•
`
`•
`
`•
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`NUCYNTA® ORAL SOLUTION safely and effectively. See full
`prescribing information for NUCYNTA® ORAL SOLUTION.
`NUCYNTA® (tapentadol) oral solution C-II
`Initial U.S. Approval: 2008
`WARNING: RISK OF MEDICATION ERRORS, ADDICTION,
`ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION
`STRATEGY (REMS); LIFE-THREATENING RESPIRATORY
`DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID
`WITHDRAWAL SYNDROME; and RISKS FROM
`CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER
`CNS DEPRESSANTS
`See full prescribing information for complete boxed warning.
`Ensure accuracy when prescribing, dispensing, and
`administering NUCYNTA oral solution. Dosing errors due to
`confusion between mg and mL, and other tapentadol oral
`solution of different concentrations can result in accidental
`overdose and death. (2.1, 5.1)
`NUCYNTA oral solution exposes users to risks of addiction,
`abuse, and misuse, which can lead to overdose and death. Assess
`patient’s risk before prescribing and monitor regularly for these
`behaviors and conditions. (5.2)
`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. (5.3)
`Serious, life-threatening, or fatal respiratory depression may
`occur. Monitor closely, especially upon initiation or following a
`dose increase. (5.4)
`Accidental ingestion of NUCYNTA oral solution, especially by
`children, can result in a fatal overdose of tapentadol. (5.4)
`Prolonged use of NUCYNTA oral solution during pregnancy can
`result in neonatal opioid withdrawal syndrome, which may be
`life-threatening if not recognized and treated. If prolonged
`opioid use is required in a pregnant woman, advise the patient of
`the risk of neonatal opioid withdrawal syndrome and ensure
`that appropriate treatment will be available. (5.5)
`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 (5.6, 7).
`
`•
`
`•
`
`•
`
`•
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Boxed Warning
`09/2018
`Warnings and Precautions (5.3)
`09/2018
`----------------------------INDICATIONS AND USAGE----------------------------
`NUCYNTA oral solution is an opioid analgesic indicated for the management
`of acute pain severe enough to require an opioid analgesic and for which
`alternative treatments are inadequate. (1)
`
`Limitations of Use (1)
`Because of the risks of addiction, abuse, and misuse with opioids, even at
`recommended doses, reserve NUCYNTA oral solution for use in patients for
`whom alternative treatment options [e.g., non-opioid analgesics or opioid
`combination products]:
`• Have not been tolerated, or are not expected to be tolerated,
`• Have not provided adequate analgesia, or are not expected to provide
`adequate analgesia
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Use the lowest effective dosage for the shortest duration consistent with
`individual patient treatment goals. (2.1)
`
`
`
`
`Reference ID: 4321321
`
`• Individualize dosing according to the severity of pain, patient response,
`prior analgesic experience, and risk factors for addiction, abuse, and misuse.
`(2.1)
`• Initiate treatment with NUCYNTA oral solution with or without food at
`a dose of 2.5 mL (50 mg), 3.75 mL (75 mg), or 5 mL (100 mg) every 4 to
`6 hours depending upon pain intensity. 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
`2.5 mL (50 mg), 3.75 mL (75 mg), or 5 mL (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, therefore,
`not recommended. (2.2)
`• Moderate Hepatic Impairment: Initiate treatment with 50 mg no more than
`once every 8 hours (maximum of three doses in 24 hours). Monitor closely for
`respiratory and central nervous system depression. (2.3)
`• Do not stop NUCYNTA oral solution abruptly in a physically dependent
`patient. (2.5)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Oral Solution: 20 mg/mL (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`• Significant respiratory depression (4)
`• Acute or severe bronchial asthma in an unmonitored setting or in absence of
`resuscitative equipment.(4)
`• Known or gastrointestinal obstruction, including suspected paralytic ileus. (4)
`• Hypersensitivity to tapentadol.(4)
`• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs
`within the last 14 days. (4)
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary
`Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely,
`particularly during initiation and titration. (5.7)
`• Serotonin Syndrome: Potentially life-threatening condition could result from
`concomitant serotonergic drug administration. Discontinue NUCYNTA oral
`solution if serotonin syndrome is suspected. (5.8)
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`corticosteroids, and wean patient off of the opioid. (5.9)
`• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use
`of NUCYNTA oral solution in patients with circulatory shock. (5.10)
`• 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 oral solution in patients with impaired
`consciousness or coma. (5.11)
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (incidence ≥10%) were nausea, dizziness,
`vomiting and somnolence. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, 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 Opioids Analgesics: Avoid
`use with NUCYNTA oral solution because they reduce analgesic effect of
`NUCYNTA oral solution or precipitate withdrawal symptoms. (7)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`• Lactation: Closely monitor infants of nursing women receiving.
`NUCYNTA oral solution. (8.2)
`• Severe Hepatic o r Renal Impairment: Use not recommended. Reduce
`dose in patients with moderate hepatic impairment. (8.6, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 09/2018
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: ADDICTION, ABUSE, AND MISUSE;
`RISK EVALUATION AND MITIGATION STRATEGY
`(REMS); LIFE-THREATENING RESPIRATORY
`DEPRESSION; ACCIDENTAL INGESTION;
`NEONATAL OPIOID WITHDRAWAL SYNDROME;
`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 Dosage Modifications in Patients with Hepatic
`Impairment
`2.4 Titration and Maintenance of Therapy
`2.5 Discontinuation of NUCYNTA oral solution
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Risk of Accidental Overdose and Death due to
`Medication Errors
`5.2 Addiction, Abuse, and Misuse
`5.3 Opioid Analgesic Risk Evaluation and Mitigation
`Strategy (REMS)
`5.4 Life Threatening-Respiratory Depression
`5.5 Neonatal Opioid Withdrawal Syndrome
`5.6 Risks from Concomitant Use with
`Benzodiazepines or Other CNS Depressants
`5.7 Life-Threatening Respiratory Depression in
`Patients with Chronic Pulmonary Disease or in
`Elderly, Cachectic, or Debilitated Patients
`5.8 Serotonin Syndrome with Concomitant Use of
`Serotonergic Drugs
`5.9 Adrenal Insufficiency
`5.10 Severe Hypotension
`5.11 Risks of Use in Patients with Increased Intracranial
`Pressure, Brain Tumors, Head Injury, or Impaired
`Consciousness
`5.12 Risks of Use in Patients with Gastrointestinal
`Conditions
`
`5.13 Increased Risk of Seizures in Patients with Seizure Disorders
`5.14 Withdrawal
`5.15 Risks of Driving and Operating Machinery
`5.16 Interactions with Alcohol, Other Opioids, and Drugs of Abuse
`5.17 Risk of Toxicity in Patients with Hepatic Impairment
`5.18 Risk of Toxicity in Patients with Renal Impairment
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-marketing Experience
`7 DRUG INTERACTIONS
`8 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
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`9.3 Dependence
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NON-CLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Orthopedic Surgery – Bunionectomy
`14.2 End-Stage Degenerative Joint Disease
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are
`not listed
`
`Reference ID: 4321321
`
`

`

`FULL PRESCRIBING INFORMATION
`WARNING: RISK OF MEDICATION ERRORS, ADDICTION, ABUSE, AND MISUSE;
`RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-
`THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION;
`NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM
`CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
`
`Risk of Medication Errors
`Ensure accuracy when prescribing, dispensing, and administering NUCYNTA oral
`solution. Dosing errors due to confusion between mg and mL can result in accidental
`overdose and death [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].
`
`Addiction, Abuse, and Misuse
`NUCYNTA oral solution 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 oral solution, and monitor all patients regularly for the
`development of these behaviors and conditions [see Warnings and Precautions (5.2)].
`
`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 REMS for these
`products [see Warnings and Precautions (5.3)]. 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
`• complete a REMS-compliant education program,
`• counsel patients and/or their caregivers, with every prescription, on safe use, serious
`risks, storage, and disposal of these products,
`• emphasize to patients and their caregivers the importance of reading the Medication
`Guide every time it is provided by their pharmacist, and
`• consider other tools to improve patient, household, and community safety.
`
`Life-Threatening Respiratory Depression
`Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA
`oral solution. Monitor for respiratory depression, especially during initiation of
`NUCYNTA oral solution or following a dose increase [see Warnings and Precautions (5.4)].
`
`Accidental Ingestion
`Accidental ingestion of even one dose of NUCYNTA oral solution, especially by children,
`can result in a fatal overdose of tapentadol [see Warnings and Precautions (5.4)].
`
`Neonatal Opioid Withdrawal Syndrome
`Prolonged use of NUCYNTA oral solution 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
`
`Reference ID: 4321321
`
`

`

`of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be
`available [see Warnings and Precautions (5.5)].
`
`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 (5.6), Drug Interactions (7)].
`• Reserve concomitant prescribing of NUCYNTA oral solution 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.
`
`
`1
`
`INDICATIONS AND USAGE
`NUCYNTA (tapentadol) oral solution is indicated for the management of acute pain severe enough
`to require an opioid analgesic and for which alternative treatments are inadequate in adults.
`
`Limitations of Use
`Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see
`Warnings and Precautions (5.2)], reserve NUCYNTA oral solution for use in patients for whom
`alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:
`• Have not been tolerated, or are not expected to be tolerated,
`• Have not provided adequate analgesia, or are not expected to provide adequate analgesia
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1
`
`Important Dosage and Administration Instructions
`
`Ensure accuracy when prescribing, dispensing, and administering NUCYNTA oral solution to avoid
`dosing errors due to confusion between mg and mL, which could result in accidental overdose and
`death. Ensure the proper dose is communicated and dispensed. The oral solution contains 20 mg
`tapentadol per milliliter (mL), when writing prescriptions, include both the total dose in mg and the
`total dose in volume.
`
`Always use the enclosed calibrated measuring syringe when administering NUCYNTA oral solution
`to ensure the dose is measured and administered accurately. An oral syringe is supplied with dose
`marks corresponding directly to 2.5 mL (equals 50 mg) oral solution, 3.75 mL (equals 75 mg) oral
`solution, and 5 mL (equals 100 mg) oral solution.
`
`Do not use household teaspoons or tablespoons to measure NUCYNTA oral solution, as using a
`tablespoon instead of a teaspoon could lead to overdosage.
`
`Inform patients of the availability of FDA-approved patient labeling, Instructions for Use, for
`step-by-step instructions for patients on how to use the medicine bottle and the oral syringe.
`
`
`
`
`Reference ID: 4321321
`
`
`
`

`

`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 (5.2)].
`
`Monitor patients closely for respiratory depression, especially within the first 24-72 hours of
`initiating therapy and following dosage increases with NUCYNTA and adjust the dosage
`accordingly [see Warnings and Precautions (5.4)]
`
`2.2
`
`Initial Dosage
`
`Initiate treatment with NUCYNTA oral solution in a dosing range of 50 mg (2.5 mL) to 100 mg (5
`mL) every 4 to 6 hours as needed for pain.
`
`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 2.5 mL
`(equivalent to 50 mg), 3.75 mL (equivalent to 75 mg), or 5 mL (equivalent to 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 oral solution may be given with or without food [see Clinical Pharmacology (12.3)].
`
`Conversion from NUCYNTA oral solution to NUCYNTA ER
`
`Patients can be converted from NUCYNTA oral solution to NUCYNTA ER using the equivalent
`total daily dose of NUCYNTA oral solution 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 oral solution four times per day (200 mg/day) may be converted to 100 mg NUCYNTA
`ER twice a day.
`
`2.3 Dosage Modifications in Patients with Hepatic Impairment
`The safety and efficacy of NUCYNTA oral solution has not been studied in patients with severe
`hepatic impairment (Child-Pugh Score 10-15) and use in this population is not recommended
`[see Warnings and Precautions (5.17)].
`
`Initiate treatment of patients with moderate hepatic impairment (Child-Pugh Score 7 to 9) with 50
`mg no more frequently than once every 8 hours (maximum of three doses in 24 hours).
`Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be
`achieved by either shortening or lengthening the dosing interval. Monitor closely for respiratory
`and central nervous system depression [see Clinical Pharmacology (12.3)].
`
`No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh
`Score 5 to 6) [see Clinical Pharmacology (12.3)].
`
`
`
`Reference ID: 4321321
`
`
`
`

`

`2.4 Titration and Maintenance of Therapy
`
`Continually reevaluate patients receiving NUCYNTA oral solution 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 (5.2)]. 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 oral solution dosage. 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.
`
`2.5 Discontinuation of NUCYNTA oral solution
`
`When a patient who has been taking NUCYNTA regularly and may be physically dependent no
`longer requires therapy with NUCYNTA 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 oral solution in a physically-dependent patient [see Warnings and
`Precautions (5.14), Drug Abuse and Dependence (9.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Oral solution: 20 mg/mL in 100 mL and 200 mL fill bottles with child-resistant closure [see
`Description (11) and How Supplied/Storage and Handling (16)].
`
`4 CONTRAINDICATIONS
`NUCYNTA oral solution is contraindicated in patients with:
`• Significant respiratory depression [see Warnings and Precautions (5.4)]
`• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
`equipment [see Warnings and Precautions (5.7)]
`• Known or suspected gastrointestinal obstruction, including suspected paralytic ileus [see
`Warnings and Precautions (5.12)]
`• Hypersensitivity to tapentadol (e.g. anaphylaxis, angioedema) or to any other ingredients of
`the product [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 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Accidental Overdose and Death due to Medication Errors
`
`Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from
`confusion between mg and mL when prescribing, dispensing, and administering NUCYNTA oral
`
`
`
`
`Reference ID: 4321321
`
`

`

`solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the
`enclosed calibrated syringe when administering NUCYNTA to ensure the dose is measured and
`administered accurately. Do not use a teaspoon or a tablespoon to measure a dose. A household
`teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the
`household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which
`could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated
`measuring device. Health care providers should recommend a calibrated device that can measure
`and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in
`measuring the dosage.
`
`5.2 Addiction, Abuse, and Misuse
`NUCYNTA oral solution contains tapentadol, a Schedule II controlled substance.
`
`As an opioid, NUCYNTA oral solution 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 oral solution. 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
`oral solution and monitor all patients receiving NUCYNTA oral solution 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
`oral solution, but use in such patients necessitates intensive counseling about the risks and proper use
`of NUCYNTA oral solution along with intensive monitoring for signs of addiction, abuse, and
`misuse.
`
`Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal
`diversion. Consider these risks when prescribing or dispensing NUCYNTA oral solution. 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 local state professional licensing board or state controlled substances authority for
`information on how to prevent and detect abuse or diversion of this product.
`
`5.3 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
`
`
`
`Reference ID: 4321321
`
`
`
`

`

`•
`
`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.
`
`5.4 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 oral solution, 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 oral solution.
`
`To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA oral solution
`are essential [see Dosage and Administration (2.2)]. Overestimating the NUCYNTA oral solution
`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 oral solution, especially by children, can result
`in respiratory depression and death due to an overdose of tapentadol.
`
`5.5 Neonatal Opioid Withdrawal Syndrome
`
`Prolonged use of NUCYNTA oral solution 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 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)].
`
`
`
`Reference ID: 4321321
`
`
`
`

`

`5.6 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 oral solution with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine
`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)].
`
`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 oral solution 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)].
`
`5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in
`Elderly, Cachectic, or Debilitated Patients
`
`The use of NUCYNTA oral solution 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 oral solution-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 oral
`solution [see Warnings and Precautions (5.7)].
`
`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 (5.7)].
`
`Monitor such patients closely, particularly when initiating and titrating NUCYNTA® and when
`NUCYNTA oral solution is given concomitantly with other drugs that depress respiration [see
`
`
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`Reference ID: 4321321
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`Warnings and Precautions (5.7)]. Alternatively, consider the use of non-opioid analgesics in these
`patients.
`
`5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
`
`Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during
`concurrent 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). 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 [see Drug Interactions (7)] The onset of symptoms generally
`occurs within several hours to a few days of concomitant use, but may occur later than that.
`Discontinue NUCYNT