`
` C-II
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION1
`
`These highlights do not include all the information needed to use
`NUCYNTA® safely and effectively. See full prescribing information for
`NUCYNTA® .
`NUCYNTA® (tapentadol) oral solution
`
`
`Initial U.S. Approval: 2008
`
`----------------------------INDICATIONS AND USAGE----------------------------
`NUCYNTA® is an opioid analgesic indicated for the management of moderate
`to severe acute pain in adults. (1)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
` Individualize dosing according to the severity of pain being treated, the
`previous experience with similar drugs and the ability to monitor the
`patient. (2.1)
` Initiate NUCYNTA® with or without food at a dose of 2.5 mL (50 mg),
`
`
`3.75 mL (75 mg), or 5 mL (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 2.5 mL (50 mg),
`
`3.75 mL (75 mg), or 5 mL (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
`
`therefore, not
`subsequent days have not been studied and are,
`recommended. (2.2)
`
`
` Instructions for Use (2.7)
`
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Oral Solution: 20 mg/mL (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`
` Significant respiratory depression (4)
`
`
` Acute or severe bronchial asthma, hypercarbia (4)
`
`
` Known or suspected paralytic ileus (4)
`
`
`
` Hypersensitivity to tapentadol or to any other ingredients of the product (4)
`
`
` Concurrent use of monoamine oxidase (MAO) inhibitors or use within the
`
`
`last 14 days. (4)
`
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`
`
` Misuse, Abuse and Diversion: NUCYNTA® is a Schedule II controlled
`
`substance with abuse liability similar to other opioids: monitor patients
`closely for signs of misuse, abuse and addiction. (5.1)
`
`
`
` Elderly, cachectic, and debilitated patients and patients with chronic
`pulmonary disease: Monitor closely because of increased risk of respiratory
`depression. (5.5)
`
`
` Interaction with CNS depressants including other opioids, sedatives,
`alcohol, and illicit drugs: Consider dose reduction of one or both drugs
`because of additive effects. (5.7)
`
`
` Hypotensive effect: Monitor for signs of hypotension. (5.8)
`
`
` Patients with head injury or increased intracranial pressure: Monitor for
`sedation and respiratory depression. Avoid use of NUCYNTA® in patients
`
`
`with impaired consciousness or coma susceptible to intracranial effects of
`
`CO2 retention. (5.9)
`
`
`
`
`
`
`Reference ID: 3658922
`
`if NUCYNTA®
`
`is
`
`
`
` Seizures: Use with caution in patients with a history of seizures. (5.10)
`
`
`
` Serotonin Syndrome: Potentially life-threatening condition could result
`from concomitant serotonergic administration. (5.11)
`
`
` Withdrawal: Withdrawal symptoms may occur
`
`discontinued abruptly. (5.13)
`
`
` Impaired mental/physical abilities: Caution must be used with potentially
`hazardous activities. (5.14)
`------------------------------ADVERSE REACTIONS------------------------------
`
`The most common (≥10%) adverse reactions were nausea, dizziness, vomiting
`
`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----------------------------
`
`
` 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)
`
` Mixed agonist/antagonist opioids (i.e., pentazocine, nalbuphine, and
`
`butorphanol): May reduce analgesic effect and/or precipitate withdrawal
`
`symptoms. (7.5)
` Monitor for signs of serotonin syndrome when NUCYNTA® is used
`
`concurrently with SSRIs, SNRIs, tricyclic antidepressants, or triptans. (7.4)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
` Nursing mothers: Closely monitor infants of nursing women receiving.
`
`
`NUCYNTA®. (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)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and the FDA
`approved Medication Guide
`
`
`
`
`Revised: 11/2014
`
`
`
`
`1
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
` 
`1
`INDICATIONS AND USAGE
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Individualization of Dosage
`2.1
` 
` 
`2.2
`Initiation of Therapy
` 
` 
`2.3 Renal Impairment
` 
` 
`2.4 Hepatic Impairment
` 
` 
`2.5 Elderly Patients
` 
` 
`2.6 Cessation of Therapy
` 
` 
`2.7
`Instructions for Use
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`5.1 Abuse Potential
` 
` 
`Life Threatening Respiratory Depression
`5.2
` 
` 
`5.3 Accidental Exposure
` 
`5.4
`Interactions with Alcohol, Other Opioids, and
` 
`Drugs of Abuse
` 
` 
`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 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 Post-marketing Experience
`
` 
` 
`7 DRUG INTERACTIONS
` 
` 
`7.1 Alcohol, Other Opioids, and Drugs of Abuse
` 
` 
`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
`
` 
` 
`10.2 Management
`
` 
` 
`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
`
`
`
`
`2
`
`Reference ID: 3658922
`
`

`

`
`FULL PRESCRIBING INFORMATION
`INDICATIONS AND USAGE
`1
`
`
`NUCYNTA® (tapentadol) is indicated for the management of moderate to severe acute pain in
`adults.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`NUCYNTA® oral solution is available in one concentration: 20 mg/mL.
`
`Take care when prescribing and administering NUCYNTA® oral solution to avoid dosing errors,
`which could result in accidental overdose and death. Take care to ensure the proper dose is
`
`communicated and dispensed. Include the dose in milliliters (mL) and milligrams (mg) when
`writing prescriptions. Always use the enclosed calibrated oral syringe when administering
`
`
`NUCYNTA® oral solution to ensure the dose is measured and administered accurately.
`
`Individualization of Dosage
`2.1
`As with any opioid drug product, adjust the dosing regimen for each patient individually, taking
`
`into account the patient’s prior analgesic treatment experience. In the selection of the initial dose
`of tapentadol, give attention to the following:
`
`
`
`
`
`
`
`the total daily dose, potency and specific characteristics of the opioid the patient has been
`taking previously;
`the reliability of the relative potency estimate used to calculate the equivalent morphine
`sulfate dose needed;
`
`the patient’s degree of opioid tolerance;
`
`
`the general condition and medical status of the patient;
`
`
` concurrent medications;
`
`the type and severity of the patient’s pain;
`
`
`risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction
`
`or diversion.
`
`The following dosing recommendations, therefore, can only be considered suggested approaches
`to what is actually a series of clinical decisions over time in the management of the pain of each
`
` individual patient. Continual re-evaluation of the patient receiving tapentadol is important, with
`special attention to the maintenance of pain control and the relative incidence of side effects
`associated with therapy. During chronic therapy, especially for non-cancer-related pain,
`periodically re-assess the continued need for the use of opioid analgesics.
`
`
`
`Reference ID: 3658922
`
`3
`
`

`

`
`During periods of changing analgesic requirements, including initial titration, frequent contact is
`recommended between physician, other members of the healthcare team, the patient, and the
`caregiver/family. Monitor the patient for signs of respiratory or central nervous system
`
`depression.
`
`2.2
`Initiation of Therapy
`
`The dose is 2.5 mL (equivalent to 50 mg), 3.75 mL (equivalent to 75 mg), or 5 mL (equivalent to
`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 2.5 mL
`(equivalent to 50 mg), 3.75 mL (equivalent to 75 mg), or 5 mL (equivalent to 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® may be given with or without food [see Clinical Pharmacology (12.3)].
`
`2.3 Renal Impairment
`
`
`
` Use of NUCYNTA® in patients with severe renal impairment is not recommended [see
`
` Warnings and Precautions (5.16) and Clinical Pharmacology (12.3)].
`
`No dosage adjustment is recommended in patients with mild or moderate renal impairment.
`
`2.4 Hepatic Impairment
`
`The safety and efficacy of NUCYNTA® 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
`
`achieved by either shortening or lengthening the dosing interval [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)].
`
`
`
`Reference ID: 3658922
`
`4
`
`

`

`
`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.
`
`2.6 Cessation of Therapy
`
` When the patient no longer requires therapy with tapentadol, gradually taper the dose to prevent
`
`signs and symptoms of withdrawal in the physically dependent patient [see Warnings and
`Precautions (5.13)].
`
`
`2.7 Instructions for Use
`
`Concentration and Dispensing: The oral solution contains 20 mg tapentadol per milliliter (mL)
`
`and prescriptions should be written in milliliters (mL) and milligrams (mg). An oral syringe is
`supplied with dose marks corresponding directly to 2.5 mL (equals 50 mg) oral solution, 3.75
`mL (equals 75 mg) oral solution, and 5 mL (equals 100 mg) oral solution.
`
`Inform patients of the availability of FDA-approved patient labeling, Instructions for Use, for
`step-by-step instructions for patients on how to use the medicine bottle and the oral syringe.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`NUCYNTA® oral solution: 20 mg/mL oral solution in 100 mL and 200 mL fill bottles with
`
`
`child-resistant closure [see Description (11) and How Supplied/Storage and Handling (16)].
`
`
`4 CONTRAINDICATIONS
`
`NUCYNTA® is contraindicated in:
`
`
` Patients with significant respiratory depression
`
` Patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or
`
`in the absence of resuscitative equipment
`
` Patients with known or suspected paralytic ileus
`
` Patients with hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other
`ingredients of the product [see Adverse Reactions (6.2)].
`
` 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 (7.2)].
`
`
`
`
`
`Reference ID: 3658922
`
`5
`
`

`

`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Abuse Potential
`
`NUCYNTA® 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® 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®. 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 opioids; 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® by injecting the oral solution will 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 [see Drug Abuse and
`
` Dependence (9)].
`
`
`
` 5.2 Life Threatening Respiratory Depression
`
`Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA® .
`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
`
`depression may include close observation, supportive measures, and use of opioid antagonists,
`depending on the patient’s clinical status [see Overdosage (10)].
`
`
`
`Reference ID: 3658922
`
`6
`
`

`

`
` Instruct patients against use by individuals other than the patient for whom NUCYNTA® was
`
`prescribed and to keep NUCYNTA® out of the reach of children, as such inappropriate use may
`result in fatal respiratory depression.
`
`Patients with conditions accompanied by hypoxia, hypercarbia or decreased respiratory reserve
`such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, central nervous system
`(CNS) depression, or coma may be at increased risk for increased airway resistance and
`
` decreased respiratory drive to the point of apnea even with usual therapeutic doses of
`NUCYNTA®. Consider the use of alternative non-mu-opioid agonist analgesics and use
`NUCYNTA® only under careful medical supervision at the lowest effective dose in such
`patients. If respiratory depression occurs, treat the patient for mu-opioid agonist-induced
`respiratory depression [see Overdosage (10)]. To reduce the risk of respiratory depression,
`proper dosing of NUCYNTA® is essential [see Dosage and Administration (2)].
`
`5.3 Accidental Exposure
`
`Accidental ingestion of NUCYNTA®, especially in children, can result in a fatal overdose of
`tapentadol.
`
`Interactions with Alcohol, Other Opioids, and Drugs of Abuse
`5.4
`Due to its mu-opioid agonist activity, NUCYNTA® 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 (7.3)]. 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® therapy [see Drug Interactions (7.1)].
`
`
`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.
`Therefore, closely monitor such patients, particularly when NUCYNTA® 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, as in these patients, even usual
`therapeutic doses of NUCYNTA® may decrease respiratory drive to the point of apnea [see
`
`
`
`
`Reference ID: 3658922
`
`7
`
`

`

`
`Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these
`
`patients if possible.
`
`5.7
`
`Interactions with CNS Depressants and Illicit Drugs
`
`Hypotension, and profound sedation, coma or respiratory depression may result if NUCYNTA®
`
`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® 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® therapy is to be initiated in a patient taking a
`CNS depressant, start with a lower NUCYNTA® 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® 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
`the dose of NUCYNTA®. In patients with circulatory shock, NUCYNTA® may cause
`vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of
`NUCYNTA® in patients with circulatory shock.
`
`5.9 Use in Patients with Head Injury or Increased Intracranial Pressure
`
`Monitor patients taking NUCYNTA® 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. NUCYNTA® 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® in patients with impaired consciousness or coma.
`
`5.10 Seizures
`
`NUCYNTA® 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® may aggravate convulsions in patients with convulsive disorders, and may induce
`
`
`
`Reference ID: 3658922
`
`8
`
`

`

`
`or aggravate seizures in some clinical settings. Monitor patients with a history of seizure
`disorders for worsened seizure control during NUCYNTA® 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 Drug Interactions (7.4)].
`
`
`5.12 Use in Patients with Gastrointestinal Conditions
`
`NUCYNTA® is contraindicated in patients with GI obstruction, including paralytic ileus. The
`tapentadol in NUCYNTA® may cause spasm of the sphincter of Oddi. Monitor patients with
`biliary tract disease, including acute pancreatitis, for worsening symptoms.
`
`5.13 Withdrawal
`
`Withdrawal symptoms may occur if NUCYNTA® 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® [see Drug Abuse and Dependence (9.3)].
`
`5.14 Driving and Operating Heavy Machinery
`
`NUCYNTA® 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® and know
`how they will react to the medication.
`
`5.15 Hepatic Impairment
`
`A study with NUCYNTA® in subjects with hepatic impairment showed higher serum
`concentrations of tapentadol than in those with normal hepatic function. Avoid use of
`NUCYNTA® in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® in
`
`
`
`Reference ID: 3658922
`
`9
`
`

`

`
`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 receiving NUCYNTA® .
`
`5.16 Renal Impairment
`
`Use of NUCYNTA® 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:
`
`
` Respiratory Depression [see Warnings and Precautions (5.2)]
`
`
`  Interaction with Alcohol [see Warnings and Precautions (5.4)]
`
`  Chronic Pulmonary Disease [see Warnings and Precautions (5.6)]
`
`
`  Hypotensive Effects [see Warnings and Precautions (5.8)]
`
`
`
`  Interactions with Other CNS Depressants [see Warnings and Precautions (5.7)]
`
`  Drug abuse, addiction, and dependence [see Drug Abuse and Dependence (9.2, 9.3)]
`
` Gastrointestinal Effects [see Warnings and Precautions (5.12)]
`
`  Seizures [see Warnings and Precautions (5.10)]
`
`
`  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 practice. Based on data from
`nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled,
`one noncontrolled and one Phase 3 active-controlled safety study) the most common adverse
`reactions (reported by 10% in any NUCYNTA® dose group) were: nausea, dizziness, vomiting
`and somnolence.
`
`The most common reasons for discontinuation due to adverse reactions in the studies described
`above (reported by 1% in any NUCYNTA® dose group) were dizziness (2.6% vs. 0.5%),
`nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache
`(0.9% vs. 0.2%) for NUCYNTA®- and placebo-treated patients, respectively.
`
`
`
`
`Reference ID: 3658922
`
`10
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`

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`Seventy-six percent of NUCYNTA®-treated patients from the nine studies experienced adverse
`
` events.
`
`NUCYNTA® was studied
`in multiple-dose, active- or placebo-controlled studies, or
`noncontrolled studies (n = 2178), in single-dose studies (n = 870), in open-label study extension
`(n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of
`50 mg to 100 mg of NUCYNTA® dosed every 4 to 6 hours.
`
`The data described below reflect exposure to NUCYNTA® in 3161 patients, including 449
`exposed for 45 days. NUCYNTA® was studied primarily in placebo- and active-controlled
`
` studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old (mean age
`
` 46 years), 68% were female, 75% white and 67% were postoperative. Most patients received
`NUCYNTA® doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours.
`
`Adverse Reactions Reported by 1% of NUCYNTA®-Treated Patients In Seven Phase 2/3
`
`
` Placebo- and/or Oxycodone-Controlled, One Non-controlled, and One Phase 3 Oxycodone-
`
`
` Controlled Safety, Multiple-Dose Clinical Studies
`NUCYNTA®
`
`System/Organ Class
`21 mg – 120 mg
`
`
`
`MedDRA Preferred Term
`(n = 2178)
`%
`
`
`30
`
`18
`8
`4
`2
`
`
`Table 1
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Constipation
`Dry mouth
`Dyspepsia
`
`General disorders and
`administration site conditions
`Fatigue
`Feeling hot
`Infections and infestations
`Nasopharyngitis
`Upper respiratory tract
`infection
`Urinary tract infection
`
`
`Metabolism and nutrition disorders
`
`Decreased appetite
`
`Nervous system disorders
`Dizziness
`Somnolence
`Tremor
`Lethargy
`
`Psychiatric disorders
`Insomnia
`Confusional state
`
`Abnormal dreams
`Anxiety
`Skin and subcutaneous tissue
`
`Placebo
`(n = 619)
`%
`
`
`
`13
`
`4
`3
`<1
`<1
`
`
`
`
`
`
`
`
`
`3
`1
`
`1
`1
`
`1
`
`2
`
`
`24
`
`15
`1
`1
`
`
`2
`1
`1
`1
`
`
`
`
`
`
`
`
`
`<1
`<1
`
`<1
`<1
`
`<1
`
`0
`
`
`8
`
`3
`<1
`<1
`
`
`<1
`0
`<1
`<1
`
`
`
`
`Reference ID: 3658922
`
`11
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`

`

`
`System/Organ Class
`
`MedDRA Preferred Term
`
`NUCYNTA®
`
`
`
`21 mg – 120 mg
`(n = 2178)
`%
`
`Placebo
`(n = 619)
`%
`
`
`disorders
`1
`5
`Pruritus
`
`
`<1
`3
`Hyperhidrosis
`
`<1
`3
`Pruritus generalized
`<1
`1
`Rash
`
`
`
`Vascular disorders
`<1
`1
`Hot flush
` The following adverse drug reactions occurred in less than 1% of NUCYNTA®-treated patients
`
` in the pooled safety data from nine Phase 2/3 clinical studies:
`
`
`
`
`
` Cardiac disorders: heart rate increased, heart rate decreased
`
`Eye disorders: visual disturbance
`
`Gastrointestinal disorders: abdominal discomfort, impaired gastric emptying
`
`General disorders and administration site conditions: irritability, edema, drug withdrawal
`syndrome, feeling drunk
`
`
`
` Immune system disorders: hypersensitivity
`
`
`
` Investigations: gamma-glutamyltransferase increased, alanine aminotransferase increased,
`
` aspartate aminotransferase increased
`
`Musculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation
`
` of heaviness
`
`
`Nervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation,
`
`dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope,
`
`coordination abnormal, seizure
`
`
`Psychiatric disorders: euphoric mood, disorientation, restlessness, agitation, nervousness,
`
`thinking abnormal
`
`
`Renal and urinary disorders: urinary hesitation, pollakiuria
`
`
`Respiratory, thoracic and mediastinal disorders: oxygen saturation decreased, cough,
`
`dyspnea, respiratory depression
`
`
`
`Skin and subcutaneous tissue disorders: urticaria
`
`
`Vascular disorders: blood pressure decreased
`
`
`
`
`Reference ID: 3658922
`
`12
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`

`

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`In the pooled safety data, the overall incidence of adverse reactions increased with increased
`dose of NUCYNTA®, as did the percentage of patients with adverse reactions of nausea,
`dizziness, vomiting, somnolence, and pruritus.
`
`6.2 Post-marketing Experience
`
` The following additional adverse reactions have been identified during post-approval use of
`
`NUCYNTA®. Because these reactions are reported voluntarily from a population of uncertain
`size, it is not always possible to estimate their frequency reliably.
`
`Gastrointestinal disorders: diarrhea
`
`
`
` Nervous system disorders: headache
`
`Psychiatric disorders: hallucination, suicidal ideation, panic attack
`
`
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` Cardiac disorders: palpitations
`
`Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with
`ingredients contained in NUCYNTA®. Advise patients how to recognize such reactions and
`when to seek medical attention.
`
`
`
` 7 DRUG INTERACTIONS
`
`NUCYNTA® is mainly metabolized by glucuronidation. The following substances have been
`included in a set of interaction studies without any clinically significant finding: acetaminophen,
`acetylsalicylic acid, naproxen and probenecid [see Clinical Pharmacology (12.3)].
`
`
` The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal
`
` motility were increased by omeprazole and metoclopramide, respectively [see Clinical
`Pharmacology (12.3)].
`
`7.1 Alcohol, Other Opioids, and Drugs of Abuse
`
`Due to its mu-opioid agonist activity, NUCYNTA® 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.
`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® therapy [see
`Warnings and Precautions (5.4)].
`
`
`
`Reference ID: 3658922
`
`13
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`

`

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`7.2 Monoamine Oxidase Inhibitors
`
`NUCYNTA® 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 Contraindications
`(4)].
`
`7.3 CNS Depressants
`
`Concurrent use of NUCYNTA® and other central nervous system (CNS) depressants including
`sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol can
`increase the risk of respiratory depression, hypotension, profound sedation or coma. Monitor
`patients receiving CNS depressants and NUCYNTA® for