FDA label 6b41cf96-27de-45bf-b2d2-6c1b9fb7fa0e

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL Abuse Potential NUCYNTA ® ER contains tapentadol, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions (5.1) ] . 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 (e.g., major depressive disorder). Routinely monitor all patients receiving NUCYNTA ® ER for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence (9) ]. Life-threatening Respiratory Depression Respiratory depression, including fatal cases, may occur with use of NUCYNTA ® ER, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions (5.2) ] . 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. Monitor for respiratory depression, especially during initiation of NUCYNTA ® ER or following a dose increase . Instruct patients to swallow NUCYNTA ® ER tablets whole. Crushing, dissolving, or chewing NUCYNTA ® ER can cause rapid release and absorption of a potentially fatal dose of tapentadol. Accidental Exposure Accidental ingestion of NUCYNTA ® ER, especially in children, can result in a fatal overdose of tapentadol [see Warnings and Precautions (5.3) ] . Interaction with Alcohol The co-ingestion of alcohol with NUCYNTA ® ER may result in an increase of plasma levels and potentially fatal overdose of tapentadol [see Warnings and Precautions (5.4) ] . Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while on NUCYNTA ® ER. WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning . NUCYNTA ® ER contains tapentadol, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during NUCYNTA ® ER therapy. ( 5.1 ) Fatal respiratory depression may occur, with highest risk at initiation and with dose increases. Instruct patients on proper administration of NUCYNTA ® ER tablets to reduce the risk. ( 5.2 ) Accidental ingestion of NUCYNTA ® ER can result in fatal overdose of tapentadol, especially in children. ( 5.3 ) Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while taking NUCYNTA ® ER because of the risk of increased and potentially fatal plasma tapentadol levels. ( 5.4 )

5 WARNINGS AND PRECAUTIONS See Boxed WARNINGS Elderly, cachectic, and debilitated patients and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.5 , 5.6 ) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.7 , 7.3 ) Hypotensive effect: Monitor during dose initiation and titration. ( 5.8 ) 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. ( 5.9 ) Seizures: Use with caution in patients with a history of seizures. ( 5.10 ) Serotonin Syndrome: Potentially life-threatening condition could result from concomitant administration of drugs with serotonergic activity. ( 5.11 ) 5.1 Abuse Potential 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 (e.g., 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 [see Overdosage (10) ]. 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 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 (CO 2 ) 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 [see Overdosage (10) ] . 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 [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. 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 [see Contraindications (4) ] . 5.3 Accidental Exposure Accidental ingestion of NUCYNTA ® ER, especially in children, can result in a fatal overdose of tapentadol. 5.4 Interaction with Alcohol 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 non-prescription products containing alcohol while on NUCYNTA ® ER therapy [see Clinical Pharmacology (12.3) ] . 5.5 Elderly, Cachectic, and Debilitated Patients 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 [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 Interactions with CNS Depressants and Illicit Drugs Hypotension, and profound sedation, coma or respiratory depression may result if NUCYNTA ® ER is used concomitantly with other CNS depressants (e.g., 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 [see Drug Interactions (7.3) ] . 5.8 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. 5.9 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. 5.10 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. 5.11 Serotonin Syndrome Risk 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 Serotonergic Drugs (7.4) ] . 5.12 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. 5.13 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist analgesics (i.e., 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 [see Dosage and Administration (2.3) ] . 5.14 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. 5.15 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. 5.16 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 adverse reactions are discussed in more detail in other sections of the labeling: Respiratory Depression [see Warnings and Precautions (5.2) ] Interaction with Alcohol [see Warnings and Precautions (5.4) ] Chronic Pulmonary Disease [see Warnings and Precautions (5.6) ] Hypotensive Effects [see Warnings and Precautions (5.8) ] Interactions with Other CNS Depressants [see Warnings and Precautions (5.7) ] Drug abuse, addiction, and dependence [see Drug Abuse and Dependence (9.2 , 9.3) ] Gastrointestinal Effects [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.10) ] Serotonin Syndrome [see Warnings and Precautions (5.11) ] 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 Studies 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 Anaphylaxis and angioedema have been reported with ingredients contained in NUCYNTA ® ER. Advise patients how to recognize such reactions and when to seek medical attention.

<table width="85%" ID="table1"> <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="34%" align="left" valign="middle"/> <col width="33%" align="center" valign="middle"/> <col width="33%" 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="80%"> <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="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <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="ft4.1">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="ft4.1"/> </td> <td styleCode="Rrule">1%</td> <td styleCode="Rrule">1%</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Feeling cold<footnoteRef IDREF="ft4.1"/> </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>