`
` 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
`
`
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`
`
`
`•
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`•
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`
`•
`
`
`•
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`
`•
`
`
`•
`
`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------------------------
`
` 09/2018
`
` Boxed Warning
`
` 09/2018
`
` Warnings and Precautions (5.2)
`
`
`
` ----------------------------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 stop NUCYNTA tablets abruptly in a physically dependent patient.
`
`(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-------------------
`
`
`
`• Life-Threatening Respiratory Depression
`in Patients with Chronic
`
`Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:
`
`
`
`Monitor closely, particularly during initiation and titration. (5.6)
`
`
`
`• Serotonin Syndrome: Potentially life-threatening condition could result
`
`
`
`administration. Discontinue
`serotonergic drug
`concomitant
`from
`
`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 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 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)
`
`
`
`• Lactation: Closely monitor
`infants of nursing women
`
`
`
`
`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: 09/2018
`
`
`
`
`
`Reference ID: 4321306
`
`
`
` 1
`
`
`
`
`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
`
`
`
`1
`
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`Important Dosage and Administration Instructions
`2.1
`
`
`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 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
`
`
`5.14 Risks of Driving and Operating Machinery
`
`
`Interactions with Alcohol, Other Opioids, and
`
`5.15
`
`
`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
`
`Reference ID: 4321306
`
`
`
` 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
`
`
`
`
` 3
`
`Reference ID: 4321306
`
`
`
`
`
` 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)].
`
`
`
`
`
` 4
`
`Reference ID: 4321306
`
`
`
` 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 Discontinuation of NUCYNTA Tablets
`
`
`
`
` When a patient who has been taking NUCYNTA tablets regularly and may be physically
`
` dependent no longer requires therapy with NUCYNTA 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 tablets in a physically-dependent patient
`
`
`
`
`
`
` [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.
`
`
`
`
` 5
`
`Reference ID: 4321306
`
`
`
`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)]
`
`
`• 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)].
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`
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`• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last
`
`14 days [see Drug Interactions (7)].
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`
`
`
`5 WARNINGS AND PRECAUTIONS
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`
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`5.1 Addiction, Abuse, and Misuse
`
`
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`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
`
`
`
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`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.
`
`
`
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`Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA
`
`
`
`
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`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
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`
`depression). The potential for these risks should not, however, prevent the proper management of
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`
`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
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`
`
`authority for information on how to prevent and detect abuse or diversion of this product.
`
`
`
` 6
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`Reference ID: 4321306
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`
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`
`
` 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:
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`
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`• Complete a REMS-compliant education program offered by an accredited provider of
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`
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`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
`
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`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.
`
`
`
`
`5.3 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
`
`
`
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`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
`
`
`
`
`
`
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`respiratory depression and death due to an overdose of tapentadol.
`
`
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`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
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` 7
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`Reference ID: 4321306
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`
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`
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` 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,
`
` 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
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`
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`
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` 8
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`Reference ID: 4321306
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`
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`pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings
`
`
`
`and Precautions (5.3)].
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`
`
`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
`
`
`
`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) 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 NUCYNTA tablets if serotonin
`
`
`
`syndrome is suspected.
`
`
`5.8 Adrenal Insufficiency
`
`
`Cases of adrenal insufficiency have been reported with opioid use, more often following greater
`
`
`than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms
`
`and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
`pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as
`
`
`soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses
`
`of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and
`
`
`continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as
`
`
`some cases reporte