other side.

100 mg: round, biconvex and film-coated orange tablets with "O-M" on one side and "100" on the other side.

• Pregnancy
  : 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 tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are risks to the mother and infant associated with use of NUCYNTA tablets for an extended period of time during pregnancy

  (see Clinical Considerations).

  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 2-4% and 15-20%, 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 psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including NUCYNTA tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, 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 subcutaneous exposure during 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 times the plasma exposure at the maximum recommended human dose (MRHD) of 700 mg/day 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 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC comparison] 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 1.7 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. Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal Day 4.
  )
• Lactation
  : Closely monitor infants of nursing women receiving NUCYNTA tablets. (
  8.2 Lactation

  Risk Summary

  There are no data on the presence of tapentadol in human milk, the effects on the breastfed infant, or the effects on milk production. Tapentadol is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to NUCYNTA tablets through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

  The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NUCYNTA tablets and any potential adverse effects on the breastfed infant from NUCYNTA tablets or from the underlying maternal condition.
  )
• Severe Renal or Hepatic Impairment
  : Not recommended. (
  8.6 Hepatic impairment

  Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function

  [see Clinical Pharmacology (12.3)]

  . Use of NUCYNTA tablets are not recommended in patients with severe hepatic impairment (Child-Pugh Score 10 to 15)

  [see Warnings and Precautions (5.17)]

  . The dose of NUCYNTA tablets should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9)

  [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 (5.17), Clinical Pharmacology (12.3)].
  ,
  8.7 Renal impairment

  Use of NUCYNTA tablets 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 (5.18), Clinical Pharmacology (12.1)]

  .
  )
• Pediatric Patients with Hepatic or Renal Impairment:
  Use not recommended. (
  2.4 DOSAGE IN PEDIATRIC PATIENTS 6 YEARS AND OLDER WITH BODY WEIGHT OF AT LEAST 40 KG

  Pediatric patients who are at least 6 years old, weigh at least 40 kg, and are able to swallow oral tablets:

  For patients weighing 40 to 59 kg, administer 50 mg every 4 hours. Do not exceed a maximum single dose of 50 mg. If adequate analgesia is not achieved with a 50 mg NUCYNTA tablet every 4 hours, do not increase to a 75 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing 60 to 79 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 75 mg. If adequate analgesia is not achieved with a 75 mg NUCYNTA tablet every 4 hours, do not increase to a 100 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution.

  For patients weighing greater than or equal to 80 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. If adequate pain relief is not attained with a 75 mg NUCYNTA tablet every 4 hours, increase the dose to 100 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 100 mg.

  The maximum daily dose is 7.5 mg/kg/day (i.e., six 1.25 mg/kg doses over 24 hours).

  Daily doses greater than 600 mg have not been studied in pediatric patients and are not recommended.

  In pediatric patients with high body mass index (BMI), the maximum daily dose must not exceed the calculated maximum dose for a body weight at the 97th percentile for a given age.

  The efficacy and safety of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight (maximum single dose of 100 mg) have not been studied; therefore, the use of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight is not recommended

  [see Clinical Studies (14.2)]

  .

  Dose reductions may be considered over time as acute pain decreases.

  NUCYNTA tablets are not recommended for use in pediatric patients who weigh less than 40 kg as the recommended dose cannot be achieved with available tablet strengths. Consider use of another NUCYNTA product, such as NUCYNTA oral solution, in patients who cannot swallow oral tablets or who weigh less than 40 kg

  [see Pediatric Use (8.4)]

  .

  Duration of Treatment

  NUCYNTA (tapentadol) tablets are intended for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. In pediatric patients, the duration of treatment should not exceed 3 days as the safety and effectiveness of longer treatment have not been established.

  Hepatic or Renal Impairment

  NUCYNTA (tapentadol) tablets have not been studied in pediatric patients with hepatic or renal impairment; therefore, use in these populations is not recommended

  [see Pediatric Use (8.4)]

  .
  ,
  8.4 Pediatric use

  The safety and effectiveness of NUCYNTA (tapentadol) tablets in pediatric patients ages 6 years and older who weigh at least 40 kg have been established. Use of NUCYNTA (tapentadol) tablets in pediatric patients ages 6 years and older who weigh at least 40 kg is based on one randomized, double-blind, placebo-controlled, multiple-dose efficacy and safety study of NUCYNTA (tapentadol) oral solution in 175 pediatric patients from birth to 17 years of age who had undergone surgery that would reliably produce moderate to severe pain and supported by pharmacokinetic and safety data from three open-label, single-dose studies of NUCYNTA (tapentadol) oral solution in 129 patients from birth to 17 years of age with moderate to severe acute pain from a surgical procedure

  [see Clinical Studies (14.2)]

  .

  The safety and effectiveness of NUCYNTA (tapentadol) tablets in pediatric patients less than 6 years of age have not been established. In pediatric patients less than 6 years of age, NUCYNTA (tapentadol) oral solution did not demonstrate efficacy compared to placebo when evaluated in one randomized, double-blind, placebo-controlled, multiple-dose study in 175 pediatric patients from birth to 17 years of age who had undergone surgery that would reliably produce moderate to severe pain

  [see Clinical Studies (14.2)]

  .

  The safety and effectiveness of NUCYNTA (tapentadol) tablets in pediatric patients who weigh less than 40 kg have not been established because the recommended dosage cannot be achieved with available tablet strengths. Consider use of another NUCYNTA product, such as NUCYNTA (tapentadol) oral solution, in patients who cannot swallow oral tablets or who weigh less than 40 kg [

  see Dosage and Administration (2.3)]

  .

  NUCYNTA (tapentadol) tablets have not been studied in pediatric patients with hepatic or renal impairment; therefore, use in these populations is not recommended

  [see Dosage and Administration (2.4)]

  .
  )