warnings and cautions
5 WARNINGS AND PRECAUTIONS Respiratory depression: Increased risk in elderly, debilitated patients, those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction. ( 5.1 ) CNS effects: Additive CNS depressive effects when used in conjunction with alcohol, other opioids, or illicit drugs. ( 5.2 ) Elevation of intracranial pressure: May be markedly exaggerated in the presence of head injury, other intracranial lesions. ( 5.3 ) Abuse potential may occur. Monitor patients closely for signs of abuse and addiction. ( 5.4 ) Impaired mental/physical abilities: Caution must be used with potentially hazardous activities. ( 5.5 ) Seizures: Use with caution in patients with a history of seizures. ( 5.7 ) Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic administration. ( 5.8 ) 5.1 Respiratory Depression Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. NUCYNTA ® should be administered with caution to patients with conditions accompanied by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA ® 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 [see Overdosage (10.2) ] . 5.2 CNS 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. 5.3 Head Injury and Increased Intracranial Pressure Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA ® should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure such as those with evidence of head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. NUCYNTA ® should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure. 5.4 Misuse and Abuse Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty. NUCYNTA ® can be abused in a manner similar to other 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. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carry the risk of addiction even under appropriate medical use [see Drug Abuse and Dependence (9.2) ] . 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 [see Drug Abuse and Dependence (9) ] . 5.5 Driving and Operating Machinery 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 [see Drug Interactions (7.3) ] . 5.6 Interactions with Alcohol 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, opioids, or illicit drugs that cause central nervous system depression, respiratory depression, hypotension, and profound sedation, coma or death [see Drug Interactions (7.3) ] . 5.7 Seizures 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. 5.8 Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with use of Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) products, including NUCYNTA ® , particularly with concomitant use of serotonergic drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs), SNRIs, tricyclic antidepressants (TCAs), MAOIs and triptans, and with 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). 5.9 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) ] . 5.10 Hepatic Impairment A study of NUCYNTA ® in subjects with hepatic impairment showed higher serum concentrations than in those with normal hepatic function. NUCYNTA ® should be used with caution in patients with moderate hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . NUCYNTA ® has not been studied in patients with severe hepatic impairment and, therefore, use in this population is not recommended. 5.11 Use in Pancreatic/Biliary Tract Disease 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.