FDA label e416a298-f629-4ad2-8989-e31212b9ce3b

WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE Proper Patient Selection Butrans is a transdermal formulation of buprenorphine indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. (1) Potential for Abuse Butrans contains buprenorphine which is a mu opioid partial agonist and a Schedule III controlled substance. Butrans can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the abuse potential when prescribing or dispensing Butrans in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. (9) Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction. (2.2) Limitations of Use Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation. (2.3) Avoid exposing the Butrans application site and surrounding area to direct external heat sources. Temperature-dependent increases in buprenorphine release from the system may result in overdose and death. (5.11) WARNING: POTENTIAL FOR ABUSE and IMPORTANCE OF PROPER PATIENT SELECTION See full prescribing information for complete boxed warning. Butrans is indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. (1) Butrans contains buprenorphine which is a mu opioid partial agonist and a Schedule III controlled substance. (9.1) Assess patients for their clinical risks for opioid abuse or addiction prior to prescribing opioids. (2.2) Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation. (2.3) Avoid exposing the Butrans application site and surrounding area to direct external heat sources. Temperature-dependent increases in buprenorphine release from the system may result in overdose and death. (5.11)

5 WARNINGS AND PRECAUTIONS Use with extreme caution in patients at risk of respiratory depression. (5.1 , 7.2) Use with caution in patients who are receiving other central nervous system (CNS) depressants. (5.2 , 7.2 , 12.2) Additive CNS effects are expected when used with alcohol, benzodiazepines, other opioids, or illicit drugs. (5.3 , 7.2) Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications. (5.4 , 12.2) Butrans may worsen increased intracranial pressure and obscure its signs, such as level of consciousness or pupillary signs. (5.5) Use with caution in patients at increased risk of hypotension and in patients in circulatory shock. (5.6 , 12.2) Ileus may occur. Monitor for decreased bowel motility. (5.16) Use with caution in patients with biliary tract disease, including acute pancreatitis. (5.16) 5.1 Respiratory Depression Respiratory depression is the chief hazard of Butrans. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids, including Butrans, are given in conjunction with other agents that depress respiration. Profound sedation, unresponsiveness, infrequent deep (“sighing”) breaths or atypical snoring frequently accompany opioid-induced respiratory depression. Use Butrans with extreme caution in patients with any of the following: significant chronic obstructive pulmonary disease or cor pulmonale other risk of substantially decreased respiratory reserve such as asthma, severe obesity, sleep apnea, myxedema, clinically-significant kyphoscoliosis, and central nervous system (CNS) depression hypoxia hypercapnia pre-existing respiratory depression 5.2 CNS Depression Butrans may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma. 5.3 Interactions with Alcohol, Central Nervous System Depressants, and Illicit Drugs Hypotension, profound sedation, coma or respiratory depression may result if Butrans is added to a regimen that includes other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids). Therefore, use caution when deciding to initiate therapy with Butrans in patients who are taking other CNS depressants. Take into account the types of other medications being taken, the duration of therapy with them, and the patient’s response to those medicines, including the degree of tolerance that has developed to CNS depression. Consider the patient’s use, if any, of alcohol and/or illicit drugs that cause CNS depression. If the decision to begin Butrans is made, start with a lower Butrans dose than usual. Consider using a lower initial dose of a CNS depressant when given to a patient currently taking Butrans due to the potential of additive CNS depressant effects. 5.4 QTc Prolongation A positive-controlled study of the effects of Butrans on the QTc interval in healthy subjects demonstrated no clinically meaningful effect at a Butrans dose of 10 mcg/hour; however, a Butrans dose of 40 mcg/hour (given as two Butrans 20 mcg/hour Transdermal Systems) was observed to prolong the QTc interval [see Clinical Pharmacology (12.2) ] . Consider these observations in clinical decisions when prescribing Butrans to patients with hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia. Avoid the use of Butrans 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). 5.5 Head Injury The respiratory depressant effects of opioids, including Butrans, include carbon dioxide retention, which can lead to an elevation of cerebrospinal fluid pressure. This effect may be exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Butrans may produce miosis that is independent of ambient light, and altered consciousness, either of which may obscure neurologic signs associated with increased intracranial pressure in persons with head injuries. 5.6 Hypotensive Effects Butrans may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Buprenorphine may produce orthostatic hypotension in ambulatory patients. Administer Butrans with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. 5.7 Misuse, Abuse, and Diversion of Opioids Butrans contains buprenorphine, a partial agonist at the mu opioid receptor and a Schedule III controlled substance. Opioid agonists have potential for being abused, are sought by drug abusers and people with addiction disorders, and are subject to criminal diversion. Butrans can be abused in a manner similar to other opioid agonists, legal or illicit. Consider this potential for abuse when prescribing or dispensing Butrans in situations where the prescriber or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, assess patients for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients; however, they will require intensive monitoring for signs of abuse. Notwithstanding concerns about abuse, addiction, and diversion, provide proper management of pain. However, all patients treated with opioid agonists require careful monitoring for signs of abuse and addiction, since use of opioid agonist analgesic products carries the risk of addiction even under appropriate medical use [see Drug Abuse and Dependence (9.2) ] . Data are not available to establish the true incidence of addiction in patients with chronic pain treated with opioids. Abuse of Butrans poses a significant risk to the abuser that could potentially result in overdose or death [see Drug Abuse and Dependence (9) ] . Contact your state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.8 Hepatotoxicity Although not observed in Butrans chronic pain clinical trials, cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and through post-marketing adverse event 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. In other cases, insufficient data were available to determine the etiology of the abnormality. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), baseline and periodic monitoring of liver function during treatment with Butrans is recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. 5.9 Application Site Skin Reactions In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of Butrans treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy. 5.10 Anaphylactic/Allergic Reactions Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the 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. A history of hypersensitivity to buprenorphine is a contraindication to the use of Butrans. 5.11 Application of External Heat Advise patients and their caregivers to avoid exposing the Butrans application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system because an increase in absorption of buprenorphine may occur [see Clinical Pharmacology (12.3) ] . Advise patients against exposure of the Butrans application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death. 5.12 Patients with Fever Patients wearing Butrans systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the Butrans dose should be adjusted if necessary [see Dosage and Administration (2.4) ] . 5.13 Driving and Operating Machinery Butrans may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. 5.14 Seizures Butrans, as with other opioids, may aggravate seizure disorders, may lower seizure threshold, and therefore, may induce seizures in some clinical settings. Use Butrans with caution in patients with a history of seizure disorders. 5.15 Special Risk Groups Use Butrans with caution in the following conditions, due to increased risk of adverse reactions: alcoholism; delirium tremens; adrenocortical insufficiency; CNS depression; debilitation; kyphoscoliosis associated with respiratory compromise; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis. 5.16 Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions Butrans may cause spasm of the sphincter of Oddi. Use with caution in patients with biliary tract disease, including acute pancreatitis. Opioids, including Butrans, may cause increased serum amylase. The administration of Butrans may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use Butrans with caution in patients who are at risk of developing ileus. 5.17 Use in Addiction Treatment Butrans has not been studied and is not approved for use in the management of addictive disorders. 5.18 MAO Inhibitors Butrans is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

6 ADVERSE REACTIONS The following adverse reactions described elsewhere in the labeling include: Respiratory Depression [see Warnings and Precautions (5.1) ] CNS Depression [see Warnings and Precautions (5.2) ] QTc Prolongation [see Warnings and Precautions (5.4) ] Hypotensive Effects [see Warnings and Precautions (5.6) ] Application Site Skin Reactions [see Warnings and Precautions (5.9) ] Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.10) ] Seizures [see Warnings and Precautions (5.14) ] Most common adverse reactions (≥5%) include: nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash. To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma L.P. at 1-888-726-7535 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 5,415 patients were treated with Butrans in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain. The most common adverse reactions (≥5%) reported by patients in clinical trials comparing Butrans 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing Butrans 20 mcg/hour to Butrans 5 mcg/hour are shown in Table 3 below: Table 2: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients Open-Label Titration Period Double-Blind Treatment Period Butrans Butrans Placebo MedDRA Preferred Term (N = 1024) (N = 256) (N = 283) Nausea 23% 13% 11% Dizziness 10% 4% 1% Headache 10% 5% 5% Application site pruritus 8% 4% 7% Somnolence 8% 2% 2% Vomiting 8% 4% 2% Constipation 7% 4% 1% Table 3: Adverse Events Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients Open-Label Titration Period Double-Blind Treatment Period Butrans Butrans 20 Butrans 5 MedDRA Preferred Term (N = 1160) (N = 219) (N = 221) Nausea 15% 12% 8% Headache 11% 11% 5% Application site pruritus 9% 13% 5% Somnolence 6% 5% 2% Vomiting 5% 5% 2% Dizziness 5% 5% 2% Constipation 4% 6% 3% Application site erythema 3% 10% 5% Application site rash 3% 9% 6% Application site irritation 2% 5% 3% The following table lists adverse events that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials. Table 4: Adverse Events Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥2% MedDRA Preferred Term Butrans (N = 392) Placebo (N = 261) Nausea 23% 8% Dizziness 16% 8% Headache 16% 11% Application site pruritus 15% 12% Constipation 14% 5% Somnolence 14% 5% Vomiting 11% 2% Peripheral edema 7% 3% Dry mouth 7% 2% Application site erythema 7% 2% Application site rash 6% 6% Fatigue 5% 1% Hyperhidrosis 4% 1% Pruritus 4% 1% Fall 4% 2% Diarrhea 3% 2% Pain in extremity 3% 2% Insomnia 3% 2% Dyspnea 3% 1% Dyspepsia 3% 3% Urinary tract infection 3% 2% Back pain 3% 2% Joint swelling 3% 1% Hypoesthesia 2% 1% Arthralgia 2% 2% Stomach discomfort 2% 1% Rash 2% 1% Anorexia 2% 1% Paraesthesia 2% 1% Tremor 2% <1% Confusional State 2% 3% The adverse events seen in controlled and open-label studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%). The most common adverse events (≥5%) reported by patients treated with Butrans in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash. The common (≥1% to <5%) adverse events reported by patients treated with Butrans in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Gastrointestinal disorders: diarrhea, dyspepsia, and upper abdominal pain General disorders and administration site conditions: fatigue, peripheral edema, application site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural complications: fall Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia Psychiatric disorders: insomnia, anxiety, and depression Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders: hypertension Other less common adverse events, including those known to occur with opioid treatment, that were seen in <1% of the patients in the Butrans trials include the following in alphabetical order: Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysmenorrhea, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.

<table border="0" cellspacing="1" cellpadding="2" width="75%"> <caption>Table 2: Adverse Events Reported in &#x2265;5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Na&#xEF;ve Patients</caption> <colgroup> <col align="left"/> <col align="center"/> <col align="center"/> <col align="center"/> </colgroup> <thead> <tr> <td/> <td> <content styleCode="bold"> <content styleCode="emphasis">Open-Label Titration Period</content> </content> </td> <td colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Double-Blind Treatment Period</content> </content> </td> </tr> <tr> <td/> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Placebo</content> </content> </td> </tr> <tr> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">MedDRA Preferred Term </content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 1024)</content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 256)</content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 283)</content> </content> </td> </tr> </thead> <tbody> <tr> <td>Nausea</td> <td>23%</td> <td>13%</td> <td>11%</td> </tr> <tr> <td>Dizziness</td> <td>10%</td> <td>4%</td> <td>1%</td> </tr> <tr> <td>Headache</td> <td>10%</td> <td>5%</td> <td>5%</td> </tr> <tr> <td>Application site pruritus</td> <td>8%</td> <td>4%</td> <td>7%</td> </tr> <tr> <td>Somnolence</td> <td>8%</td> <td>2%</td> <td>2%</td> </tr> <tr> <td>Vomiting</td> <td>8%</td> <td>4%</td> <td>2%</td> </tr> <tr> <td>Constipation</td> <td>7%</td> <td>4%</td> <td>1%</td> </tr> </tbody> </table>

<table border="0" cellspacing="1" cellpadding="2" width="75%"> <caption>Table 3: Adverse Events Reported in &#x2265;5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients</caption> <colgroup> <col align="left"/> <col align="center"/> <col align="center"/> <col align="center"/> </colgroup> <thead> <tr> <td/> <td> <content styleCode="bold"> <content styleCode="emphasis">Open-Label Titration Period</content> </content> </td> <td colspan="2"> <content styleCode="bold"> <content styleCode="emphasis">Double-Blind Treatment Period</content> </content> </td> </tr> <tr> <td/> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans 20</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans 5 </content> </content> </td> </tr> <tr> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">MedDRA Preferred Term </content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 1160)</content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 219)</content> </content> </td> <td styleCode="toprule"> <content styleCode="bold"> <content styleCode="emphasis">(N = 221)</content> </content> </td> </tr> </thead> <tbody> <tr> <td>Nausea</td> <td>15%</td> <td>12%</td> <td>8%</td> </tr> <tr> <td>Headache</td> <td>11%</td> <td>11%</td> <td>5%</td> </tr> <tr> <td>Application site pruritus</td> <td>9%</td> <td>13%</td> <td>5%</td> </tr> <tr> <td>Somnolence</td> <td>6%</td> <td>5%</td> <td>2%</td> </tr> <tr> <td>Vomiting</td> <td>5%</td> <td>5%</td> <td>2%</td> </tr> <tr> <td>Dizziness</td> <td>5%</td> <td>5%</td> <td>2%</td> </tr> <tr> <td>Constipation</td> <td>4%</td> <td>6%</td> <td>3%</td> </tr> <tr> <td>Application site erythema</td> <td>3%</td> <td>10%</td> <td>5%</td> </tr> <tr> <td>Application site rash</td> <td>3%</td> <td>9%</td> <td>6%</td> </tr> <tr> <td>Application site irritation</td> <td>2%</td> <td>5%</td> <td>3%</td> </tr> </tbody> </table>

<table border="1" cellspacing="1" cellpadding="2" width="75%"> <caption>Table 4: Adverse Events Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence &#x2265;2%</caption> <colgroup> <col align="left"/> <col align="center"/> <col align="center"/> </colgroup> <thead> <tr> <td> <content styleCode="bold"> <content styleCode="emphasis">MedDRA Preferred Term</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Butrans</content> </content> <content styleCode="bold"> <content styleCode="emphasis">(N = 392)</content> </content> </td> <td> <content styleCode="bold"> <content styleCode="emphasis">Placebo</content> </content> <content styleCode="bold"> <content styleCode="emphasis">(N = 261)</content> </content> </td> </tr> </thead> <tbody> <tr> <td>Nausea</td> <td>23%</td> <td>8%</td> </tr> <tr> <td>Dizziness</td> <td>16%</td> <td>8%</td> </tr> <tr> <td>Headache</td> <td>16%</td> <td>11%</td> </tr> <tr> <td>Application site pruritus</td> <td>15%</td> <td>12%</td> </tr> <tr> <td>Constipation</td> <td>14%</td> <td>5%</td> </tr> <tr> <td>Somnolence</td> <td>14%</td> <td>5%</td> </tr> <tr> <td>Vomiting</td> <td>11%</td> <td>2%</td> </tr> <tr> <td>Peripheral edema</td> <td>7%</td> <td>3%</td> </tr> <tr> <td>Dry mouth</td> <td>7%</td> <td>2%</td> </tr> <tr> <td>Application site erythema</td> <td>7%</td> <td>2%</td> </tr> <tr> <td>Application site rash</td> <td>6%</td> <td>6%</td> </tr> <tr> <td>Fatigue</td> <td>5%</td> <td>1%</td> </tr> <tr> <td>Hyperhidrosis</td> <td>4%</td> <td>1%</td> </tr> <tr> <td>Pruritus</td> <td>4%</td> <td>1%</td> </tr> <tr> <td>Fall</td> <td>4%</td> <td>2%</td> </tr> <tr> <td>Diarrhea</td> <td>3%</td> <td>2%</td> </tr> <tr> <td>Pain in extremity</td> <td>3%</td> <td>2%</td> </tr> <tr> <td>Insomnia</td> <td>3%</td> <td>2%</td> </tr> <tr> <td>Dyspnea</td> <td>3%</td> <td>1%</td> </tr> <tr> <td>Dyspepsia</td> <td>3%</td> <td>3%</td> </tr> <tr> <td>Urinary tract infection</td> <td>3%</td> <td>2%</td> </tr> <tr> <td>Back pain</td> <td>3%</td> <td>2%</td> </tr> <tr> <td>Joint swelling</td> <td>3%</td> <td>1%</td> </tr> <tr> <td>Hypoesthesia</td> <td>2%</td> <td>1%</td> </tr> <tr> <td>Arthralgia</td> <td>2%</td> <td>2%</td> </tr> <tr> <td>Stomach discomfort</td> <td>2%</td> <td>1%</td> </tr> <tr> <td>Rash</td> <td>2%</td> <td>1%</td> </tr> <tr> <td>Anorexia</td> <td>2%</td> <td>1%</td> </tr> <tr> <td>Paraesthesia</td> <td>2%</td> <td>1%</td> </tr> <tr> <td>Tremor</td> <td>2%</td> <td>&lt;1%</td> </tr> <tr> <td>Confusional State</td> <td>2%</td> <td>3%</td> </tr> </tbody> </table>