FDA label 6d8fd03f-1f00-44c7-9d72-394e12fefc79

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse BELBUCA 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 BELBUCA, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 ) and Overdosage ( 10 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of BELBUCA. Monitor for respiratory depression, especially during initiation of BELBUCA or following a dose increase. Misuse or abuse of BELBUCA by chewing, swallowing, snorting or injecting buprenorphine extracted from the buccal film will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions ( 5.2 )] . Accidental Exposure Accidental exposure to even one dose of BELBUCA, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions ( 5.2 )] . Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA 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 )] . 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 ( 5.4 ), Drug Interactions ( 7 )] . Reserve concomitant prescribing of BELBUCA Injection 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: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. BELBUCA 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. ( 5.1 , 10 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients on proper administration of BELBUCA to reduce the risk. ( 5.2 ) Accidental exposure to BELBUCA, especially in children, can result in fatal overdose of buprenorphine. ( 5.2 ) Prolonged use of BELBUCA 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. ( 5.3 ) 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. ( 5.4 , 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. ( 5.5 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.6 ) Risk of Prolonged QTc Interval : Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications. ( 5.7 , 12.2 ) Severe Hypotension : Monitor during dose initiation and titration. Avoid use of BELBUCA in patients with circulatory shock. ( 5.8 ) 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 BELBUCA in patients with impaired consciousness or coma. ( 5.9 ) 5.1 Addiction, Abuse, and Misuse BELBUCA contains buprenorphine, a Schedule III controlled substance. As an opioid, BELBUCA 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 BELBUCA. 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 BELBUCA and monitor all patients receiving BELBUCA 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 BELBUCA, but use in such patients necessitates intensive counseling about the risks and proper use of BELBUCA, along with intensive monitoring for signs of addiction, abuse, or misuse. Abuse or misuse of BELBUCA by swallowing may cause choking, overdose, and death [see Overdosage ( 10 )]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing BELBUCA. Strategies to reduce the risk 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 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 BELBUCA, the risk is greatest during initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression when initiating therapy with BELBUCA and following a dosage increases. To reduce the risk of respiratory depression, proper dosing and titration of BELBUCA are essential [see Dosage and Administration ( 2 )] . Overestimating the dose of BELBUCA when converting patients from another opioid product may result in fatal overdose with the first dose. Accidental exposure to BELBUCA, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of BELBUCA 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 for 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 )] . 5.4 Risks due to Interactions with Benzodiazepines or Other Central Nervous System Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BELBUCA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine 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 BELBUCA 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 ), Patient Counseling Information ( 17 )] . 5.5 Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of BELBUCA 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 :BELBUCA-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with 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 BELBUCA [see Warnings and Precautions ( 5.2 )]. Elderly, Cachectic, or 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. Monitor such patients closely, particularly when initiating and titrating BELBUCA and when BELBUCA is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.4 )]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.6 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. 5.7 QTc Prolongation BELBUCA has been observed to prolong the QTc interval in some subjects participating in clinical trials. Consider these observations in clinical decisions when prescribing BELBUCA to patients with hypokalemia, hypomagnesemia, or clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Periodic electrocardiographic (ECG) monitoring is recommended in these patients. Avoid the use of BELBUCA in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval [see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.2 )]. 5.8 Severe Hypotension BELBUCA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. 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 )]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of BELBUCA. In patients with circulatory shock, BELBUCA may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BELBUCA in patients with circulatory shock. 5.9 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), BELBUCA 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 BELBUCA. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BELBUCA in patients with impaired consciousness or coma. 5.10 Hepatotoxicity Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual formulations of buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse events reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically during treatment with BELBUCA. 5.11 Risk of Overdose in Patients With Moderate to Severe Hepatic Impairment In a pharmacokinetic study in subjects dosed with buprenorphine sublingual tablets, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration ( 2.5 ) , Use in Specific Populations ( 8.6 )] . 5.12 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. BELBUCA is contraindicated in patients with a history of hypersensitivity to buprenorphine. 5.13 Risk of Use in Patients with Gastrointestinal Conditions BELBUCA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. BELBUCA may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The buprenorphine in BELBUCA 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 BELBUCA therapy. 5.15 Risks of Use in Cancer Patients with Oral Mucositis Cancer patients with oral mucositis may absorb buprenorphine more rapidly than intended and are likely to experience higher plasma levels of the opioid. For patients with known or suspected mucositis, a dose reduction is recommended. Monitor these patients carefully for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. [see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] . 5.16 Risks of Driving and Operating Machinery BELBUCA may impair the mental and 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 side effects of BELBUCA and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions described elsewhere in the labeling include: 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 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.4 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.6 )] QTc Prolongation [see Warnings and Precautions ( 5.7 )] Severe Hypotension [see Warnings and Precautions ( 5.8 )] Hepatotoxicity [see Warnings and Precautions ( 5.10 )] Anaphylactic/Allergic Reactions [see Warnings and Precautions ( 5.12 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13 )] Seizures [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (>5%) include nausea, constipation, headache, vomiting, dizziness, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals Inc. at 1-800-462-3636 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 practice. A total of 2,127 patients were treated with BELBUCA in controlled and open-label chronic pain trials. There were 504 patients treated for approximately six months and 253 patients treated for approximately one year. The clinical trial population consisted of patients with chronic moderate-to-severe pain. The most common serious adverse drug reactions (all ≤ 0.2%) occurring during clinical trials with BELBUCA were: cellulitis, pneumonia, ileus, atrial fibrillation, coronary artery disease, cerebrovascular accident, syncope, transient ischemic attack, chest pain, non-cardiac chest pain, ankle fracture, cholecystitis, osteoarthritis, and dehydration. The most common adverse events (≥ 2%) leading to discontinuation were nausea, vomiting, and liver function test abnormality. The most common adverse events (≥ 5%) reported by opioid naïve, opioid experienced, and overall patients exposed to BELBUCA in clinical trials and compared against placebo are shown in Tables 2, 3 and 4: Table 2: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Naïve Patients Open-Label Titration Phase Double-Blind Treatment Phase MedDRA Preferred Term BELBUCA (N=749) BELBUCA (N=229) Placebo (N=232) Nausea 50% 10% 7% Constipation 13% 4% 3% Vomiting 8% 4% <1% Headache 8% 2% 3% Dizziness 6% 2% <1% Somnolence 7% 1% <1% Fatigue 5% 0% 1% Table 3: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Experienced Patients Open-Label Titration Phase Double-Blind Treatment Phase MedDRA Preferred Term BELBUCA (N=810) BELBUCA (N=254) Placebo (N=256) Nausea 17% 7% 7% Constipation 8% 3% 1% Vomiting 7% 5% 2% Headache 7% 2% 3% Dizziness 5% 2% <1% Somnolence 5% 1% <1% Drug Withdrawal Syndrome 0% 4% 10% Table 4: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies Open-Label Titration Phase Double-Blind Treatment Phase MedDRA Preferred Term BELBUCA (N=1889) BELBUCA (N=600) Placebo (N=606) Nausea 33% 9% 8% Constipation 11% 4% 2% Vomiting 7% 5% 2% Headache 8% 4% 3% Dizziness 6% 2% <1% Somnolence 6% <1% <1% Drug Withdrawal Syndrome 1% 2% 5% The most common (≥ 5%), common (≥ 1% to < 5%), and least common (< 1%) adverse reactions reported by patients taking BELBUCA in the controlled and open-label clinical studies are presented below: Most common adverse reactions (≥ 5%): nausea, constipation, headache, vomiting, fatigue, dizziness, somnolence, diarrhea, dry mouth, and upper respiratory tract infection. Common (≥ 1% to < 5%) adverse reactions (organized by MedDRA [Medical Dictionary for Regulatory Activities] System Organ Class: Blood and lymphatic system disorders : anemia Gastrointestinal disorders : abdominal pain General disorders and administration site conditions : peripheral edema, pyrexia, drug withdrawal syndrome Infections and infestations : urinary tract infection, nasopharyngitis, sinusitis, bronchitis, gastroenteritis Injury, poisoning, and procedural complications : contusion, fall Metabolism and nutrition disorders : decreased appetite Musculoskeletal and connective tissue disorders : muscle spasms, back pain Psychiatric disorders : anxiety, insomnia, depression Respiratory, thoracic and mediastinal disorders : oropharyngeal pain, sinus congestion Skin and subcutaneous tissue disorders : hyperhidrosis, pruritus, rash Vascular disorders : hot flush, hypertension Least common (<1%) adverse reactions: Abdominal discomfort, acute sinusitis, dyspepsia, toothache, asthenia, chills, cellulitis, tooth abscess, excoriation, laceration, aspartate aminotransferase increased, blood pressure increased, blood testosterone decreased, electrocardiogram QT prolonged, liver function test abnormal, musculoskeletal pain, neck pain, hypoesthesia, lethargy, migraine, tremor, cough, dyspnea, nasal congestion, rhinorrhea 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of buprenorphine. 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. 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 BELBUCA. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2 )] .

<table width="87%" border="0" cellspacing="0" cellpadding="0"> <caption>Table 2: Adverse Events Reported in &#x2265; 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Na&#xEF;ve Patients</caption> <col width="147.35pt"/> <col width="118.1pt"/> <col width="112.5pt"/> <col width="103.5pt"/> <thead> <tr> <td styleCode=" Botrule "/> <td> <paragraph> <content styleCode="bold">Open-Label </content> </paragraph> <paragraph> <content styleCode="bold">Titration Phase</content> </paragraph> </td> <td colspan="2" styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Double-Blind </content> </paragraph> <paragraph> <content styleCode="bold">Treatment Phase</content> </paragraph> </td> </tr> <tr> <td styleCode=" Botrule "> <paragraph> <content styleCode="bold">MedDRA Preferred Term</content> </paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=749)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=229)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph>(N=232)</paragraph> </td> </tr> </thead> <tbody> <tr> <td> <paragraph>Nausea</paragraph> </td> <td styleCode=" Lrule "> <paragraph>50%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>10%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Constipation</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>13%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>4%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Vomiting</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>8%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>4%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Headache</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>8%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Dizziness</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>6%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Somnolence</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>7%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>1%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Fatigue</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>0%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>1%</paragraph> </td> </tr> </tbody> </table>

<table width="87%" border="0" cellspacing="0" cellpadding="0"> <caption>Table 3: Adverse Events Reported in &#x2265; 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Experienced Patients</caption> <col width="147.4pt"/> <col width="118.1pt"/> <col width="112.5pt"/> <col width="103.5pt"/> <thead> <tr> <td styleCode=" Botrule "/> <td> <paragraph> <content styleCode="bold">Open-Label </content> </paragraph> <paragraph> <content styleCode="bold">Titration Phase</content> </paragraph> </td> <td colspan="2" styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Double-Blind </content> </paragraph> <paragraph> <content styleCode="bold">Treatment Phase</content> </paragraph> </td> </tr> <tr> <td styleCode=" Botrule "> <paragraph> <content styleCode="bold">MedDRA Preferred Term</content> </paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=810)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=254)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph>(N=256)</paragraph> </td> </tr> </thead> <tbody> <tr> <td> <paragraph>Nausea</paragraph> </td> <td styleCode=" Lrule "> <paragraph>17%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>7%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>7%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Constipation</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>8%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>3%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Vomiting</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>7%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Headache</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>7%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Dizziness</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Somnolence</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>1%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Drug Withdrawal Syndrome</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>0%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>4%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>10%</paragraph> </td> </tr> </tbody> </table>

<table width="88%" border="0" cellspacing="0" cellpadding="0"> <caption>Table 4: Adverse Events Reported in &#x2265; 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies</caption> <col width="147.45pt"/> <col width="127.1pt"/> <col width="116.95pt"/> <col width="99pt"/> <thead> <tr> <td styleCode=" Botrule "/> <td> <paragraph> <content styleCode="bold">Open-Label </content> </paragraph> <paragraph> <content styleCode="bold">Titration Phase</content> </paragraph> </td> <td colspan="2" styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Double-Blind </content> </paragraph> <paragraph> <content styleCode="bold">Treatment Phase</content> </paragraph> </td> </tr> <tr> <td styleCode=" Botrule "> <paragraph> <content styleCode="bold">MedDRA Preferred Term</content> </paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=1889)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">BELBUCA</content> </paragraph> <paragraph>(N=600)</paragraph> </td> <td styleCode=" Botrule Lrule "> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph>(N=606)</paragraph> </td> </tr> </thead> <tbody> <tr> <td> <paragraph>Nausea</paragraph> </td> <td styleCode=" Lrule "> <paragraph>33%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>9%</paragraph> </td> <td styleCode=" Lrule "> <paragraph>8%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Constipation</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>11%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>4%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Vomiting</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>7%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Headache</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>8%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>4%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Dizziness</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>6%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Somnolence</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>6%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode=" Toprule "> <paragraph>Drug Withdrawal Syndrome</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>1%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>2%</paragraph> </td> <td styleCode=" Toprule Lrule "> <paragraph>5%</paragraph> </td> </tr> </tbody> </table>