FDA label 144e0e1c-c057-4e12-8f12-dab53d8a758a

WARNING: RISK OF MEDICATION ERRORS, ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering NUCYNTA oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ]. Addiction, Abuse, and Misuse NUCYNTA oral solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing NUCYNTA oral solution, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA oral solution. Monitor for respiratory depression, especially during initiation of NUCYNTA oral solution or following a dose increase [see Warnings and Precautions (5.3) ]. Accidental Ingestion Accidental ingestion of even one dose of NUCYNTA oral solution, especially by children, can result in a fatal overdose of tapentadol [see Warnings and Precautions (5.3) ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA oral solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4) ]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5) , Drug Interactions (7) ]. Reserve concomitant prescribing of NUCYNTA oral solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. WARNING: RISK OF MEDICATION ERRORS, ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. Ensure accuracy when prescribing, dispensing, and administering NUCYNTA oral solution. Dosing errors due to confusion between mg and mL, and other tapentadol oral solution of different concentrations can result in accidental overdose and death. ( 2.1 , 5.1 ) NUCYNTA oral solution exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.3 ) Accidental ingestion of NUCYNTA oral solution, especially by children, can result in a fatal overdose of tapentadol. ( 5.3 ) Prolonged use of NUCYNTA oral solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.4 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation ( 5.5 , 7 ).

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.6 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue NUCYNTA oral solution if serotonin syndrome is suspected. ( 5.7 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.8 ) Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of NUCYNTA oral solution in patients with circulatory shock. ( 5.9 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of NUCYNTA oral solution in patients with impaired consciousness or coma. ( 5.10 ) 5.1 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL when prescribing, dispensing, and administering NUCYNTA oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the enclosed calibrated syringe when administering NUCYNTA to ensure the dose is measured and administered accurately. Do not use a teaspoon or a tablespoon to measure a dose. A household teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage. 5.2 Addiction, Abuse, and Misuse NUCYNTA oral solution contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA oral solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA oral solution. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA oral solution and monitor all patients receiving NUCYNTA oral solution 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 proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA oral solution, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA oral solution along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA oral solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ]. 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. 5.3 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 (CO 2 ) 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 oral solution, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA oral solution. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA oral solution are essential [see Dosage and Administration (2.2) ]. Overestimating the NUCYNTA oral solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of NUCYNTA oral solution, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA oral solution 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ]. 5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA oral solution with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA oral solution 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 depressant 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) and Patient Counseling Information (17) ]. 5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA oral solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: NUCYNTA oral solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA oral solution [see Warnings and Precautions (5.6) ]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.6) ]. Monitor such patients closely, particularly when initiating and titrating NUCYNTA ® and when NUCYNTA oral solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.6) ]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.7 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concurrent 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), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal [see Drug Interactions (7) ] The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA oral solution if serotonin syndrome is suspected. 5.8 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. 5.9 Severe Hypotension NUCYNTA oral solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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) ]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA oral solution. In patients with circulatory shock, NUCYNTA oral solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA oral solution in patients with circulatory shock. 5.10 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA oral solution may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA oral solution. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA oral solution in patients with impaired consciousness or coma. 5.11 Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA oral solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in NUCYNTA oral solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. 5.12 Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA oral solution 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. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA oral solution therapy. 5.13 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including NUCYNTA oral solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7) ]. When discontinuing NUCYNTA oral solution in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.5) ]. Do not abruptly discontinue NUCYNTA in these patients [see Drug Abuse and Dependence (9.3) ]. 5.14 Risks of Driving and Operating Machinery NUCYNTA oral solution 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 oral solution and know how they will react to the medication. 5.15 Interactions with Alcohol, Other Opioids, and Drugs of Abuse Due to its mu-opioid agonist activity, NUCYNTA oral solution 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) ]. 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 oral solution therapy [see Drug Interactions (7) ]. 5.16 Risk of Toxicity in Patients with Hepatic Impairment A study with NUCYNTA oral solution in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA oral solution in patients with severe hepatic impairment. Reduce the dose of NUCYNTA oral solution in patients with moderate hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA oral solution. 5.17 Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA oral solution 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, or described in greater detail in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Interactions with CNS Benzodiazepine or Other Depressants [see Warnings and Precautions (5.5) ] Serotonin Syndrome [see Warnings and Precautions (5.7) ] Adrenal Insufficiency [see Warnings and Precautions (5.8) ] Severe Hypotension [see Warnings and Precautions (5.9) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)] Seizures [see Warnings and Precautions (5.12) ] Withdrawal [see Warnings and Precautions (5.13) ] The most common adverse reactions (incidence ≥10%) were nausea, dizziness, vomiting and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, Depomed, Inc. at 1-866-458-6389 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials 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 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. 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. Table 1 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 System/Organ Class MedDRA Preferred Term NUCYNTA 21 mg – 120 mg (n = 2178) % Placebo (n = 619) % Gastrointestinal disorders Nausea 30 13 Vomiting 18 4 Constipation 8 3 Dry mouth 4 <1 Dyspepsia 2 <1 General disorders and administration site conditions Fatigue 3 <1 Feeling hot 1 <1 Infections and infestations Nasopharyngitis 1 <1 Upper respiratory tract infection 1 <1 Urinary tract infection 1 <1 Metabolism and nutrition disorders Decreased appetite 2 0 Nervous system disorders Dizziness 24 8 Somnolence 15 3 Tremor 1 <1 Lethargy 1 <1 Psychiatric disorders Insomnia 2 <1 Confusional state 1 0 Abnormal dreams 1 <1 Anxiety 1 < Skin and subcutaneous tissue disorders Pruritus 5 1 Hyperhidrosis 3 <1 Pruritus generalized 3 <1 Rash 1 <1 Vascular disorders Hot flush 1 <1 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: urticarial Vascular disorders: blood pressure decreased 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 tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: diarrhea Nervous system disorders: headache Psychiatric disorders: hallucination, suicidal ideation, panic attack Cardiac disorders: palpitations 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 oral solution. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2) ] .

<table width="800" styleCode="Noautorules"> <caption>Table 1 Adverse Reactions Reported by &#x2265;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</caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Toprule Botrule Lrule">System/Organ Class MedDRA Preferred Term</th> <th styleCode="Toprule Botrule Lrule">NUCYNTA 21 mg &#x2013; 120 mg (n = 2178) %</th> <th styleCode="Toprule Botrule Lrule Rrule">Placebo (n = 619) %</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule">Gastrointestinal disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Nausea</td> <td styleCode="Lrule">30</td> <td styleCode="Lrule Rrule">13</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Vomiting</td> <td styleCode="Lrule">18</td> <td styleCode="Lrule Rrule">4</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Constipation</td> <td styleCode="Lrule">8</td> <td styleCode="Lrule Rrule">3</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Dry mouth</td> <td styleCode="Lrule">4</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Dyspepsia</td> <td styleCode="Lrule">2</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">General disorders and administration site conditions</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Fatigue</td> <td styleCode="Lrule">3</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Feeling hot</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Infections and infestations</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Nasopharyngitis</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Upper respiratory tract infection</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Urinary tract infection</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Metabolism and nutrition disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Decreased appetite</td> <td styleCode="Lrule">2</td> <td styleCode="Lrule Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Nervous system disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Dizziness</td> <td styleCode="Lrule">24</td> <td styleCode="Lrule Rrule">8</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Somnolence</td> <td styleCode="Lrule">15</td> <td styleCode="Lrule Rrule">3</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Tremor</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule"> Lethargy</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Psychiatric disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Insomnia</td> <td styleCode="Lrule">2</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Confusional state</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">0</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Abnormal dreams</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Anxiety</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Skin and subcutaneous tissue disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Pruritus</td> <td styleCode="Lrule">5</td> <td styleCode="Lrule Rrule">1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Hyperhidrosis</td> <td styleCode="Lrule">3</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Pruritus generalized</td> <td styleCode="Lrule">3</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Rash</td> <td styleCode="Lrule">1</td> <td styleCode="Lrule Rrule">&lt;1</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule">Vascular disorders</td> <td styleCode="Lrule"/> <td styleCode="Lrule Rrule"/> </tr> <tr> <td styleCode="Lrule Botrule">Hot flush</td> <td styleCode="Lrule Botrule">1</td> <td styleCode="Botrule Lrule Rrule">&lt;1</td> </tr> </tbody> </table>