`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: 2011
`
`WARNING: Potential for Abuse, proper patient selection and limitations of
`
`use
`See full prescribing information for complete boxed warning.
`NUCYNTA® ER contains tapentadol, a mu-opioid agonist and Schedule
`II controlled substance, with risk of misuse, abuse, and diversion similar
`to other opioid analgesics. (5.5)
`
`
`NUCYNTA® ER is not intended for use as an as-needed analgesic (1).
`
`NUCYNTA® ER is not intended for the management of acute or postoperative
`
`
`pain (1)
`Swallow NUCYNTA® ER tablets whole. Taking split, broken, chewed,
`
`dissolved, or crushed NUCYNTA® ER tablets could lead to rapid release
`and absorption of a potentially fatal dose of tapentadol. (5.1)
`Patients must not consume alcoholic beverages, prescription or non­
`
`prescription medications containing alcohol. Co-ingestion of alcohol with
`
`
`NUCYNTA® ER
`
`
`fatal overdose of
`may
`result
`in a potentially
`tapentadol.(12.3)
`
`—————————INDICATIONS AND USAGE————————
`
` NUCYNTA® ER is an opioid analgesic indicated for the management of
`
` moderate to severe chronic pain in adults when a continuous, around-the­
`
`clock opioid analgesic is needed for an extended period of time. (1)
`——————— DOSAGE AND ADMINISTRATION———————
`
`
`• As with many centrally acting analgesic medications, the dosing
`
` regimen of NUCYNTA® ER should be individualized according to the
`
` severity of pain being treated, the previous experience with similar
`
`drugs and the ability to follow-up and provide oversight of treatment.
`(2)
` The recommended NUCYNTA® ER total daily dose is 100 mg to 250
`
`
`mg twice daily approximately every 12 hours. Patients not currently
`taking opioid analgesics should begin NUCYNTA® ER therapy with
`
`
`50 mg twice a day.(2)
` Patients receiving NUCYNTA® (immediate-release formulation) may
`
`
`be converted to NUCYNTA® ER by administering the same total
`
`daily dose. Administer half the total daily dose of NUCYNTA® ER
`
`
`approximately every 12 hours. Do not exceed the maximum daily
`dose of NUCYNTA® ER of 500 mg. (2)
`
`——————— DOSAGE FORMS AND STRENGTHS——————
`
`•
`
`
`
` Tablets: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg (3)
`—————————— CONTRAINDICATIONS—————————
`
`•
`
` Impaired pulmonary function (significant respiratory depression,
`acute or severe bronchial asthma or hypercapnia in unmonitored
`settings or the absence of resuscitative equipment) (4)
`Paralytic ileus (4)
` Concurrent use of monoamine oxidase (MAO) inhibitors or use
`
`within the last 14 day (4)
`
`• Hypersensitivity (4)
`
`
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`
`——————— WARNINGS AND PRECAUTIONS———————
`
`•
` Respiratory depression: Increased risk in elderly, debilitated patients,
`
`from conditions accompanied by hypoxia,
`those
`suffering
`hypercapnia, or upper airway obstruction. (5.2)
`CNS effects: Additive CNS depressive effects when used in
`conjunction with alcohol, other opioids, or illicit drugs. (5.3)
`
`
` Elevation of intracranial pressure: Use with caution in patients with
`
` head injury, intracranial lesions, or other sources of preexisting
`increased intracranial pressure. (5.4)
`
`• Abuse potential may occur. Monitor patients closely for signs of abuse
`
`and addiction. (5.5)
`
`• Hypotension may occur, particularly in patients at high risk (5.6)
`
`
`•
`Impaired mental/physical abilities: Caution must be used with
`potentially hazardous activities. (5.7)
`Interaction with alcohol and drugs of abuse: CNS, respiratory
`depression, hypotension and sedation effects may be additive (5.8)
` Seizures: Use with caution in patients with a history of seizures. (5.9)
`
`
` Serotonin Syndrome: Potentially life-threatening condition could
` result from concomitant administration of drugs with serotonergic
`
`activity. (5.10)
`
`• Withdrawal symptoms may occur if NUCYNTA® ER is discontinued
`
`
`abruptly. Tapering may reduce withdrawal symptoms. (5.11)
`
` —————————— ADVERSE REACTIONS—————————
` The most common (≥10%) adverse reactions were nausea, constipation,
`
`headache, dizziness, and somnolence. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1–800–526–7736 or FDA at 1–800–FDA–1088
`or www.fda.gov/medwatch.
`—————————— DRUG INTERACTIONS—————————
`
`• Use NUCYNTA® ER with caution in patients currently using
`
`specified centrally acting drugs or alcohol. (7.3)
`
`• Do not use NUCYNTA® ER in patients currently using or within 14
`
`days of using a monoamine oxidase inhibitor (MAOI). (7.4)
`
`• Use NUCYNTA® ER with caution in patients currently using
`SSRIs, SNRIs, tricyclic antidepressants, or triptans (7.5)
`
`• Use of NUCYNTA® ER in patients currently using mixed
`
` agonist/antagonist opioid analgesics or anticholinergic medications
`
`is not recommended (7.6, 7.7)
`
` ——————— USE IN SPECIFIC POPULATIONS———————
`
`•
`
` Labor and delivery: should not use during and immediately prior to
`labor and delivery. Monitor neonates, whose mothers have been
`taking NUCYNTA® ER, for respiratory depression. (8.2)
`
`
`• Nursing mothers: should not breast-feed. (8.3)
`
`•
` Pediatric use: safety and effectiveness not established in patients
`
` less than 18 years of age. (8.4)
`Renal or hepatic impairment: not recommended in patients with
`severe renal or hepatic impairment. Use with caution in patients
`with moderate hepatic impairment. (8.7, 8.8)
`Elderly: care should be taken when selecting an initial dose. (2.5)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`
`
`•
`
`
`
`
`for PATIENT COUNSELING INFORMATION AND
`See 17
`MEDICATION GUIDE.
`
`Revised: 08/2011
`
`
`
`
`Reference ID: 3006589
`
`1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING
` 
` 
`INDICATIONS AND USAGE
`1
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Initiating Therapy with NUCYNTA® ER
`
`2.1
` 
` 
`2.2 Cessation of Therapy
`
` 
` 
`2.3 Renal Impairment
`
` 
` 
`2.4 Hepatic Impairment
`
` 
` 
`2.5 Elderly Patients
`
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`Information Essential for Safe Administration
`
`5.1
` 
` 
`5.2 Respiratory Depression
`
` 
` 
`5.3 CNS Depression
`
` 
`5.4 Head Injury and Increased Intracranial
`
` 
`Pressure
`
` 
` 
`5.5 Misuse and Abuse
`
` 
` 
`5.6 Hypotension
`
` 
` 
`5.7 Driving and Operating Machinery
`
` 
` 
`5.8
`Interactions with Alcohol and Drugs of Abuse
`
` 
` 
`5.9 Seizures
`
` 
` 
`5.10 Serotonin Syndrome Risk
`
` 
` 
`5.11 Withdrawal
`
` 
` 
`5.12 Hepatic Impairment
`
` 
` 
`5.13 Use in Pancreatic/Biliary Tract Disease
`
` 
` 
`5.14 Other Special Risk Groups
`
` 
` 
`6 ADVERSE REACTIONS
` 
` 
`6.1 Clinical Studies Experience
`
` 
`6.2 Commonly-Observed Adverse Reactions in
`
`Double-Blind Controlled Clinical Studies with
`
` 
`NUCYNTA® ER
`
` 
`6.3 Other Adverse Reactions Observed During the
`
`
` 
`Premarketing Evaluation of NUCYNTA® ER
`
` 
` 
`6.4 Postmarketing Experience
`
` 
` 
`7 DRUG INTERACTIONS
` 
`7.1 Drugs Metabolized by Cytochrome P450
`
` 
`Enzymes
`
`
`
`
`
`
`Reference ID: 3006589
`
` 
`7.2 Drugs That Inhibit or Induce Cytochrome P450
`
` 
`Enzymes
`
` 
` 
`7.3 Centrally Acting Drugs and Alcohol
`
` 
` 
`7.4 Monoamine Oxidase Inhibitors
`
` 
` 
`7.5 Serotonergic Drugs
`
` 
` 
`7.6 Mixed Agonist/Antagonist Opioid Analgesics
`
` 
` 
`7.7 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 Human Experience
`
` 
` 
`10.2 Management of Overdose
`
`
` 
` 
`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
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
` 
` 
`17.1 Medication Guide
`
`
`
`
`[*Sections or subsections omitted from the full prescribing information are
`
`not listed]
`
`
`
`2
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTON, AND
`LIMITATIONS OF USE
`
`
`
` Potential for Abuse
`
`
`
` NUCYNTA® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled
`substance with an abuse liability similar to other opioid analgesics.
`
`NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit.
`These risks should be considered when prescribing, or dispensing NUCYNTA® ER in
`situations where the physician or pharmacist is concerned about an increased risk of
`misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone,
`morphine, oxycodone, fentanyl, oxymorphone, and methadone have the highest potential
`for abuse and risk of fatal overdose due to respiratory depression. (9)
`
`
`
`
`Proper Patient Selection
`
`NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the
`
` management of moderate to severe chronic pain in adults when a continuous, around-the­
`clock opioid analgesic is needed for an extended period of time.
`
`Limitations of Use
`
`
`NUCYNTA® ER is not intended for use as an as-needed analgesic. (1)
`
`
`
` NUCYNTA® ER is not intended for the management of acute or postoperative pain. (1)
`
`NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed,
`
` dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER
`
` tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.
`
` (5)
`
` Patients must not consume alcoholic beverages, prescription or non-prescription
`
`medications containing alcohol. Co-ingestion of alcohol with NUCYNTA® ER may result in
`a potentially fatal overdose of tapentadol. (12.3)
`
`INDICATIONS AND USAGE
`1
`NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the
`management of moderate to severe chronic pain in adults when a continuous, around-the-clock
`opioid analgesic is needed for an extended period of time.
`
`
`
`3
`
`Reference ID: 3006589
`
`

`

`
`NUCYNTA® ER is NOT intended for use as an as-needed analgesic.
`
`NUCYNTA® ER is not indicated for the management of acute or postoperative pain.
`
`2 DOSAGE AND ADMINISTRATION
`Selection of patients for treatment with NUCYNTA® ER is governed by the same principles
`that apply to the use of similar opioid analgesics. Physicians should individualize treatment in
`every case, using non-opioid analgesics, opioids on an as needed basis and/or combination
`
` products, and chronic opioid therapy in a progressive plan of pain management such as outlined
`by the World Health Organization and Federation of State Medical Boards Model Guidelines.
`
`
` NUCYNTA® ER tablets must be swallowed whole and must not be split, broken, chewed,
`
` dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA®
`ER Tablets could lead to rapid release and absorption of a potentially fatal dose of
`tapentadol.
`
`NUCYNTA® ER tablets must be taken one tablet at a time, with enough water to ensure
`complete swallowing immediately after placing in the mouth [see Patient Counseling
`Information (17)].
`
`
`Initiating Therapy with NUCYNTA® ER
`2.1
`
`It is critical to initiate the dosing regimen for each patient individually giving attention to:
`
`
`•
`
`risk factors for abuse or addiction; including whether the patient has a previous or current
`substance abuse problem, a family history of substance abuse, or a history of mental
`illness or depression;
`
`the age, general condition and medical status of the patient;
`•
`
`the patient's opioid exposure and opioid tolerance (if any);
`•
`
`the daily dose, potency, and kind of the analgesic(s) the patient has been taking;
`•
`
`the balance between pain management and adverse reactions.
`•
`Discontinue all other tapentadol and tramadol products when beginning and while taking
`NUCYNTA® ER [see Serotonin Syndrome Risk (5.10)]. 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.
`
`Once therapy with NUCYNTA® ER is initiated, assess pain intensity and adverse reactions
`
`frequently.
`
`
`
`4
`
`Reference ID: 3006589
`
`

`

`
` Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily
`every three days.
`
`
`
`During periods of changing analgesic requirements, including initial titration, maintain frequent
`contact between the healthcare provider and the patient.
`
`Patients Currently Not Taking Opioid Analgesics
` The starting dose of NUCYNTA® ER in patients currently not taking opioid analgesics is 50 mg
`
`twice a day (approximately every 12 hours). Individually titrate the dose within the therapeutic
`range of 100 mg to 250 mg twice daily.
`
` Patients Currently Taking Opioid Analgesics
`
`There are no adequate data on the direct conversion from other opioids to NUCYNTA® ER.
`
`The initial dose of NUCYNTA® ER in patients previously taking other opioids is 50 mg titrated
`
`to an effective and tolerable dose within the therapeutic range of 100 mg to 250 mg twice daily.
`
`In the dose selection of NUCYNTA® ER in patients currently taking opioids, give attention to
`the following:
`
`
`• There is a substantial patient variation in the relative potency of different opioid drugs
`
`and formulations;
`
`
`•
`
`It is extremely important to monitor all patients closely when converting from methadone
`to other opioid agonists. The ratio between methadone and other opioid agonists may
`vary widely as a function of previous dose exposure. Methadone has a long half-life and
`tends to accumulate in the plasma.
`
`
`• The recommended doses are only a starting point, and close observation and titration are
`indicated until a satisfactory dose is obtained on the new therapy.
`
`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.
`
`2.2 Cessation of Therapy
`
`Periodically reassess the continued need for NUCYNTA® ER during chronic therapy. When
`discontinuing NUCYNTA® ER, potential withdrawal symptoms may be reduced by tapering the
`dose of NUCYNTA® ER [see Withdrawal (5.11, 9.3)].
`
`
`
`
`
`5
`
`Reference ID: 3006589
`
`

`

`
`2.3 Renal Impairment
` NUCYNTA® ER has not been studied in patients with severe renal impairment; therefore, the
`
`use of NUCYNTA® ER in this population is not recommended. No dosage adjustment is
`recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology
`(12.3)].
`
`2.4 Hepatic Impairment
` NUCYNTA® ER has not been studied in patients with severe hepatic impairment. The use of
`NUCYNTA® ER in this population is not recommended.
`
`
`
` Use NUCYNTA® ER with caution in patients with moderate hepatic impairment. Initiate
`
`treatment in these patients 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 [see Clinical
`Pharmacology (12.3)].
`
`
`2.5 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`NUCYNTA® ER 50 mg, 100 mg, and 150 mg extended-release tablets are available in the
`following colors and prints:
`
`
`• 50 mg extended-release tablets are white oblong-shaped with a black print “OMJ 50” on
`one side
`
`• 100 mg extended-release tablets are light-blue oblong-shaped with a black print “OMJ
`100” on one side
`
`• 150 mg extended-release tablets are blue-green oblong-shaped with a black print “OMJ
`150” on one side
`NUCYNTA® ER 200 mg and 250 mg extended-release tablets are available in the following
`
`colors and prints:
`
`
`• 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
`
`
`
`6
`
`Reference ID: 3006589
`
`

`

`
`
`
`• 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 patients with significant respiratory depression, or severe
`
`bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative
`equipment [see Warnings and Precautions (5.1)].
`
`
`NUCYNTA® ER is contraindicated in any patient who has or is suspected of having a paralytic
`ileus.
`
`NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase (MAO)
`inhibitors 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
`(7.4)].
`
`NUCYNTA® ER is contraindicated in patients with a known hypersensitivity to the active
`
`substance, tapentadol, or any component of the product. Angioedema has been reported in
`association with use of tapentadol.
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Information Essential for Safe Administration
`NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed,
`dissolved, or crushed. Taking split, broken, chewed, crushed or dissolved NUCYNTA® ER
`
` tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.
`
`NUCYNTA® ER tablets must be kept in a secure place out of the reach of children. Accidental
`
`consumption of NUCYNTA® ER, especially in children, can result in a fatal overdose of
`
`tapentadol.
`
`5.2 Respiratory Depression
`Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs
`more frequently in elderly or debilitated patients and in those suffering from conditions
`accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate
`therapeutic doses may significantly decrease pulmonary ventilation.
`
`Use NUCYNTA® ER with caution in patients with conditions accompanied by hypoxia,
`hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary
`disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis,
`central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses
`of NUCYNTA® ER may increase airway resistance and decrease respiratory drive to the point of
`
`
`
`7
`
`Reference ID: 3006589
`
`

`

`
` apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA® ER
`
`
` should be employed only under careful medical supervision at the lowest effective dose in such
`patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced
`respiratory depression [see Overdosage (10.2)].
`
`5.3 CNS Depression
`Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, other
`tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants
`(including alcohol) concomitantly with NUCYNTA® ER may exhibit additive CNS depression.
`
` Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma or
`death may result if these drugs are taken in combination with NUCYNTA® ER. When such
`combined therapy is contemplated, a dose reduction of one or both agents should be considered.
`
`5.4 Head Injury and Increased Intracranial Pressure
`Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with
`carbon dioxide retention. Therefore, NUCYNTA® ER should not be used in patients who may be
`
`
` susceptible to the effects of raised cerebrospinal fluid pressure such as those with evidence of
`head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical
`course of patients with head injury due to effects on pupillary response and consciousness.
`NUCYNTA® ER should be used with caution in patients with head injury, intracranial lesions, or
`other sources of preexisting increased intracranial pressure.
`
`5.5 Misuse and Abuse
`Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are
`sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is
`an act subject to criminal penalty.
`
`Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being
`prescribed opioids.
`
`NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This
`
`should be considered when prescribing or dispensing NUCYNTA® ER in situations where the
`
`physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns
`about abuse and addiction should not prevent the proper management of pain. However, all
`patients treated with mu-opioid agonists require careful monitoring for signs of abuse and
`addiction, since use of mu-opioid agonist analgesic products carry the risk of addiction even
`under appropriate medical use [see Drug Abuse and Dependence (9.2)].
`
`
`
`8
`
`Reference ID: 3006589
`
`

`

`
`Drug abusers may attempt to abuse NUCYNTA® ER by crushing, chewing, snorting or injecting
`
` the product. These practices may result in the uncontrolled delivery of NUCYNTA® ER and
`pose a significant risk to the abuser that could result in overdose and death [see Drug Abuse and
`Dependence (9)].
`
`5.6 Hypotension
`NUCYNTA® ER may cause severe hypotension. Patients at higher risk of hypotension include
`those with hypovolemia or those taking concurrent products that compromise vasomotor tone
`(e.g., phenothiazines, general anesthetics).
`
`
`5.7 Driving and Operating Machinery
`Patients should be cautioned that NUCYNTA® ER may impair the mental and/or physical
`abilities required for the performance of potentially hazardous tasks such as driving a car or
`operating machinery. This is to be expected especially at the beginning of treatment, at any
`
`change of dosage, as well as in combination with alcohol or tranquilizers [see Drug Interactions
`(7.3)].
`
`Interactions with Alcohol and Drugs of Abuse
`5.8
`NUCYNTA® ER may be expected to have additive effects when used in conjunction with
`
`
`alcohol, other opioids, or illicit drugs that cause central nervous system depression, because
`respiratory depression, hypotension, hypertension, and profound sedation, coma or death may
`result [see Drug Interactions (7.3)].
`
`
`5.9 Seizures
`NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder,
`
`and such patients were excluded from clinical studies. As with other opioids, NUCYNTA® ER
`
`should be prescribed with care in patients with a history of a seizure disorder or any condition
`that would put the patient at risk of seizures.
`
`5.10 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,
`
`
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`incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be
`fatal [see Serotonergic Drugs (7.5)].
`
`5.11 Withdrawal
`
` Withdrawal symptoms may occur if NUCYNTA® ER is discontinued abruptly. These symptoms
`
`may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper
`respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be
`
` reduced by tapering NUCYNTA® ER [see Drug Abuse and Dependence (9.3)].
`
`5.12 Hepatic Impairment
`A study with the immediate-release formulation of tapentadol in subjects with hepatic
`
` impairment showed higher serum concentrations of tapentadol than in those with normal hepatic
`function. Tapentadol should be used with caution in patients with moderate hepatic impairment
`[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
`
`NUCYNTA® ER has not been studied in patients with severe hepatic impairment and use in this
`population is not recommended.
`
`5.13 Use in Pancreatic/Biliary Tract Disease
`Like other drugs with mu-opioid agonist activity, NUCYNTA® ER may cause spasm of the
`
` sphincter of Oddi and should be used with caution in patients with biliary tract disease, including
`acute pancreatitis.
`
`5.14 Other Special Risk Groups
`NUCYNTA® ER should be used with caution in the following conditions: adrenocortical
`
` insufficiency (e.g., Addison's disease); delirium tremens; myxedema or hypothyroidism;
`prostatic hypertrophy or urethral stricture; and, toxic psychosis.
`
`6 ADVERSE REACTIONS
` The following adverse reactions are discussed in more detail in other sections of the labeling:
`
`
`
`
`• Respiratory Depression [see Contraindications (4) and Warnings and Precautions (5.2)]
`
`
` • CNS Depression [see Warnings and Precautions (5.3)]
`
`
` • Hypotension [see Warnings and Precautions (5.6)]
`
`
` • Seizures [see Warnings and Precautions (5.9)]
`
`
` • Serotonin Syndrome [see Warnings and Precautions (5.10)]
`
`
`
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`6.1 Clinical Studies Experience
`A causal relationship with NUCYNTA® ER often cannot be reliably established in individual
`
` cases. 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 practice.
`
`The safety data described in Table 1 below are based on three pooled, randomized, double-blind,
`
` placebo-controlled, parallel group, 15-week studies of NUCYNTA® ER (dosed 100 to 250 mg
`BID after a 50 mg BID starting dose) in patients with chronic pain due to low back pain (LBP)
`and osteoarthritis (OA). These trials included 980 NUCYNTA® ER-treated patients and 993
`placebo-treated patients. The mean age was 57 years old; 63% were female and 37% were male;
`83% were White, 10% were Black, and 5% were Hispanic.
`
`The most common adverse reactions (reported by ≥10% in any NUCYNTA® ER dose group)
`were: nausea, constipation, headache, dizziness, and somnolence.
`
`The most common reasons for discontinuation due to adverse reactions in nine Phase 2/3 pooled
`studies reported by ≥1% in any NUCYNTA® ER dose group for NUCYNTA® ER- and placebo-
`treated patients were nausea (4% vs. <1%), dizziness (4% vs. <1%), vomiting (3% vs. <1%),
`somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1%
`vs. <1%), respectively.
`
`6.2
`
`
` Commonly-Observed Adverse Reactions in Double-Blind Controlled Clinical
`Studies with NUCYNTA® ER
`Table 1 lists the common adverse reactions reported in 1% or more of NUCYNTA® ER-treated
`
`patients and greater than placebo-treated patients with chronic moderate to severe pain in the
`three pooled studies. The types of adverse reactions seen in the study of patients with painful
`diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and
`osteoarthritis trials.
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` Table 1:
`
`
`
`
`
`
` Adverse Drug Reactions Reported by ≥ 1% of NUCYNTA® ER-Treated Patients and Greater than
` Placebo-treated Patients in Pooled Parallel-Group Trials (i.e., Studies LBP-1, OA-1, and OA-2)1
`
` NUCYNTA® ER 50 to 250 mg BID2
`
`Placebo
`
`
`
`(n=980)
`
`(n=993)
`
`
`
` Gastrointestinal disorders
`
`Nausea
`
`Constipation
`
` Vomiting
`
` Dry mouth
`
`
`Dyspepsia
`
`
`Nervous system disorders
`
`
` Dizziness
`
` Headache
`
` Somnolence
`
`
` Lethargy
`
`
`
`Disturbance in attention
`
`Tremor
`
`
`
`21%
`
`17%
`
`8%
`
`7%
`
`3%
`
`
`
`17%
`
`15%
`
`12%
`
`2%
`
`1%
`
`1%
`
`
`General disorders and administration
`site conditions
`
`
`
`
` Fatigue
`
`Asthenia
`
`Chills
`
`
`Psychiatric disorders
`
` Insomnia
`
`
`Anxiety
`
` Depressed mood3
`
`
`Abnormal dreams
`
`Depression
`
`9%
`
`2%
`
`1%
`
`
`
`4%
`
`2%
`
`1%
`
`1%
`
`1%
`
`
`
`7%
`
`7%
`
`3%
`
`3%
`
`2%
`
`
`
`7%
`
`13%
`
`4%
`
`0%
`
`0%
`
`0%
`
`
`
`4%
`
`1%
`
`0%
`
`
`
`2%
`
`1%
`
`1%
`
`0%
`
`0%
`
`
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`
`
`
` Skin and subcutaneous tissue disorders
`
`
`
` Hyperhidrosis
`
`Pruritus
`
`Rash3
`
`
`
`Metabolism and nutrition disorders
`
` Decreased appetite
`
`
`Ear and labyrinth disorders
`
` Vertigo
`
`
`Vascular disorders
`
` Hot flush
`
`
`Eye disorders
`
` Vision blurred
`
`5%
`
`5%
`
`1%
`
`
`
`2%
`
`
`
`2%
`
`
`
`2%
`
`
`
`1%
`
`Respiratory, thoracic and mediastinal
`
`disorders
`
`
`
` Dyspnea3
`
`
`Reproductive
`disorders
`
`
`system
`
`and
`
`breast
`
`
` Erectile dysfunction
`
`1%
`
`
`
`1%
`
`
`
`1%
`
`2%
`
`1%
`
`
`
`1%
`
`
`
`1%
`
`
`
`0%
`
`
`
`0%
`
`
`
`1%
`
`
`
`0%
`
`1 MedDRA preferred terms. The trials included forced titration during the first week of dosing.
`
`
`
`2 NUCYNTA® ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID
`
`
`3Depressed mood was observed in 1.2% of NUCYNTA® ER-treated subjects vs. 0.5% in placebo group, rash- in 1.1 vs.
`
`
`0.7 in placebo, and dyspnea- in 1.1 vs. 0.5 in placebo.
`6.3 Other Adverse Reactions Observed During the Premarketing Evaluation of
`NUCYNTA® ER
` The following adverse drug reactions occurred in less than 1% of NUCYNTA® ER-treated
`patients in nine Phase 2/3 clinical studies:
`
`
`
`
`• Nervous System Disorders: Paresthesia, Hypoesthesia, Balance disorder, Sedation,
`Syncope, Memory impairment, Mental impairment, Depressed level of consciousness,
`Dysarthria, Coordination abnormal, Presyncope
`
`
`• Gastrointestinal disorders: Impaired gastric emptying
`
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`
`• General disorders and administration site conditions: Drug withdrawal syndrome,
`Irritability, Feeling abnormal, Feeling drunk, Feeling of relaxation
`
`
`• Psychiatric disorders: Perception disturbances, Disorientation, Agitation, Confusional state,
`Euphoric mood, Drug dependence, Thinking abnormal
`
`
`• Skin and subcutaneous tissue disorders: Urticaria
`
`
`• Metabolism and nutrition disorders: Weight decreased
`
`
`• Cardiac disorders: Heart rate increased, Heart rate decreased
`
`
`
`• Vascular Disorder: Blood pressure decreased
`
`
`• Respiratory, thoracic and mediastinal disorders: Respiratory depression
`
`
`• Renal and urinary disorders: Pollakiuria, Urinary hesitation
`
`
`• Reproductive system and breast disorders: Sexual dysfunction
`
`
`• Eye disorders: Visual disturbance
`
`
`Immune system disorders: Drug hypersensitivity
`•
`6.4 Postmarketing Experience
`The following adverse reactions have been identified during post approval use of tapentadol.
`
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`Gastrointestinal disorders: diarrhea
`
`Immune system disorders: angioedema
`
`
`Psychiatric disorders: hallucination, suicidal ideation
`
`Cardiac disorders: palpitations
`
`7 DRUG INTERACTIONS
`Tapentadol is mainly metabolized by glucuronidation. The following substances have been
`included in a set of interaction studies witho