HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`NUCYNTA® ER safely and effectively. See full prescribing information
`for NUCYNTA® ER
`
`NUCYNTA® ER (tapentadol) extended-release tablets for oral use
`C-II Initial U.S. Approval: 2008
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-
`THREATENING RESPIRATORY DEPRESSION;
`ACCIDENTAL INGESTION; NEONATAL OPIOID
`WITHDRAWAL SYNDROME; INTERACTION WITH
`ALCOHOL and RISKS FROM CONCOMITANT USE WITH
`BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
`
`See full prescribing information for complete boxed warning.
`
`• 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
`monitor regularly for development of these behaviors
`or conditions. (5.1)
`• Serious, life-threatening, or fatal respiratory depression
`may occur. Monitor closely, especially upon initiation
`or following a dose
`increase. Instruct patients to
`swallow NUCYNTA ER tablets whole to avoid exposure
`to a potentially fatal dose of tapentadol. (5.2)
`• Accidental ingestion of NUCYNTA ER, especially in
`children, can result in fatal overdose of tapentadol. (5.2)
`• Prolonged use of NUCYNTA ER during pregnancy can
`result in neonatal opioid withdrawal syndrome, which
`may be life-threatening if not recognized and treated.
`If opioid use is required for a prolonged period in a
`pregnant woman, advise the patient of the risk of
`neonatal opioid withdrawal syndrome and ensure that
`appropriate treatment will be available (5.3).
`Instruct patients not to consume alcohol or any products
`taking NUCYNTA® ER
`containing alcohol while
`because co-ingestion can result
`in
`fatal plasma
`tapentadol levels. (5.4)
`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; limit dosages and
`durations to the minimum required; and follow patients
`for signs and symptoms of respiratory depression and
`sedation. (5.4), (7).
`
`•
`
`•
`
`•
`
`
`—————————RECENT MAJOR CHANGES————————
`Boxed Warning
`12/2016
`Warnings and Precautions (5)
`12/2016
`
`—————————INDICATIONS AND USAGE————————
`NUCYNTA ER is an opioid agonist indicated for the management of:
`•
`pain severe enough to require daily, around-the-clock, long-term opioid
`treatment and for which alternative treatment options are inadequate (1)
`neuropathic pain associated with diabetic peripheral neuropathy (DPN)
`in adults severe enough to require daily, around-the-clock, long-term
`opioid treatment and for which alternative treatment options are
`inadequate. (1)
`Limitations of Use
`• Because of the risks of addiction, abuse, and misuse with opioids, even
`at recommended doses, and because of the greater risks of overdose and
`death with extended-release opioid formulations, reserve NUCYNTA
`ER for use in patients for whom alternative treatment options (e.g., non-
`opioid analgesics or immediate-release opioids) are ineffective, not
`tolerated, or would be otherwise inadequate to provide sufficient
`management of pain.
`• NUCYNTA ER is not indicated as an as-needed (prn) analgesic. (1)
`
`——————— DOSAGE AND ADMINISTRATION———————
`•
`To be prescribed only by healthcare providers knowledgeable in use of
`potent opioids for management of chronic pain. (2.1)
`• Use the lowest effective dosage for the shortest duration consistent with
`individual patient treatment goals (2.1).
`Reference ID: 4028547
`
`
`
`
`
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Individualize dosing based on the severity of pain, patient response,
`prior analgesic experience, and risk factors for addiction, abuse, and
`misuse. (2.1)
`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, 5.1)
`Instruct patients to take tablets one at a time, with enough water to
`ensure complete swallowing immediately after placing in mouth. (2.1)
`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. (2.2, 2.3)
`Titrate patients with dose increases of 50 mg no more than twice daily
`every three days. (2.3)
`• Maximum daily dose is 500 mg per day. (2.1)
`• Moderate Hepatic Impairment: Initiate treatment with 50 mg
`NUCYNTA ER no more than every 24 hours. Do not exceed 100 mg
`per day. Monitor closely for respiratory and central nervous system
`depression (2.4)
`• Do not abruptly discontinue NUCYNTA® ER in a physically-dependent
`patient. (2.5)
`
`———————DOSAGE FORMS AND STRENGTHS——————
`Extended-release tablets: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg (3)
`
`
`——————————CONTRAINDICATIONS—————————
`•
`Significant respiratory depression (4)
`• Acute or severe bronchial asthma (4)
`• Known or suspected paralytic ileus (4)
`• Hypersensitivity to tapentadol or to any other ingredients of the
`product (4)
`• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of
`MAOIs within the last 14 days. (4)
`
`———————WARNINGS AND PRECAUTIONS———————
`• Risk of Life-Threatening Respiratory Depression in Patients with
`Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated
`Patients: Monitor closely, particularly during initiation and titration.
`(5.1)
`Serotonin Syndrome: Potentially life-threatening condition could result
`from concomitant serotonergic drug administration. Discontinue
`NUCYNTA® ER if serotonin syndrome is suspected. (5.6)
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement
`of corticosteroids, and wean patient off of the opioid. (5.7)
`Severe Hypotension: Monitor during dosage initiation and titration.
`Avoid use of NUCYNTA® ER in patients with circulatory shock. (5.8)
`• 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® ER in patients
`with impaired consciousness or coma. (5.9)
`
`—————————— ADVERSE REACTIONS—————————
`The most common (≥10%) adverse reactions were nausea, constipation,
`dizziness, headache, and somnolence. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Depomed,
`Inc. at 1-866-458-6389 or FDA at 1–800–FDA–1088 or
`www.fda.gov/medwatch.
`
`——————————DRUG INTERACTIONS—————————
`• 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. (5.12, 7)
`
`•
`
`•
`
`
`——————— USE IN SPECIFIC POPULATIONS———————
`•
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`• Nursing mothers: Nursing is not recommended. (8.2)
`•
`Severe Hepatic or Renal Impairment: Use not recommended. (8.6,
`8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide.
`
`Revised: 12/2016
`
`

`

`7
`8
`
`9
`
`Clinical Trial Experience
`6.1
`Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`8.7
`Renal Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse
`9.3
`Dependence
`10 OVERDOSAGE
`10.1 Clinical Presentation
`10.2
`Treatment of Overdose
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Clinical Trials Summary
`14.2 Moderate to Severe Chronic Low Back Pain
`14.3 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-
`THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
`INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;
`INTERACTION WITH ALCOHOL and RISKS FROM
`CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS
`DEPRESSANTS
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Important Dosage and Administration Instructions
`2.2
`Initial Dosage
`2.3
`Titration and Maintenance of Therapy
`2.4
`Dosage Modification in Patients with Hepatic Impairment
`
`2.5
`Discontinuation of NUCYNTA
`ER
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Addiction, Abuse, and Misuse
`5.2
`Life-Threatening Respiratory Depression
`5.3
`Neonatal Opioid Withdrawal Syndrome
`5.4
`Risk from Concomitant Use with Benzodiazepines or Other CNS
`Depressants
`Risk of Life-Threatening Respiratory Depression in Patients with
`Chronic Pulmonary Disease or in Elderly, Cachectic, or
`Debilitated Patients
`Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
`Adrenal Insufficiency
`Severe Hypotension
`Risks of Use in Patients with Increased Intracranial Pressure,
`Brain Tumors, Head Injury, or Impaired Consciousness
`5.10 Risks of Use in Patients with Gastrointestinal Conditions
`5.11
`Increased Risk of Seizures in Patients with Seizure Disorders
`5.12 Withdrawal
`5.13 Risks of Driving and Operating Machinery
`5.14 Risk of Toxicity in Patients with Hepatic Impairment
`5.15 Risk of Toxicity in Patients with Renal Impairment
`ADVERSE REACTIONS
`
`5.6
`5.7
`5.8
`5.9
`
`5.5
`
`6
`
`
`Reference ID: 4028547
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY
`DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL
`SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE
`WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
`
`Addiction, Abuse, and Misuse
`NUCYNTA ER exposes patients and other users to the risks of opioid addiction, abuse, and
`misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing
`NUCYNTA ER, and monitor all patients regularly for the development of these behaviors and
`conditions [see Warnings and Precautions (5.1)].
`
`Life-threatening Respiratory Depression
`Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA ER.
`Monitor for respiratory depression, especially during initiation of NUCYNTA ER or following a
`dose increase. Instruct patients to swallow NUCYNTA ER tablets whole; crushing, chewing, or
`dissolving NUCYNTA ER tablets can cause rapid release and absorption of a potentially fatal
`dose of tapentadol [see Warnings and Precautions (5.2)].
`
`Accidental Ingestion
`Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in a
`fatal overdose of tapentadol [see Warnings and Precautions (5.2)].
`
`Neonatal Opioid Withdrawal Syndrome
`Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal
`syndrome, which may be life-threatening if not recognized and treated, and requires
`management according to protocols developed by neonatology experts. If opioid use is
`required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal
`opioid withdrawal syndrome and ensure that appropriate treatment will be available [see
`Warnings and Precautions (5.3)].
`Interaction with Alcohol
`Instruct patients not to consume alcoholic beverages or use prescription or non-prescription
`products that contain alcohol while taking NUCYNTA ER. The co-ingestion of alcohol with
`NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal
`overdose of tapentadol [see Warnings and Precautions (5.4)].
`Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
`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 [see
`Warnings and Precautions (5.4), Drug Interactions (7)].
`• Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other CNS
`depressants for use in patients for whom alternative treatment options are inadequate.
`• Limit dosages and durations to the minimum required.
`• Follow patients for signs and symptoms of respiratory depression and sedation
`
`
`
`
`
`
`Reference ID: 4028547
`
`

`

`1
`
`INDICATIONS AND USAGE
`
`NUCYNTA ER (tapentadol) is indicated for the management of:
`• pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which
`alternative treatment options are inadequate
`• neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily,
`around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
`Limitations of Use
`
`
`• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and
`because of the greater risks of overdose and death with extended-release opioid formulations [see
`Warnings and Precautions (5.1)], reserve NUCYNTA ER for use in patients for whom alternative
`treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not
`tolerated, or would be otherwise inadequate to provide sufficient management of pain.
`• NUCYNTA ER is not indicated as an as-needed (prn) analgesic.
`
`2
`2.1
`
`DOSAGE AND ADMINISTRATION
`Important Dosage and Administration Instructions
`
`•
`
`NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable in the use of
`potent opioids for the management of chronic pain.
`• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment
`goals [see Warnings and Precautions (5)].
`Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain,
`patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse
`[see Warnings and Precautions (5.1)]
`• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating
`therapy and following dosage increases with NUCYNTA ER and adjust the dosage accordingly [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 [see Patient Counseling Information (17)].
`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 (5.6)]. 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.
`Initial Dosage
`2.2
`
`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.
`
`Reference ID: 4028547
`
`

`

`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
`
`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.
`Monitor 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
`
`Close monitoring is of particular importance when converting from methadone to other opioid agonists. The
`ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure.
`Methadone has a long half-life and can accumulate in the plasma.
`2.3
`
`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 and the relative incidence of adverse reactions, as well as monitoring for the development of addiction,
`abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the
`prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of
`changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the
`continued need for opioid analgesics.
`
`Patients who experience breakthrough pain may require a dosage adj ust m ent 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. 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)].
`
`
`Reference ID: 4028547
`
`

`

`If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage
`to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
`2.4
`
`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 (5.14)].
`
`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 monitor closely 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. Monitor
`closely 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 (5.14), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`Discontinuation of NUCYNTA ER
`2.5
`
`When a patient no longer requires therapy with NUCYNTA ER tablets, taper the dose gradually, by 25% to
`50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops
`these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the
`interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue
`NUCYNTA ER [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`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.
`
`4
`
`CONTRAINDICATIONS
`
`NUCYNTA ER is contraindicated in patients with:
`• Significant respiratory depression
`• Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of
`resuscitative equipment
`• Known or suspected gastrointestinal obstruction, including paralytic ileus
`• Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product
`Reference ID: 4028547
`
`

`

`[see Adverse Reactions (6.2)].
`• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see
`Drug Interactions (7)].
`
`5
`5.1
`
`WARNINGS AND PRECAUTIONS
`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
`monitor 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 intensive
`monitoring for signs of addiction, abuse, and misuse.
`
`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)].
`
`Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
`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 the proper disposal of
`unused drug [see Patient Counseling Information (17)]. 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. Monitor
`patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and
`following dosage increases of NUCYNTA ER.
`
`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
`Reference ID: 4028547
`
`

`

`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.
`5.3
`
`Neonatal Opioid Withdrawal Syndrome
`
`Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid
`withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not
`recognized and treated, and requires management according to protocols developed by neonatology experts.
`Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant
`women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that
`appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information
`(17)].
`5.4
`
`Risk 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 or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics,
`tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks,
`reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are
`inadequate.
`
`Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines
`increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar
`pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS
`depressant drugs with opioid analgesics [see Drug Interactions (7.4)].
`
`If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid
`analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already
`receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than
`indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a
`patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid
`analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory
`depression and sedation.
`
`Advise both patients and caregivers about the risks of respiratory depression and sedation when 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
`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) and Patient Counseling Information (17)].
`5.5
`
`Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary
`Disease or in Elderly, Cachectic, or Debilitated Patients
`
`The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the
`Reference ID: 4028547
`
`

`

`absence of resuscitative equipment is contraindicated.
`
`Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive
`pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia,
`hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including
`apnea, even at recommended dosages of NUCYNTA ER [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)]. Alternatively, consider the use of
`non-opioid analgesics in these patients.
`
`Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA
`ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].
`5.6
`
`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), and drugs that impair metabolism of serotonin (including MAO 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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The
`onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later
`than that. Discontinue NUCYNTA® ER if serotonin syndrome is suspected.
`Adrenal Insufficiency
`5.7
`
`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.
`5.8
`
`Severe Hypotension
`
`NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory
`patients. There is an increased risk in patients whose abili