Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1)], reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• NUCYNTA ER is not indicated as an as-needed (prn) analgesic.

2.1 Important Dosage and Administration Instructions

• NUCYNTA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA ER. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2)].
• Instruct patients to swallow NUCYNTA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
• Crushing, chewing, or dissolving NUCYNTA ER tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death [see Warnings and Precautions (5.1)].
• Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA ER [see Warnings and Precautions (5.7)].
• 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.

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with NUCYNTA ER [see Warnings and Precautions (5.2)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.3)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Initial Dosage

2.4 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, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.14)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of NUCYNTA ER or may need rescue medication with an appropriate dose of an immediate-release analgesic.

If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the NUCYNTA ER dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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)].

2.5 Dosage Modification in Patients with Hepatic Impairment

The use of NUCYNTA ER in patients with severe hepatic impairment (Child-Pugh Score 10-15) is not recommended [see Warnings and Precautions (5.16)].

In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate treatment using 50 mg NUCYNTA ER, administer no more frequently than once every 24 hours, and regularly evaluate for respiratory and central nervous system depression, particularly during initiation and titration of NUCYNTA ER. The maximum recommended dose for patients with moderate hepatic impairment is 100 mg of NUCYNTA ER per day. Regularly evaluate patients for respiratory and central nervous system depression [see Clinical Pharmacology (12.2)].

No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6) [see Warnings and Precautions (5.16), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.6 Safe Reduction or Discontinuation of NUCYNTA ER

Do not abruptly discontinue NUCYNTA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking NUCYNTA ER, there are a variety of factors that should be considered, including the total daily dose of opioid (including NUCYNTA ER) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on NUCYNTA ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].

5.1 Addiction, Abuse, and Misuse

NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and reassess all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death [see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)].

Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

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 dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol [see Clinical Pharmacology (12.3)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

5.4 Neonatal Opioid Withdrawal Syndrome

Use of NUCYNTA ER for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.

Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

5.6 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.6), Warnings and Precautions (5.14)].

5.7 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

5.9 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension

NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. 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)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage 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.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER.

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.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

5.14 Withdrawal

Do not abruptly discontinue NUCYNTA ER in a patient physically dependent on opioids. When discontinuing NUCYNTA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of tapentadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.6), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics 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 and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].

5.15 Risks of Driving and Operating 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.

5.16 Risk of Toxicity in Patients with 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 (2.5) and Clinical Pharmacology (12.3)].

Frequently evaluate patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER.

5.17 Risk of Toxicity in Patients with 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)].

6.1 Clinical Trial 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.

6.2 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.

Psychiatric disorders: hallucination, suicidal ideation, panic attack

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)]

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established.

8.5 Geriatric Use

Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients.

Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8)].

Tapentadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

8.6 Hepatic Impairment

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), dosage reduction of NUCYNTA ER is recommended [see Dosage and Administration (2.5)]. No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6) [see Warnings and Precautions (5.16), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. No dosage adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30-90 mL/minute) [see Warnings and Precautions (5.17), Clinical Pharmacology (12.3)].

9.1 Controlled Substance

NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

9.2 Abuse

NUCYNTA ER contains tapentadol, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of NUCYNTA ER increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of NUCYNTA ER with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of NUCYNTA ER abuse include those with a history of prolonged use of any opioid, including products containing tapentadol, those with a history of drug or alcohol abuse, or those who use NUCYNTA ER in combination with other abused drugs.

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

NUCYNTA ER, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.3 Dependence

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not abruptly discontinue NUCYNTA ER in a patient physically dependent on opioids. Rapid tapering of NUCYNTA ER in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing NUCYNTA ER, gradually taper the dosage using a patient-specific plan that considers the following: the dose of NUCYNTA ER the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.6), Warnings and Precautions (5.3)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

Acute overdosage with tapentadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to tapentadol overdose, administer an opioid antagonist.

Because the duration of reversal would be expected to be less than the duration of action of tapentadol in NUCYNTA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished.

NUCYNTA ER will continue to release tapentadol and add to the tapentadol load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, additional antagonist should be given as directed in the product's prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

12.1 Mechanism of Action

Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

In toxicological studies with tapentadol, the most common systemic effects of tapentadol were related to the mu-opioid receptor agonist and norepinephrine reuptake inhibition pharmacodynamic properties of the compound. Transient, dose-dependent and predominantly CNS-related findings were observed, including impaired respiratory function and convulsions, the latter occurring in the dog at plasma levels (Cmax), which are in the range associated with the maximum recommended human dose (MRHD).

14.1 Clinical Trials Summary

The efficacy of NUCYNTA ER was studied in five studies in patients with chronic pain and DPN. Efficacy was demonstrated in one randomized, double-blind, placebo- and active-controlled study in patients with chronic low back pain (LBP), and two randomized, double-blind, placebo-controlled studies in patients with pain related to diabetic peripheral neuropathy (DPN-1 and DPN-2).

14.2 Moderate to Severe Chronic Low Back Pain

In the LBP study, patients 18 years of age or older with chronic low back pain and a baseline pain score of ≥5 on an 11-point numerical rating scale (NRS), ranging from 0 to 10 were enrolled and randomized to 1 of 3 treatments: NUCYNTA ER, active-control (an extended-release Schedule II opioid analgesic), or placebo.

Patients randomized to NUCYNTA ER initiated therapy with a dose of 50 mg twice daily for three days. After three days, the dose was increased to 100 mg twice daily. Subsequent titration was allowed over a 3-week titration period to a dose up to 250 mg twice daily, followed by a 12-week maintenance period. There were 981 patients randomized. The mean age of the study population was 50 (range 18 to 89) years; the mean baseline pain intensity score was 8 (SD 1). Approximately half of the patients were opioid-naïve (had not taken opioids during the three months prior to the screening visit).

The number of patients completing the study was 51% in the placebo group, 54% in the NUCYNTA ER group and 43% in the active-control group. Lack of efficacy was the most common reason for discontinuation among placebo-treated patients (21%), whereas adverse events were the most common reason for discontinuation among the active treatment groups (17% and 32% for NUCYNTA ER and active-control, respectively).

After 15 weeks of treatment, patients taking NUCYNTA ER had a significantly greater pain reduction compared to placebo. The proportion of patients with various degrees of improvement is shown in Figure 1. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Figure 1. Percentage of Patients Achieving Various Levels of Improvement in Pain Intensity - Study LBP*
* The last week of Study LBP was Week 15.

14.3 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

In the two DPN studies, patients 18 years of age or older with pain due to diabetic peripheral neuropathy and a pain score of ≥5 on an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain) were enrolled. Following an open-label treatment period in which NUCYNTA ER was administered to all patients for three weeks and titrated to an individually stable dose, patients who had tolerated the drug and demonstrated at least a 1-point improvement in pain intensity on the NRS at the end of the open-label titration period were randomized to either continue the NUCYNTA ER dose (100 mg to 250 mg twice a day) reached during the open-label titration period, or receive placebo for 12 weeks of maintenance treatment. During the first 4 days of the double-blind maintenance period patients were permitted to take tapentadol ER 25 mg up to two times a day as additional medication. After the first 4 days, patients were allowed to take tapentadol ER 25 mg once daily as needed for pain, in addition to the patient's assigned study drug. Patients recorded their pain in a diary twice daily.

Study DPN-1: A total of 591 patients entered open-label treatment and 389 patients met the criteria for randomization into the double-blind treatment period. The mean age of the randomized population was 60 (range 29 to 87) years; approximately two-thirds of the patients were opioid-naïve (had not taken opioids during the three months prior to the screening visit).

During the titration period, 34% of patients discontinued open-label NUCYNTA ER. The most common reasons for discontinuation in the double-blind treatment period were lack of efficacy in the placebo group (14%) and adverse events in the NUCYNTA ER group (15%).

After 12 weeks of treatment, NUCYNTA ER provided a significantly greater reduction in pain intensity from baseline to the end of the 12-week double-blind period compared to placebo. Figure 2 displays the proportion of randomized patients achieving various degrees of improvement in pain intensity from the start of the open-label titration period to the last week of the randomized withdrawal period. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Figure 2. Percentage of Patients Achieving Various Levels of Improvement in Pain Intensity - PN-1

Study DPN-2: A total of 459 patients entered open-label treatment and 320 patients met the criteria for randomization into the double-blind treatment period. The mean age of the randomized population was 59 (range 28 to 83) years; approximately two-thirds of the patients were opioid-naïve (had not taken opioids during the three months prior to the screening visit).

During the titration period, 22% of patients discontinued open-label NUCYNTA ER and 6% of patients were not subsequently randomized because they failed to have at least 1-point improvement in pain intensity. The most common reason for discontinuation in the double-blind treatment period was adverse events in both the placebo group (9%) and the NUCYNTA ER group (14%).

After 12 weeks of treatment, NUCYNTA ER provided a significantly greater reduction in pain intensity from baseline to the end of the 12-week double-blind period compared to placebo. Figure 3 displays the proportion of randomized patients achieving various degrees of improvement in pain intensity from the start of the open-label titration period to the last week of the randomized withdrawal period. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.

Figure 3. Percentage of Patients Achieving Various Levels of Improvement in Pain Intensity - DPN-2

Storage and Handling

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15° C - 30°C (59° F - 86°F) [see USP Controlled Room Temperature].

Protect from moisture.

Store NUCYNTA ER securely and dispose of properly.

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store NUCYNTA ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving NUCYNTA ER unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused NUCYNTA ER Tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of NUCYNTA ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share NUCYNTA ER with others and to take steps to protect NUCYNTA ER from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting NUCYNTA ER or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)].

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

Interactions with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if NUCYNTA ER is used with benzodiazepines or other CNS depressants, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.3), Drug Interactions (7)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with NUCYNTA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.6); Adverse Reactions (6.2)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.7), Drug Interactions (7)].

Seizures

Inform patients that NUCYNTA ER could cause seizures if they are at risk for seizures or have epilepsy. Patients should be advised to stop taking NUCYNTA ER if they have a seizure while taking NUCYNTA ER and call their healthcare provider right away [see Warnings and Precautions (5.13)].

MAOI Interaction

Inform patients not to take NUCYNTA ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking NUCYNTA ER [see Drug Interactions (7)].

Important Administration Instructions

Instruct patients how to properly take NUCYNTA ER, including the following:

• Using NUCYNTA ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Dosage and Administration (2)]
• Swallowing NUCYNTA ER tablets whole [see Dosage and Administration (2.1)]
• To take each tablet with enough water to ensure complete swallowing immediately after placing in mouth [see Dosage and Administration (2.1)]
• Not cutting, crushing, chewing, or dissolving the tablets [see Dosage and Administration (2.1)]

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue NUCYNTA ER without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.6)]

Driving or Operating Heavy Machinery

Inform patients that NUCYNTA ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.15)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Adrenal Insufficiency

Inform patients that NUCYNTA ER could cause adrenal insufficiency, a potentially life- threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9)].

Hypotension

Inform patients that NUCYNTA ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.10)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6.2)].

Pregnancy

Lactation

Advise patients that breastfeeding is not recommended during treatment with NUCYNTA ER [see Use in Specific Populations (8.2)]

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].