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; 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)
`Serious, life-threatening, or fatal respiratory depression may occur.
`Monitor closely, especially upon initiation or following a dose increase.
`(5.2)
`Accidental ingestion of NUCYNTA tablets, especially by children, can
`result in a fatal overdose of tapentadol. (5.2)
`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. (5.3)
`Concomitant use of opioids with benzodiazepines or other central
`nervous system (CNS) depressants, including alcohol, may result in
`profound sedation, respiratory depression, coma, and death. Reserve
`concomitant prescribing for use in patients for whom alternative
`treatment options are inadequate; limit dosages and durations to the
`minimum required; and follow patients for signs and symptoms of
`respiratory depression and sedation (5.4), (7).
`
`•
`
`•
`
`•
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Boxed Warning
`12/2016
`Indications and Usage (1)
`12/2016
`Dosage and Administration (2)
`12/2016
`Contraindications (4)
`12/2016
`Warnings and Precautions (5)
`12/2016
`----------------------------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. (5.5)
`• Serotonin Syndrome: Potentially life-threatening condition could result from
`concomitant serotonergic drug administration. Discontinue NUCYNTA tablets
`if serotonin syndrome is suspected. (5.6)
`• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
`corticosteroids, and wean patient off of the opioid. (5.7)
`• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use
`of NUCYNTA tablets in patients with circulatory shock. (5.8)
`• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors,
`Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory
`depression. Avoid use of NUCYNTA tablets in patients with impaired
`consciousness or coma. (5.9)
`•
`------------------------------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 receiving NUCYNTA
`tablets. (8.2)
`• Severe Renal or Hepatic Impairment: Not recommended. (8.6, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 12/2016
`
`
`
`Reference ID: 4028347
`
`1
`
`

`

`5.15 Risk of Toxicity in Patients with Hepatic
`Impairment
`5.16 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;
`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 Discontinuation of NUCYNTA Tablets
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Addiction, Abuse, and Misuse
`5.2
`Life-Threatening Respiratory Depression
`5.3 Neonatal Opioid Withdrawal Syndrome
`5.4 Risks from Concomitant Use with
`Benzodiazepines or Other CNS Depressants
`5.5
`Life-Threatening Respiratory Depression in
`Patients with Chronic Pulmonary Disease or in
`Elderly, Cachectic, or Debilitated Patients
`5.6 Serotonin Syndrome with Concomitant Use of
`Serotonergic Drugs
`5.7 Adrenal Insufficiency
`5.8 Severe Hypotension
`5.9 Risks of Use in Patients with Increased
`Intracranial Pressure, Brain Tumors, Head Injury,
`or Impaired Consciousness
`5.10 Risks of Use in Patients with Gastrointestinal
`Conditions
`5.11 Increased Risk of Seizures in Patients with
`Seizure Disorders
`5.12 Withdrawal
`5.13 Risks of Driving and Operating Machinery
`5.14 Interactions with Alcohol, Other Opioids, and
`Drugs of Abuse
`
` 1
`
`Reference ID: 4028347
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: ADDICTION, ABUSE, AND MISUSE; 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)].
`
`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 (5.2)].
`
`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 (5.2)].
`
`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 (5.3)].
`
`Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
`Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)
`depressants, including alcohol, may result in profound sedation, respiratory depression,
`coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7)].
`• Reserve concomitant prescribing of NUCYNTA tablets 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) 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:
`
`
`3
`
`Reference ID: 4028347
`
`

`

`• 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 (5.2)]
`
`
`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)].
`
`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 (5.15)].
`
`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
`
`4
`
`Reference ID: 4028347
`
`

`

`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 (5.12), 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 (5.2)]
`• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
`equipment [see Warnings and Precautions (5.5)]
`
`Reference ID: 4028347
`
`5
`
`

`

`• Known or suspected gastrointestinal obstruction, including suspected paralytic ileus [see
`Warnings and Precautions (5.10)]
`• 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 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.
`
`
`Reference ID: 4028347
`
`6
`
`

`

`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.
`
`5.3 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)].
`
`5.4 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)].
`
`Reference ID: 4028347
`
`7
`
`

`

`5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary
`Disease or in Elderly, Cachectic, or Debilitated Patients
`The use of NUCYNTA tablets in patients with acute or severe bronchial asthma in an
`unmonitored setting or in the absence of resuscitative equipment is contraindicated.
`
`Patients with Chronic Pulmonary Disease: NUCYNTA tablets-treated patients with significant
`chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially
`decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at
`increased risk of decreased respiratory drive including apnea, even at recommended dosages of
`NUCYNTA tablets [see Warnings and Precautions (5.2)].
`
`Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely
`to occur in elderly, cachectic, or debilitated patients because they may have altered
`pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings
`and Precautions (5.2)].
`
`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 (5.4)]. Alternatively, consider the use of non-opioid analgesics in
`these patients.
`
`5.6 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.
`
`5.7 Adrenal Insufficiency
`Cases of adrenal insufficiency have been reported with opioid use, more often following greater
`than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms
`and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
`pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as
`soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses
`of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and
`continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as
`some cases reported use of a different opioid without recurrence of adrenal insufficiency. The
`
`Reference ID: 4028347
`
`8
`
`

`

`information available does not identify any particular opioids as being more likely to be
`associated with adrenal insufficiency.
`
`5.8 Severe Hypotension
`NUCYNTA tablets may cause severe hypotension including orthostatic hypotension and syncope
`in ambulatory patients. There is increased risk in patients whose ability to maintain blood
`pressure has already been compromised by a reduced blood volume or concurrent administration
`of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug
`Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the
`dosage of NUCYNTA tablets. In patients with circulatory shock, NUCYNTA tablets may cause
`vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of
`NUCYNTA tablets in patients with circulatory shock.
`
`5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head
`Injury, or Impaired Consciousness
` retention (e.g., those with
`In patients who may be susceptible to the intracranial effects of CO2
`evidence of increased intracranial pressure or brain tumors), NUCYNTA tablets may reduce
`respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.
`Monitor such patients for signs of sedation and respiratory depression, particularly when
`initiating therapy with NUCYNTA tablets.
`
`Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of
`NUCYNTA tablets in patients with impaired consciousness or coma.
`
`5.10 Risks of Use in Patients with Gastrointestinal Conditions
`NUCYNTA tablets are contraindicated in patients with known or suspected gastrointestinal
`obstruction, including paralytic ileus.
`
`The tapentadol in NUCYNTA tablets may cause spasm of the sphincter of Oddi. Opioids may
`cause increases in serum amylase. Monitor patients with biliary tract disease, including acute
`pancreatitis for worsening symptoms.
`
`5.11 Increased Risk of Seizures in Patients with Seizure Disorders
`The tapentadol in NUCYNTA tablets may increase the frequency of seizures in patients with
`seizure disorders, and may increase the risk of seizures occurring in other clinical settings
`associated with seizures. Monitor patients with a history of seizure disorders for worsened
`seizure control during NUCYNTA tablets therapy.
`
`5.12 Withdrawal
`Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or
`partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist
`analgesic, including NUCYNTA tablets. In these patients, mixed agonist/antagonist and partial
`agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see
`Drug Interactions (7)].
`
`When discontinuing NUCYNTA tablets in a physically-dependent patient, gradually taper the
`dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue NUCYNTA tablets
`in these patients [see Drug Abuse and Dependence (9.3)].
`
`9
`
`Reference ID: 4028347
`
`

`

`5.13 Risks of Driving and Operating Machinery
`NUCYNTA tablets may impair the mental or physical abilities needed to perform potentially
`hazardous activities such as driving a car or operating machinery. Warn patients not to drive or
`operate dangerous machinery unless they are tolerant to the effects of NUCYNTA tablets and
`know how they will react to the medication.
`
`5.14 Interactions with Alcohol, Other Opioids, and Drugs of Abuse
`Due to its mu-opioid agonist activity, NUCYNTA tablets may be expected to have additive
`effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central
`nervous system depression, respiratory depression, hypotension, and profound sedation, coma or
`death [see Drug Interactions (7)]. Instruct patients not to consume alcoholic beverages or use
`prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse
`while on NUCYNTA tablets therapy [see Drug Interactions (7)].
`
`5.15 Risk of Toxicity in Patients with Hepatic Impairment
`A study with NUCYNTA tablets in subjects with hepatic impairment showed higher serum
`concentrations of tapentadol than in those with normal hepatic function. Avoid use of
`NUCYNTA tablets in patients with severe hepatic impairment. Reduce the dose of NUCYNTA
`tablets in patients with moderate hepatic impairment [see Dosage and Administration (2.3) and
`Clinical Pharmacology (12.3)]. Closely monitor patients with moderate hepatic impairment for
`respiratory and central nervous system depression when receiving NUCYNTA tablets.
`
`5.16 Risk of Toxicity in Patients with Renal Impairment
`Use of NUCYNTA tablets in patients with severe renal impairment is not recommended due to
`accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of
`the elevated metabolite is not known [see Clinical Pharmacology (12.3)].
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed, or described in greater detail, in other sections:
`• Addiction, Abuse, and Misuse [see Warn