HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`NUCYNTA® TABLETS safely and effectively. See full prescribing
`information for NUCYNTA® TABLETS.
`NUCYNTA® (tapentadol) tablets for oral use C-II
`Initial U.S. Approval: 2008
`
`•
`
`•
`
`•
`
`•
`
`•
`
`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
`See full prescribing information for complete boxed warning.
`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 monitor regularly for these behaviors and
`conditions. (5.1)
`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. (5.2)
`Serious, life-threatening, or fatal respiratory depression may occur.
`Monitor closely, especially upon initiation or following a dose
`increase. (5.3)
`Accidental ingestion of NUCYNTA tablets, especially by children,
`can result in a fatal overdose of tapentadol. (5.3)
`Prolonged use of NUCYNTA tablets 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. (5.4)
`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 (5.5), (7).
`
`•
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Dosage and Administration (2.5)
`
`
`10/2019
`Warnings and Precautions (5.3, 5.13)
`
`
`10/2019
`----------------------------INDICATIONS AND USAGE----------------------------
`NUCYNTA tablets are 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 tablets 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)
`• Individualize dosing based on the severity of pain, patient response, prior
`analgesic experience, and risk factors for addiction, abuse, and misuse.
`(2.1)
`• Initiate treatment with NUCYNTA tablets at a dose of 50 mg, 75 mg, or
`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 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, 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 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. (2.5)
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 50 mg, 75 mg, 100 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`• Significant respiratory depression (4)
`• Acute or severe bronchial asthma in an unmonitored setting or in absence
`of resuscitative equipment. (4)
`• Known or suspected gastrointestinal obstruction, including 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--------------------
`in Patients with Chronic
`• Life-Threatening Respiratory Depression
`Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:
`Monitor closely, particularly during initiation and titration. (5.6)
`• Serotonin Syndrome: Potentially life-threatening condition could result
`from
`concomitant
`serotonergic drug
`administration. Discontinue
`NUCYNTA tablets if serotonin syndrome is suspected. (5.7)
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`corticosteroids, and wean patient off of the opioid. (5.8)
`• Severe Hypotension: Monitor during dosage initiation and titration. Avoid
`use of NUCYNTA tablets in patients with circulatory shock. (5.9)
`• 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. (5.10)
`------------------------------ADVERSE REACTIONS------------------------------
`The most common adverse reactions (incidence ≥10%) were nausea,
`dizziness, vomiting and somnolence. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Collegium
`Pharmaceutical, Inc. at 1-855-331-5615 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 tablets because they reduce analgesic effect of
`NUCYNTA tablets or precipitate withdrawal symptoms. (7).
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`infants of nursing women
`• Lactation: Closely monitor
`NUCYNTA tablets. (8.2)
`• Severe Renal or Hepatic Impairment: Not recommended. (8.6, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`receiving
`
`Revised: 10/2019
`
`
`
`Reference ID: 4501032
`
`1
`
`

`

`5.14 Risks of Driving and Operating Machinery
`5.15 Interactions with Alcohol, Other Opioids, and
`Drugs of Abuse
`5.16 Risk of Toxicity in Patients with Hepatic
`Impairment
`5.17 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
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: ADDICTION, ABUSE, AND MISUSE; RISK
`EVALUATION AND MITIGATION STRATEGY (REMS);
`LIFE-THREATENTING RESPIRATORY DEPRESSION;
`ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL
`SYNDROME; and RISKS FROM CONCOMITANT USE WITH
`BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
`
`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 Safe Reduction or Discontinuation of NUCYNTA
`Tablets
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Addiction, Abuse, and Misuse
`5.2 Opioid Analgesic Risk Evaluation and Mitigation
`Strategy (REMS)
`5.3
`Life-Threatening Respiratory Depression
`5.4 Neonatal Opioid Withdrawal Syndrome
`5.5 Risks from Concomitant Use with
`Benzodiazepines or Other CNS Depressants
`5.6
`Life-Threatening Respiratory Depression in
`Patients with Chronic Pulmonary Disease or in
`Elderly, Cachectic, or Debilitated Patients
`5.7 Serotonin Syndrome with Concomitant Use of
`Serotonergic Drugs
`5.8 Adrenal Insufficiency
`5.9 Severe Hypotension
`5.10 Risks of Use in Patients with Increased
`Intracranial Pressure, Brain Tumors, Head Injury,
`or Impaired Consciousness
`5.11 Risks of Use in Patients with Gastrointestinal
`Conditions
`5.12 Increased Risk of Seizures in Patients with
`Seizure Disorders
`5.13 Withdrawal
`
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`Reference ID: 4501032
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`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
`
`
`Addiction, Abuse, and Misuse
`NUCYNTA tablets 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 tablets, and monitor all patients regularly for the development of
`these behaviors and conditions [see Warnings and Precautions (5.1)].
`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 (5.2)]. 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
`tablets. Monitor for respiratory depression, especially during initiation of NUCYNTA
`tablets or following a dose increase [see Warnings and Precautions (5.3)].
`
`Accidental Ingestion
`Accidental ingestion of even one dose of NUCYNTA tablets, especially by children, can
`result in a fatal overdose of tapentadol [see Warnings and Precautions (5.3)].
`
`Neonatal Opioid Withdrawal Syndrome
`Prolonged use of NUCYNTA tablets 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 (5.4)].
`
`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 (5.5), Drug Interactions (7)].
`• Reserve concomitant prescribing of NUCYNTA tablets and benzodiazepines or other
`
`Reference ID: 4501032
`
`3
`
`

`

`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) tablets are 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 (5.1)], reserve NUCYNTA tablets 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
`
`Important Dosage and Administration Instructions
`2.1
`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 and adjust the dosage
`accordingly [see Warnings and Precautions (5.3)]
`
`
`Initial Dosage
`2.2
`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.
`
`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)].
`
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`

`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.
`
`2.3 Dosage Modifications in Patients with Hepatic Impairment
`The safety and efficacy of NUCYNTA tablets 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 (5.16)].
`
`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)].
`
`2.4 Titration and Maintenance of Therapy
`Continually reevaluate patients receiving NUCYNTA tablets 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.
`
`If the level of pain increases after dosage stabilization, attempt to identify the source of increased
`pain before increasing the NUCYNTA tablets 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 Safe Reduction or Discontinuation of NUCYNTA Tablets
`
`Do not abruptly discontinue NUCYNTA Tablets in patients who may be physically dependent
`on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent
`on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid
`discontinuation has also been associated with attempts to find other sources of opioid analgesics,
`which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain
`or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
`
`When a decision has been made to decrease the dose or discontinue therapy in an opioid-
`dependent patient taking NUCYNTA Tablets, there are a variety of factors that should be
`considered, including the dose of NUCYNTA Tablets the patient has been taking, the duration of
`treatment, the type of pain being treated, and the physical and psychological attributes of the
`patient. It is important to ensure ongoing care of the patient and to agree on an appropriate
`tapering schedule and follow-up plan so that patient and provider goals and expectations are
`clear and realistic. When opioid analgesics are being discontinued due to a suspected substance
`
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`

`use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance
`use disorder. Treatment should include evidence-based approaches, such as medication assisted
`treatment of opioid use disorder. Complex patients with co-morbid pain and substance use
`disorders may benefit from referral to a specialist.
`
`There are no standard opioid tapering schedules that are suitable for all patients. Good clinical
`practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on
`NUCYNTA Tablets who are physically opioid-dependent, initiate the taper by a small enough
`increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal
`symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who
`have been taking opioids for briefer periods of time may tolerate a more rapid taper.
`
`It may be necessary to provide the patient with lower dosage strengths to accomplish a
`successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms,
`should they emerge. Common withdrawal symptoms include restlessness, lacrimation,
`rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms
`also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal
`cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory
`rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a
`period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed
`with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal
`thoughts, or use of other substances.
`
`When managing patients taking opioid analgesics, particularly those who have been treated for a
`long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain
`management, including mental health support (if needed), is in place prior to initiating an opioid
`analgesic taper. A multimodal approach to pain management may optimize the treatment of
`chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings
`and Precautions (5.13), Drug Abuse and Dependence (9.3)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`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.
`
`4 CONTRAINDICATIONS
`
`NUCYNTA tablets are contraindicated in patients with:
`
` •
`
` Significant respiratory depression [see Warnings and Precautions (5.3)]
`• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
`equipment [see Warnings and Precautions (5.6)]
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`

`• Known or suspected gastrointestinal obstruction, including suspected paralytic ileus [see
`Warnings and Precautions (5.11)]
`• 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 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 monitor 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 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 tablets.
`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.
`5.2 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 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.
`
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`

`• 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.
`
`5.3 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. Monitor patients closely for respiratory depression, especially within the first
`24-72 hours of initiating therapy with and following dosage increases of NUCYNTA tablets.
`
`To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA tablets
`are essential [see Dosage and Administration (2.2)]. 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.
`
`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 (2.5)].
`
`5.4 Neonatal Opioid Withdrawal Syndrome
`Prolonged use of NUCYNTA tablets 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)].
`
`5.5 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 or other CNS depressants (e.g., non-benzodiazepine
`sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
`
`8
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`
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`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 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) and Patient Counseling Information (17)].
`
`5.6 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 (5.3)].
`
`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 (5.3)].
`
`Monitor 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 (5.5)]. Alternatively, consider the use of non-opioid analgesics in
`these patients.
`
`5.7 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
`
`9
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`Reference ID: 4501032
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`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 MAO inhibitors, both those intended to treat psychiatric disorders and also others,
`such as linezolid and intravenous methylene blue) [see Drug Interactions (7)