HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`NUCYNTA® ER safely and effectively. See full prescribing information
`for NUCYNTA® ER.
`
` NUCYNTA® ER (tapentadol) extended-release oral tablets C-II
`Initial U.S. Approval: 2008
`LIFE-THREATENING
`POTENTIAL,
`WARNING:
`ABUSE
`RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and
`INTERACTION WITH ALCOHOL
`See full prescribing information for complete boxed warning.
`
` NUCYNTA® ER contains tapentadol, a Schedule II controlled
`x
`
` substance. Monitor for signs of misuse, abuse, and addiction during
`
`NUCYNTA® ER therapy. (5.1)
`
`Fatal respiratory depression may occur, with highest risk at
`
`initiation and with dose increases. Instruct patients on proper
`administration of NUCYNTA® ER tablets to reduce the risk. (5.2)
`
`Accidental ingestion of NUCYNTA® ER can result in fatal overdose
`
`of tapentadol, especially in children. (5.3)
`Instruct patients not to consume alcoholic beverages or use
`
`prescription or non-prescription products containing alcohol while
`taking NUCYNTA® ER because of the risk of increased and
`
`
`potentially fatal plasma tapentadol levels. (5.4)
`
`-----------------------------RECENT MAJOR CHANGES-------------------­
`Boxed Warning
`
`
`
`
`7/2012
`Indications and Usage (1)
`7/2012
`
`
`
`Indications and Usage, Neuropathic pain associated with
`8/2012
`diabetic peripheral neuropathy (1)
`
`
`8/2012
`Dosage and Administration (2)
`
`
`
`7/2012
`
`
`
`Contraindications (4)
`
`
`
`7/2012
`Warnings and Precautions (5)
`—————————INDICATIONS AND USAGE————————
`NUCYNTA® ER is an opioid agonist indicated for the management of:
`
`x moderate to severe chronic pain in adults (1)
`
`neuropathic pain associated with diabetic peripheral neuropathy
`x
`(DPN) in adults (1)
`when a continuous, around-the-clock opioid analgesic is needed for an
`extended period of time.
`Limitations of Use
`
`x NUCYNTA® ER is not for use:
`
` As an as-needed (prn) analgesic (1)
`
`
`For pain that is mild or not expected to persist for an
`
`
`extended period of time (1)
`For acute pain (1)
`For postoperative pain, unless the patient is already
`receiving chronic opioid therapy prior to surgery, or if the
`postoperative pain is expected to be moderate to severe
`
`
`and persist for an extended period of time. (1)
`——————— DOSAGE AND ADMINISTRATION———————
`
`x
`Individualize dosing based on patient’s prior analgesic treatment
`experience, and titrate as needed to provide adequate analgesia and
`
`minimize adverse reactions. (2.1, 2.2)
`The initial dose in patients not currently taking opioid analgesics is 50
`mg twice a day. (2.1).
`x
`Instruct patients to swallow NUCYNTA® ER tablets whole. (2.7)
`x Use a gradual downward
`titration when NUCYNTA® ER
`discontinued in a physically dependent patient. (2.3, 5.13)
`Reduce the dose of NUCYNTA® ER in patients with moderate hepatic
`
`impairment. (2.4)
`x NUCYNTA® ER use in patients with severe renal impairment is not
`recommended. (2.5)
`
`x
`
`x
`
`x
`
`x
`
`x
`
`
`
`
`is
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3181514
`
`x
`
`x
`
`x
`
`x
`x
`
`x
`
`Conservative initial dosing of NUCYNTA® ER in elderly patients is
`
`recommended due to possible decreased renal and hepatic function.
`(2.6)
`——————— DOSAGE FORMS AND STRENGTHS——————
`x
`Extended-Release Tablets: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg
`
`(3)
`—————————— CONTRAINDICATIONS—————————
`x
`Significant respiratory depression (4)
`
`x Acute or severe bronchial asthma (4)
`
`x Known or suspected paralytic ileus (4)
`
`x Hypersensitivity to tapentadol or to any other ingredients of the product
`
`
`(4)
`Concurrent use of monoamine oxidase inhibitors (MAOI) or use within
`
`the last 14 days. (4)
`——————— WARNINGS AND PRECAUTIONS———————
`
`See Boxed WARNINGS
`x
`Elderly, cachectic, and debilitated patients and patients with chronic
`
`pulmonary disease: Monitor closely because of increased risk of
`respiratory depression. (5.5, 5.6)
`Interaction with CNS depressants: Consider dose reduction of one or
`both drugs because of additive effects. (5.7, 7.3)
`x Hypotensive effect: Monitor during dose initiation and titration. (5.8)
`x
`Patients with head injury or increased intracranial pressure: Monitor for
`sedation and respiratory depression. Avoid use of NUCYNTA® ER in
`patients with impaired consciousness or coma susceptible to intracranial
`
`effects of CO2 retention. (5.9)
`Seizures: Use with caution in patients with a history of seizures. (5.10)
`Serotonin Syndrome: Potentially life-threatening condition could result
`
`from concomitant administration of drugs with serotonergic activity.
`(5.11)
`
`—————————— ADVERSE REACTIONS—————————
`
`The most common (•10%) adverse reactions were nausea, constipation,
`dizziness, headache, and somnolence. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`
`Pharmaceuticals, Inc. at 1–800–526–7736 (1-800-JANSSEN) or FDA at 1–
`800–FDA–1088 or www.fda.gov/medwatch.
`
`—————————— DRUG INTERACTIONS—————————
`x
`CNS depressants: Increased risk of respiratory depression, hypotension,
`profound sedation, coma or death. When combined therapy with CNS
`depressant is contemplated, the dose of one or both agents should be
`
`
`reduced. (7.3)
`x Mixed agonist/antagonist opioids (i.e., pentazocine, nalbuphine, and
`
`
`butorphanol): May reduce analgesic effect and/or precipitate withdrawal
`
`symptoms. (7.5)
`x Monitor for signs of serotonin syndrome when NUCYNTA® ER is used
`
`concurrently with SSRIs, SNRIs, tricyclic antidepressants, or triptans.
`
`(7.4)
`——————— USE IN SPECIFIC POPULATIONS———————
`
`x
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`x Nursing mothers: Closely monitor infants of nursing women
`
`
`receiving. NUCYNTA® ER. (8.3)
`Renal or hepatic impairment: not recommended in patients with severe
`renal or hepatic impairment. Reduce dose in patients with moderate
`hepatic impairment. (8.7, 8.8)
`
`
`
`for PATIENT COUNSELING
`See 17
`MEDICATION GUIDE.
`
`INFORMATION AND
`
`
`
`Revised: 8/2012
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ABUSE POTENTIAL, LIFE-THREATENING
`
`
`RESPIRATORY DEPRESSION, ACCIDENTAL
`
`EXPOSURE, AND INTERACTION WITH ALCOHOL
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`
`Initial Dosing
`
`2.1
`2.2 Titration and Maintenance of Therapy
`
`2.3 Discontinuation of NUCYNTA® ER
`
`2.4 Patients with Hepatic Impairment
`
`2.5 Patients with Renal Impairment
`
`2.6 Elderly Patients
`
`2.7 Administration of NUCYNTA® ER
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Abuse Potential
`
`5.2 Life Threatening Respiratory Depression
`
`5.3 Accidental Exposure
`
`5.4
`Interaction with Alcohol
`
`5.5 Elderly, Cachectic, and Debilitated Patients
`
`5.6 Use in Patients with Chronic Pulmonary Disease
`
`5.7
`Interactions with CNS Depressants and Illicit
`
`Drugs
`
`5.8 Hypotensive Effect
`
`5.9 Use in Patients with Head Injury or Increased
`
`Intracranial Pressure
`
`5.10 Seizures
`
`5.11 Serotonin Syndrome Risk
`
`5.12 Use in Patients with Gastrointestinal Conditions
`
`5.13 Avoidance of Withdrawal
`
`5.14 Driving and Operating Heavy Machinery
`
`5.15 Hepatic Impairment
`
`5.16 Renal Impairment
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`Reference ID: 3181514
`
`7.1 Alcohol
`
`7.2 Monoamine Oxidase Inhibitors
`
`7.3 CNS Depressants
`
`7.4 Serotonergic Drugs
`
`7.5 Mixed Agonist/Antagonist Opioid Analgesics
`
`7.6 Anticholinergics
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Neonatal Withdrawal Syndrome
`
`8.7 Renal Impairment
`
`8.8 Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`9.2 Abuse
`
`9.3 Dependence
`
`10 OVERDOSAGE
`10.1 Clinical Presentation
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`14 CLINICAL STUDIES
`
`14.1 Moderate to Severe Chronic Low Back Pain
`
`
`14.2 Neuropathic Pain Associated with Diabetic
`
`Peripheral Neuropathy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`[*Sections or subsections omitted from the full prescribing information are not
`
`listed]
`
`
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`LIFE-THREATENING RESPIRATORY
`POTENTIAL,
`WARNING: ABUSE
`DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL
`
`Abuse Potential
`
`
`NUCYNTA® ER contains tapentadol, an opioid agonist and Schedule II controlled
`
`
`substance with an abuse liability similar to other opioid agonists, legal or illicit [see
`Warnings and Precautions (5.1)]. Assess each patient’s risk for opioid abuse or addiction
`prior to prescribing NUCYNTA® ER. The risk for opioid abuse is 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 depressive disorder). Routinely monitor all patients
`receiving NUCYNTA® ER for signs of misuse, abuse, and addiction during treatment [see
`Drug Abuse and Dependence (9)].
`
`Life-threatening Respiratory Depression
`
`
`Respiratory depression, including fatal cases, may occur with use of NUCYNTA® ER, even
`when the drug has been used as recommended and not misused or abused [see Warnings
`and Precautions (5.2)]. Proper dosing and titration are essential and NUCYNTA® ER
`
`
`should only be prescribed by healthcare professionals who are knowledgeable in the use of
`
`potent opioids for the management of chronic pain. Monitor for respiratory depression,
`especially during initiation of NUCYNTA® ER or following a dose increase. Instruct
`patients to swallow NUCYNTA® ER tablets whole. Crushing, dissolving, or chewing
`
`NUCYNTA® ER can cause rapid release and absorption of a potentially fatal dose of
`
`tapentadol.
`
`
`Accidental Exposure
`
`Accidental ingestion of NUCYNTA® ER, especially in children, can result in a fatal
`overdose of tapentadol [see Warnings and Precautions (5.3)].
`
`Interaction with Alcohol
`
`
`The co-ingestion of alcohol with NUCYNTA® ER may result in an increase of plasma levels
`and potentially fatal overdose of tapentadol [see Warnings and Precautions (5.4)]. Instruct
`
`patients not to consume alcoholic beverages or use prescription or non-prescription
`products that contain alcohol while on NUCYNTA® ER.
`
`
`
`Reference ID: 3181514
`
`3
`
`

`

`INDICATIONS AND USAGE
`1
`NUCYNTA® ER (tapentadol) is indicated for the management of:
`ƒ moderate to severe chronic pain in adults
`
`ƒ
`
`neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults
`
`when a continuous, around-the-clock opioid analgesic is needed for an extended period of time
`[see Clinical Studies (14.1, 14.2)].
`
`Limitations of Usage
`
`NUCYNTA® ER is not intended for use:
`
`x As an as-needed (prn) analgesic
`x For pain that is mild or not expected to persist for an extended period of time
`x For acute pain
`x For postoperative pain unless the patient is already receiving chronic opioid therapy prior
`to surgery or if the postoperative pain is expected to be moderate to severe and persist for
`an extended period of time.
`2 DOSAGE AND ADMINISTRATION
`2.1
`Initial Dosing
`Initiate the dosing regimen for each patient individually, taking into account the patient's prior
`analgesic treatment experience. Monitor patients closely for respiratory depression, especially
`within the first 72 hours of initiating therapy with NUCYNTA® ER [see Warnings and
`
`Precautions (5.2)].
`
`Consider the following factors when selecting an initial dose of NUCYNTA® ER:
`
`x Total daily dose, potency, and kind of any prior analgesic the patient has been taking
`
`previously;
`x Reliability of the relative potency estimate used to calculate the equivalent dose of
`tapentadol needed (Note: potency estimates may vary with the route of administration);
`x Patient's degree of opioid experience and opioid tolerance;
`x General condition and medical status of the patient;
`x Concurrent medication;
`x Type and severity of the patient's pain.
`NUCYNTA® ER tablets must be taken whole, one tablet at a time, with enough water to ensure
`complete swallowing immediately after placing in the mouth [see Patient Counseling
`
`Information (17)].
`
`
`
`Reference ID: 3181514
`
`4
`
`

`

`NUCYNTA® ER is administered at a frequency of twice daily (every 12 hours).
`
`Discontinue all other tapentadol and tramadol products when beginning and while taking
`NUCYNTA® ER [see Serotonin Syndrome Risk (5.11)]. Although the maximum approved total
`daily dose of NUCYNTA® immediate-release formulation is 600 mg per day, the maximum total
`
` daily dose of NUCYNTA® ER is 500 mg. Do not exceed a total daily dose of NUCYNTA® ER
`of 500 mg.
`
`Use of NUCYNTA® ER as the First Opioid Analgesic
`Initiate NUCYNTA® ER therapy with the 50 mg tablet twice daily (at 12 hour intervals).
`
`Conversion from NUCYNTA® to NUCYNTA® ER
`Patients can be converted from NUCYNTA® to NUCYNTA® ER using the equivalent total daily
`dose of NUCYNTA® and dividing it into two equal doses of NUCYNTA® ER separated by
`approximately 12-hour intervals. As an example, a patient receiving 50 mg of NUCYNTA® four
`times per day (200 mg/day) may be converted to 100 mg NUCYNTA® ER twice a day.
`
`Conversion from other Opioids to NUCYNTA® ER
`While there are useful tables of oral and parenteral equivalents, there is substantial inter-patient
`
`variation in the relative potency of different opioid drugs and formulations. Specific
`recommendations are not available because of a lack of systematic evidence for these types of
`analgesic substitutions. As such, it is safer to underestimate a patient's 24-hour NUCYNTA® ER
`
`requirement and provide rescue medication (e.g., immediate-release opioid or non-opioid) than
`to overestimate and manage an adverse reaction. In general, begin with half of the estimated
`daily
`tapentadol requirement as
`the
`initial dose, managing
`inadequate analgesia by
`supplementation with immediate-release rescue medication.
`
`Published relative potency/equianalgesia data are available and may be referred to in clinical
`practice guidelines such as those published by authorities in the field of pain medicine, but such
`ratios are approximations. Consider contacting your specific state medical or pharmacy
`professional societies for further information on how to safely convert patients from one opioid
`to another.
`
`
`2.2 Titration and Maintenance of Therapy
`Individually titrate NUCYNTA® ER to a dose that provides adequate analgesia and minimizes
`
`adverse reactions. Continually reevaluate patients receiving NUCYNTA® ER to assess the
`maintenance of pain control and the relative incidence of adverse reactions. During chronic
`therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses),
`periodically reassess the continued need for the use of opioid analgesics.
`
`
`
`Reference ID: 3181514
`
`5
`
`

`

` Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily
`
`every three days. In clinical studies, efficacy with NUCYNTA® ER was demonstrated relative to
`placebo in the dosage range of 100 mg to 250 mg twice daily [see Clinical Studies (14)].
`
`If the level of pain increases, attempt to identify the source of increased pain, while adjusting the
`NUCYNTA® ER dose to decrease the level of pain.
`
`Patients who experience breakthrough pain may require dosage adjustment or rescue medication
`with an appropriate dose of an immediate-release opioid or non-opioid medication.
`
`If signs of excessive opioid-related adverse reactions are observed, the next dose may be
`reduced. Adjust the dose to obtain an appropriate balance between management of pain and
`opioid-related adverse reactions.
`
`During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes,
`reassess the continued need for around-the-clock opioid therapy regularly (e.g., every 6 to 12
`months) as appropriate.
`
`2.3 Discontinuation of NUCYNTA® ER
`When the patient no longer requires therapy with NUCYNTA® ER tablets, use a gradual
`downward titration of the dose to prevent signs and symptoms of withdrawal in the
`physically-dependent patient.
`
`2.4 Patients with Hepatic Impairment
`The use of NUCYNTA® ER in patients with severe hepatic impairment (Child-Pugh Score
`
`10-15) is not recommended.
`
`In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate treatment using
`50 mg NUCYNTA® ER and administer no more frequently than once every 24 hours. The
`maximum recommended dose for patients with moderate hepatic impairment is 100 mg of
`NUCYNTA® ER once daily [see Clinical Pharmacology (12.3)].
`
`
`No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh
`Score 5 to 6) [see Warnings and Precautions (5.15) and Clinical Pharmacology (12.3)].
`
`
`2.5 Patients with Renal Impairment
`No dosage adjustment is recommended in patients with mild or moderate renal impairment.
`NUCYNTA® ER use in patients with severe renal impairment is not recommended [see
`
`Warnings and Precautions (5.16) and Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 3181514
`
`6
`
`

`

` 2.6 Elderly Patients
`
`In general, recommended dosing for elderly patients with normal renal and hepatic function is
`the same as for younger adult patients with normal renal and hepatic function. Because elderly
`patients are more likely to have decreased renal and hepatic function, consideration should be
`
` given to starting elderly patients with the lower range of recommended doses [see Clinical
`Pharmacology (12.3)].
`
`2.7 Administration of NUCYNTA® ER
`Instruct patients to swallow NUCYNTA® ER tablets whole. The tablets are not to be cut,
`crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal
`dose of tapentadol [see Warnings and Precautions (5.1, 5.2)].
`
`Instruct patients to take NUCYNTA® ER one tablet at a time and with enough water to ensure
`complete swallowing immediately after placing in the mouth [see Warnings and Precautions
`(5.2), and Patient Counseling Information (17)].
`
`
`3 DOSAGE FORMS AND STRENGTHS
`NUCYNTA® ER 50 mg, 100 mg, 150 mg, 200 mg and 250 mg extended-release tablets are
`
` available in the following colors and prints:
`
`x 50 mg extended-release tablets are white oblong-shaped with a black print “OMJ 50” on
`one side
`x 100 mg extended-release tablets are light-blue oblong-shaped with a black print “OMJ
`100” on one side
`x 150 mg extended-release tablets are blue-green oblong-shaped with a black print “OMJ
`150” on one side
`x 200 mg extended-release tablets are blue oblong-shaped with a depression in the middle
`running lengthwise on each side and a black print “OMJ 200” on one side
`x 250 mg extended-release tablets are dark blue oblong-shaped with a depression in the
`middle running lengthwise on each side and a white print “OMJ 250” on one side.
`
`4 CONTRAINDICATIONS
`NUCYNTA® ER is contraindicated in:
`
`x Patients with significant respiratory depression
`x Patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting
`or in the absence of resuscitative equipment
`x Patients with known or suspected paralytic ileus
`
`
`
`Reference ID: 3181514
`
`7
`
`

`

`x Patients with hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any
`other ingredients of the product [see Adverse Reactions (6.2)].
` x Patients who are receiving monoamine oxidase inhibitors (MAOI) or who have taken
`
`them within the last 14 days due to potential additive effects on norepinephrine levels
`which may result in adverse cardiovascular events [see Drug Interactions(7.2)].
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Abuse Potential
`NUCYNTA® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance.
`
`Tapentadol can be abused in a manner similar to other opioid agonists legal or illicit. Opioid
`agonists are sought by drug abusers and people with addiction disorders and are subject to
`criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® ER in
`
`situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns
`about abuse, addiction, and diversion should not, however, prevent the proper management of
`pain.
`
`Assess each patient’s risk for opioid abuse or addiction prior to prescribing NUCYNTA® ER.
`The risk for opioid abuse is 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).
`Patients at increased risk may still be appropriately treated with modified-release opioid
`formulations; however these patients will require intensive monitoring for signs of misuse,
`abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse,
`and addiction because these drugs carry a risk for addiction even under appropriate medical use.
`
`Misuse or abuse of NUCYNTA® ER by crushing, chewing, snorting, or injecting the dissolved
`
`product will result in the uncontrolled delivery of the opioid and pose a significant risk that could
`result in overdose and death [see Overdosage (10)].
`
`
`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
`Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA® ER.
`Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest
`and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a
`decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths
`separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced
`respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory
`
`
`
`Reference ID: 3181514
`
`8
`
`

`

`depression may include close observation, supportive measures, and use of opioid antagonists,
`depending on the patient’s clinical status [see Overdosage (10)].
`
` While serious, life-threatening, or fatal respiratory depression can occur at any time during the
`
`use of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose
`increase. Closely monitor patients for respiratory depression when initiating therapy with
`NUCYNTA® ER and following dose increases. Instruct patients against use by individuals other
`than the patient for whom NUCYNTA® ER was prescribed and to keep NUCYNTA® ER out of
`the reach of children, as such inappropriate use may result in fatal respiratory depression.
`
`To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA® ER are
`essential [see Dosage and Administration (2)]. Overestimating the NUCYNTA® ER dose when
`
`converting patients from another opioid product can result in fatal overdose with the first dose.
`Respiratory depression has also been reported with use of modified-release opioids when used as
`recommended and not misused or abused.
`
`To further reduce the risk of respiratory depression, consider the following:
`
`x
`
`x Proper dosing and titration are essential and NUCYNTA® ER should only be prescribed
`by healthcare professionals who are knowledgeable in the use of potent opioids for the
`management of chronic pain.
`Instruct patients to swallow NUCYNTA® ER tablets whole. The tablets are not to be cut,
`
`crushed, dissolved, or chewed. The resulting tapentadol dose may be fatal, particularly in
`opioid-naïve individuals.
`x NUCYNTA® ER is contraindicated in patients with respiratory depression and in patients
`with conditions that increase the risk of life-threatening respiratory depression [see
`Contraindications (4)].
`5.3 Accidental Exposure
`Accidental ingestion of NUCYNTA® ER, especially in children, can result in a fatal overdose of
`
`tapentadol.
`
`Interaction with Alcohol
`5.4
`The co-ingestion of alcohol with NUCYNTA® ER can result in an increase of tapentadol plasma
`
`levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic
`beverages or use prescription or non-prescription products containing alcohol while on
`NUCYNTA® ER therapy [see Clinical Pharmacology (12.3)].
`
`5.5 Elderly, Cachectic, and Debilitated Patients
`Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they
`may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
`
`
`
`Reference ID: 3181514
`
`9
`
`

`

` Therefore, monitor such patients closely, particularly when initiating and titrating NUCYNTA®
`
`ER and when NUCYNTA® ER is given concomitantly with other drugs that depress respiration
`[see Warnings and Precautions (5.2)].
`
` 5.6 Use in Patients with Chronic Pulmonary Disease
`
`Monitor for respiratory depression those patients with significant chronic obstructive pulmonary
`
` disease or cor pulmonale, and patients having a substantially decreased respiratory reserve,
`hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy
`and titrating with NUCYNTA® ER, as in these patients, even usual therapeutic doses of
`NUCYNTA® ER may decrease respiratory drive to the point of apnea [see Warnings and
`Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if
`possible.
`
`Interactions with CNS Depressants and Illicit Drugs
`5.7
`Hypotension, and profound sedation, coma or respiratory depression may result if NUCYNTA®
`
`ER is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics,
`neuroleptics, muscle relaxants, other opioids and illicit drugs). When considering the use of
`NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS
`depressant and the patient’s response, including the degree of tolerance that has developed to
`CNS depression. Additionally, consider the patient’s use, if any, of alcohol and/or illicit drugs
`that can cause CNS depression. If NUCYNTA® ER therapy is to be initiated in a patient taking a
`CNS depressant, start with a lower NUCYNTA® ER dose than usual and monitor patients for
`
`signs of sedation and respiratory depression and consider using a lower dose of the concomitant
`CNS depressant [see Drug Interactions (7.3)].
`
`5.8 Hypotensive Effect
`NUCYNTA® ER may cause severe hypotension. There is an 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 (7.3)]. Monitor these patients for signs of hypotension after
`initiating or titrating the dose of NUCYNTA® ER. In patients with circulatory shock,
`NUCYNTA® ER may cause vasodilation that can further reduce cardiac output and blood
`pressure. Avoid the use of NUCYNTA® ER in patients with circulatory shock.
`
`5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
`Monitor patients taking NUCYNTA® ER who may be susceptible to the intracranial effects of
`
`
`CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for
`
`signs of sedation and respiratory depression, particularly when initiating therapy with
`
`
`
`Reference ID: 3181514
`
`10
`
`

`

`NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2
`
`retention can further increase intracranial pressure. Opioids may also obscure the clinical course
`in a patient with a head injury.
`
`Avoid the use of NUCYNTA® ER in patients with impaired consciousness or coma.
`
`5.10 Seizures
`NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder,
`
`and such patients were excluded from clinical studies. The active ingredient tapentadol in
`NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may
`induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure
`disorders for worsened seizure control during NUCYNTA® ER therapy.
`
`5.11 Serotonin Syndrome Risk
`
`Cases of life-threatening serotonin syndrome have been reported with the concurrent use of
`tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake
`Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic
`antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g.
`mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including
`MAOIs). This may occur within the recommended dose. Serotonin syndrome 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 Serotonergic Drugs (7.4)].
`
`5.12 Use in Patients with Gastrointestinal Conditions
`NUCYNTA® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The
`tapentadol in NUCYNTA® ER may cause spasm of the sphincter of Oddi. Monitor patients with
`biliary tract disease, including acute pancreatitis, for worsening symptoms.
`
`
`5.13 Avoidance of Withdrawal
`Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and
`butorphanol) in patients who have received or are receiving a course of therapy with a full opioid
`agonist analgesic, including NUCYNTA® ER. In these patients, mixed agonists/antagonists
`analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
`
`When discontinuing NUCYNTA® ER, gradually taper the dose [see Dosage and Administration
`(2.3)].
`
`
`
`Reference ID: 3181514
`
`11
`
`

`

` 5.14 Driving and Operating Heavy Machinery
`
`NUCYNTA® ER 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® ER and
`know how they will react to the medication.
`
`5.15 Hepatic Impairment
`A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment
`showed higher serum concentrations of tapentadol than in those with normal hepatic function.
`Avoid use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce the dose of
`NUCYNTA® ER in patients with moderate hepatic impairment [see Dosage and Administration
`(2.4) and Clinical Pharmacology (12.3)]. Closely monitor patients with moderate hepatic
`
`
`impairment for respiratory and central nervous system depression when initiating and titrating
`NUCYNTA® ER.
`
`5.16 Renal Impairment
`Use of NUCYNTA® ER 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 in more detail in other sections of the labeling:
`
`x Respiratory Depression [see Warnings and Precautions (5.2)
`
`Interaction with Alcohol [see Warnings and Precautions (5.4)]
`x
`
`x Chronic Pulmonary Disease [see Warnings and Precautions (5.6)]
`
`x Hypotensive Effects [see Warnings and Precautions (5.8)]
`
`Interactions with Other CNS Depressants [see Warnings and Precautions (5.7)]
`x
`
`x Drug abuse, addiction, and dependence [see Drug Abuse and Dependence (9.2, 9.3)]
`
`x Gastrointestinal Effects [see Warnings and Precautions (5.12)]
`
`x Seizures [see Warnings and Precautions (5.10)]
`
`x Serotonin Syndrome [see Warnings and Precautions (5.11)]
`6.1 Clinical Studies Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
`of another drug and may not reflect the rates observed in clinical practic