NUCYNTA^® ER is an opioid agonist indicated for the management of:

• • Moderate to severe chronic pain in adults.

• •Neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults.

When a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

NUCYNTA^® ER IMPORTANT SAFETY INFORMATION

LIMITATIONS OF USAGE

• NUCYNTA^® ER is not intended for use as an as-needed (PRN) analgesic; for pain that is mild or not expected to persist for an extended period of time; for acute pain; for postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

CONTRAINDICATIONS

• NUCYNTA^® ER is contraindicated in patients with significant respiratory depression.
• NUCYNTA^® ER is contraindicated in patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment.
• NUCYNTA^® ER is contraindicated in patients with known or suspected paralytic ileus.
• NUCYNTA^® ER is contraindicated in patients with hypersensitivity (eg, anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product.
• NUCYNTA^® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) 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.

WARNINGS and PRECAUTIONS

• NUCYNTA^® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance. Tapentadol can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA^® ER in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.
• Assess each patient’s risk for opioid abuse or addiction prior to prescribing NUCYNTA^® ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.
• Misuse or abuse of NUCYNTA^® ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death.
• 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.
• Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA^® ER. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.
• While serious, life-threatening or fatal respiratory depression can occur at any time during the use of NUCYNTA^® ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA^® ER and following dose increases. Instruct patients against use by individuals other than the patient for whom NUCYNTA^® ER was prescribed and to keep NUCYNTA^® ER out of the reach of children, as such inappropriate use may result in fatal respiratory depression.
• To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA^® ER are essential. Overestimating the NUCYNTA^® ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.
• To further reduce the risk of respiratory depression, consider the following:
  • Proper dosing and titration are essential and NUCYNTA^® ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
  • Instruct patients to swallow NUCYNTA^® ER tablets whole. The tablets are not to be cut, crushed, dissolved, or chewed. The resulting tapentadol dose may be fatal, particularly in opioid-naïve individuals.
  • NUCYNTA^® ER is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression.
• Accidental ingestion of NUCYNTA^® ER, especially in children, can result in a fatal overdose of tapentadol.
• The co-ingestion of alcohol with NUCYNTA^® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on NUCYNTA^® ER therapy.
• 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, monitor such patients closely, particularly when initiating and titrating NUCYNTA^® ER and when NUCYNTA^® ER is given concomitantly with other drugs that depress respiration.
• Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA^® ER, as in these patients even usual therapeutic doses of NUCYNTA^® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients, if possible.
• Hypotension and profound sedation, coma or respiratory depression may result if NUCYNTA^® ER is used concomitantly with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids, and illicit drugs). When considering the use of NUCYNTA^® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If NUCYNTA^® ER therapy is to be initiated in a patient taking a CNS depressant, start with a lower NUCYNTA^® ER dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.
• NUCYNTA^® ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of NUCYNTA^® ER. In patients with circulatory shock, NUCYNTA^® ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA^® ER in patients with circulatory shock.
• Monitor patients taking NUCYNTA^® ER who may be susceptible to the intracranial effects of CO₂ retention (eg, those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA^® ER. NUCYNTA^® ER may reduce respiratory drive and the resultant CO₂ retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.
• Avoid the use of NUCYNTA^® ER in patients with impaired consciousness or coma.
• NUCYNTA^® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA^® ER may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA^® ER therapy.
• 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 (eg, 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 (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination), and/or gastrointestinal (GI) symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.
• NUCYNTA^® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA^® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
• Avoid the use of mixed agonist/antagonist analgesics (ie, pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA^® ER. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
• When discontinuing NUCYNTA^® ER, gradually taper the dose.
• 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.
• 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. Closely monitor patients with moderate hepatic impairment for respiratory and CNS depression when initiating and titrating NUCYNTA^® ER.
• 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.

ADVERSE REACTIONS IN CLINICAL STUDIES

• Management of moderate to severe chronic pain: The most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence.
• Management of neuropathic pain associated with diabetic peripheral neuropathy (DPN): The most common (≥10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

K02TLE121027

For the relief of moderate to severe acute pain in patients 18 years of age
or older

NUCYNTA^® IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• Like other drugs with mu-opioid agonist activity, NUCYNTA^® is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment. NUCYNTA^® is contraindicated in patients who have or are suspected to have paralytic ileus. NUCYNTA^® is also contraindicated in patients currently using or within 14 days of using monoamine oxidase inhibitors (MAOIs) due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

WARNINGS & PRECAUTIONS

• 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. NUCYNTA^® should be administered with caution to the elderly, debilitated patients, and 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, CNS depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA^® may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA^® 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.
• Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUCYNTA^® 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^®. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
• Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA^® should not be used in patients susceptible to the effects of raised cerebrospinal fluid pressure such as those with 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^® should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.
• NUCYNTA^® 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. NUCYNTA^® can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA^® in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction. NUCYNTA^® may be abused by crushing, chewing, snorting or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.
• Experience with NUCYNTA^® overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of NUCYNTA^® is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
• Patients should be cautioned that NUCYNTA^® 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.
• NUCYNTA^® has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. NUCYNTA^® 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.
• The development of a potentially life-threatening serotonin syndrome may occur with use of SNRI products, including NUCYNTA^®, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea).
• 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^®.
• Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA^® in pregnant women. NUCYNTA^® should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus. NUCYNTA^® is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking NUCYNTA^® should be monitored for respiratory depression. NUCYNTA^® should not be used during breastfeeding.
• NUCYNTA^® is not recommended in patients with severe renal or hepatic impairment. NUCYNTA^® should be used with caution in patients with moderate hepatic impairment. Like other drugs with mu-opioid agonist activity, NUCYNTA^® may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

ADVERSE EVENTS

• The most common adverse events are nausea, dizziness, vomiting, somnolence and headache.