FDA label c85dc4b7-b3f0-4575-948a-b892106597f6

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning . NUCYNTA ® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing, and monitor regularly for development of these behaviors or conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA ® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. ( 5.2 ) Accidental ingestion of NUCYNTA ® ER, especially in children, can result in fatal overdose of tapentadol. ( 5.2 ) Prolonged use of NUCYNTA ® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. 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 ( 5.3 ). Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ® ER because co-ingestion can result in fatal plasma tapentadol levels. ( 5.4 ) Addiction, Abuse, and Misuse NUCYNTA ® ER 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 ® ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) ] . Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA ® ER. Monitor for respiratory depression, especially during initiation of NUCYNTA ® ER or following a dose increase. Instruct patients to swallow NUCYNTA ® ER tablets whole; crushing, chewing, or dissolving NUCYNTA ® ER tablets can cause rapid release and absorption of a potentially fatal dose of tapentadol [see Warnings and Precautions (5.2) ] . Accidental Ingestion Accidental ingestion of even one dose of NUCYNTA ® ER, especially by children, can result in a fatal overdose of tapentadol [see Warnings and Precautions (5.2) ] . Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ® ER 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 (5.3) ] . Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking NUCYNTA ® ER. The co-ingestion of alcohol with NUCYNTA ® ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol [see Warnings and Precautions (5.4) ] .

5 WARNINGS AND PRECAUTIONS See Boxed WARNINGS Interaction with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If co-administration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. ( 5.4 , 7.3 ) Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. ( 5.5 , 5.6 ) Hypotensive effect: Monitor during dose initiation and titration. ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of NUCYNTA ® ER in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8 ) Seizures: Use with caution in patients with a history of seizures. ( 5.9 ) Serotonin Syndrome: Potentially life-threatening condition could result from concomitant administration of drugs with serotonergic activity. ( 5.10 ) 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 [see Drug Abuse and Dependence (9) ] . As modified-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. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ® ER and in those who obtain the drug illicitly. 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 monitor all patients receiving NUCYNTA ® ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) 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 modified-release opioid formulations such as NUCYNTA ® ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ® ER along with intensive monitoring for signs of addiction, abuse, and misuse. 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) ] . Opioid agonists such as NUCYNTA ® ER 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. 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. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, 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 ® 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. 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 dose 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. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ® ER during pregnancy can result in withdrawal signs 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. 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. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System 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) ] . Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA ® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). 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, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin NUCYNTA ® ER is made, start with NUCYNTA ® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.3) ] . 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when initiating and titrating NUCYNTA ® ER and when NUCYNTA ® ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2) ] . 5.6 Use in Patients with Chronic Pulmonary Disease Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, 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 [see Warnings and Precautions (5.2) ]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Hypotensive Effect 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 (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.3) ] . 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. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking NUCYNTA ® ER who may be susceptible to the intracranial effects of CO 2 retention (e.g., 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 CO 2 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. 5.9 Seizures 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. 5.10 Serotonin Syndrome Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal [see Drug Interactions (7.4) ] . 5.11 Use in Patients with Gastrointestinal Conditions 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. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (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. When discontinuing NUCYNTA ® ER, gradually taper the dose [see Dosage and Administration (2.3) ] . 5.13 Driving and Operating Heavy 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. 5.14 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 (2.4) and Clinical Pharmacology (12.3) ] . Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ® ER. 5.15 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 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3) ] Interaction with Other CNS Depressants [see Warnings and Precautions (5.4) ] Hypotensive Effects [see Warnings and Precautions (5.7) ] Gastrointestinal Effects [see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.9) ] Serotonin Syndrome [see Warnings and Precautions (5.10) ] The most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1–800–526–7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ® ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The safety data described in Table 1 below are based on three pooled, randomized, double-blind, placebo-controlled, parallel group, 15-week studies of NUCYNTA ® ER (dosed 100 to 250 mg BID after a 50 mg BID starting dose) in patients with chronic pain due to low back pain (LBP) and osteoarthritis (OA). These trials included 980 NUCYNTA ® ER-treated patients and 993 placebo-treated patients. The mean age was 57 years old; 63% were female and 37% were male; 83% were White, 10% were Black, and 5% were Hispanic. The most common adverse reactions (reported by ≥10% in any NUCYNTA ® ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ® ER dose group for NUCYNTA ® ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Table 1 Adverse Drug Reactions Reported by ≥ 1% of NUCYNTA ® ER-Treated Patients and Greater than Placebo-Treated Patients in Pooled Parallel-Group Trials MedDRA preferred terms. The trials included forced titration during the first week of dosing. NUCYNTA ® ER 50 to 250 mg BID NUCYNTA ® ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID (n=980) Placebo (n=993) Nausea 21% 7% Constipation 17% 7% Dizziness 17% 6% Headache 15% 13% Somnolence 12% 4% Fatigue 9% 4% Vomiting 8% 3% Dry mouth 7% 2% Hyperhidrosis 5% <1% Pruritus 5% 2% Insomnia 4% 2% Dyspepsia 3% 2% Lethargy 2% <1% Asthenia 2% <1% Anxiety 2% 1% Decreased appetite 2% <1% Vertigo 2% <1% Hot flush 2% <1% Disturbance in attention 1% <1% Tremor 1% <1% Chills 1% 0% Abnormal dreams 1% <1% Depression 1% <1% Vision blurred 1% <1% Erectile dysfunction 1% <1% Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ® ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The types of adverse reactions seen in the studies of patients with painful diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and osteoarthritis trials. The safety data described in Table 2 below are based on two pooled, randomized withdrawal, double-blind, placebo-controlled, 12-week studies of NUCYNTA ® ER (dosed 100 to 250 mg BID) in patients with neuropathic pain associated with diabetic peripheral neuropathy. These trials included 1040 NUCYNTA ® ER-treated patients and 343 placebo-treated patients. The mean age was 60 years old; 40% were female and 60% were male; 76% were White, 12% were Black, and 12% were "Other". The most commonly reported ADRs (incidence ≥ 10% in NUCYNTA ® ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Table 2 lists the common adverse reactions reported in 1% or more of NUCYNTA ® ER-treated patients and greater than placebo-treated patients with neuropathic pain associated with diabetic peripheral neuropathy in the two pooled studies. Table 2: Adverse Drug Reactions Reported by ≥ 1% of NUCYNTA ® ER-Treated Patients and Greater than Placebo-Treated Patients in Pooled Trials (Studies DPN-1 and DPN-2) MedDRA preferred terms. NUCYNTA ® ER 50 to 250 mg BID NUCYNTA ® ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID. It includes ADR reported in the open-label titration period for all subjects and in the double-blind maintenance period for the subjects who were randomized to NUCYNTA ® ER. (n=1040) Placebo It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving NUCYNTA ® ER during the open-label titration period. (n=343) Nausea 27% 8% Dizziness 18% 2% Somnolence 14% <1% Constipation 13% <1% Vomiting 12% 3% Headache 10% 5% Fatigue 9% <1% Pruritus 8% 0% Dry mouth 7% <1% Diarrhea 7% 5% Decreased appetite 6% <1% Anxiety 5% 4% Insomnia 4% 3% Hyperhidrosis 3% 2% Hot flush 3% 2% Tremor Tremor was observed in 3.4% of NUCYNTA ® ER-treated subjects vs. 3.2% in placebo group, chills- in 1.3% vs.1.2% in placebo, and feeling cold- in 1.3% vs.1.2% in placebo. 3% 3% Abnormal dreams 2% 0% Lethargy 2% 0% Asthenia 2% <1% Irritability 2% 1% Dyspnea 1% 0% Nervousness 1% 0% Sedation 1% 0% Vision blurred 1% 0% Pruritus generalized 1% 0% Vertigo 1% <1% Abdominal discomfort 1% <1% Hypotension 1% <1% Dyspepsia 1% <1% Hypoesthesia 1% <1% Depression 1% <1% Rash 1% <1% Chills 1% 1% Feeling cold 1% 1% Drug withdrawal syndrome 1% <1% Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA ® ER The following additional adverse drug reactions occurred in less than 1% of NUCYNTA ® ER-treated patients in ten Phase 2/3 clinical studies: Nervous system disorders: paresthesia, balance disorder, syncope, memory impairment, mental impairment, depressed level of consciousness, dysarthria, presyncope, coordination abnormal Gastrointestinal disorders: impaired gastric emptying General disorders and administration site conditions: feeling abnormal, feeling drunk Psychiatric disorders: perception disturbances, disorientation, confusional state, agitation, euphoric mood, drug dependence, thinking abnormal, nightmare Skin and subcutaneous tissue disorders: urticaria Metabolism and nutrition disorders: weight decreased Cardiac disorders: heart rate increased, palpitations, heart rate decreased, left bundle branch block Vascular disorder: blood pressure decreased Respiratory, thoracic and mediastinal disorders: respiratory depression Renal and urinary disorders: urinary hesitation, pollakiuria Reproductive system and breast disorders: sexual dysfunction Eye disorders: visual disturbance Immune system disorders: drug hypersensitivity 6.2 Postmarketing Experience The following adverse reactions, not noted in Section 6.1 above, 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 Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA ® ER. Advise patients how to recognize such reactions and when to seek medical attention.

<table width="75%"> <caption>Table 1 Adverse Drug Reactions Reported by &#x2265; 1% of NUCYNTA^&#xAE; ER-Treated Patients and Greater than Placebo-Treated Patients in Pooled Parallel-Group Trials<footnote>MedDRA preferred terms. The trials included forced titration during the first week of dosing.</footnote> </caption> <col width="35%" align="left" valign="middle"/> <col width="35%" align="center" valign="middle"/> <col width="30%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">NUCYNTA^&#xAE; ER 50 to 250 mg BID<footnote>NUCYNTA^&#xAE; ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID</footnote> (n=980)</th> <th styleCode="Rrule">Placebo (n=993)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">21%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Constipation</td> <td styleCode="Rrule">17%</td> <td styleCode="Rrule">7%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dizziness</td> <td styleCode="Rrule">17%</td> <td styleCode="Rrule">6%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">15%</td> <td styleCode="Rrule">13%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Somnolence</td> <td styleCode="Rrule">12%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dry mouth</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hyperhidrosis</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pruritus</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Insomnia</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dyspepsia</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Lethargy</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Asthenia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Anxiety</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Decreased appetite</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vertigo</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hot flush</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Disturbance in attention</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Tremor</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Chills</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abnormal dreams</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Depression</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vision blurred</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr> <td styleCode="Lrule Rrule">Erectile dysfunction</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> </tbody> </table>

<table width="75%"> <caption>Table 2: Adverse Drug Reactions Reported by &#x2265; 1% of NUCYNTA^&#xAE; ER-Treated Patients and Greater than Placebo-Treated Patients in Pooled Trials (Studies DPN-1 and DPN-2)<footnote>MedDRA preferred terms.</footnote> </caption> <col width="35%" align="left" valign="middle"/> <col width="35%" align="center" valign="middle"/> <col width="30%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule">NUCYNTA^&#xAE; ER 50 to 250 mg BID<footnote>NUCYNTA^&#xAE; ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID. It includes ADR reported in the open-label titration period for all subjects and in the double-blind maintenance period for the subjects who were randomized to NUCYNTA^&#xAE; ER.</footnote> (n=1040)</th> <th styleCode="Rrule">Placebo<footnote> It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving NUCYNTA^&#xAE; ER during the open-label titration period.</footnote> (n=343)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">27%</td> <td styleCode="Rrule">8%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dizziness</td> <td styleCode="Rrule">18%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Somnolence</td> <td styleCode="Rrule">14%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Constipation</td> <td styleCode="Rrule">13%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">12%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">10%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">9%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pruritus</td> <td styleCode="Rrule">8%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dry mouth</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">7%</td> <td styleCode="Rrule">5%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Decreased appetite</td> <td styleCode="Rrule">6%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Anxiety</td> <td styleCode="Rrule">5%</td> <td styleCode="Rrule">4%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Insomnia</td> <td styleCode="Rrule">4%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hyperhidrosis</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hot flush</td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">2%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Tremor<footnote ID="t2f4">Tremor was observed in 3.4% of NUCYNTA^&#xAE; ER-treated subjects vs. 3.2% in placebo group, chills- in 1.3% vs.1.2% in placebo, and feeling cold- in 1.3% vs.1.2% in placebo.</footnote> </td> <td styleCode="Rrule">3%</td> <td styleCode="Rrule">3%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abnormal dreams</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Lethargy</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Asthenia</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Irritability</td> <td styleCode="Rrule">2%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dyspnea</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nervousness</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Sedation</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vision blurred</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pruritus generalized</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">0%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vertigo</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abdominal discomfort</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hypotension</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dyspepsia</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hypoesthesia</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Depression</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Rash</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Chills<footnoteRef IDREF="t2f4"/> </td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Feeling cold<footnoteRef IDREF="t2f4"/> </td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr> <td styleCode="Lrule Rrule">Drug withdrawal syndrome</td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">&lt;1%</td> </tr> </tbody> </table>