FDA label c2ce2345-2d9c-48a7-b179-35c9d0855a61

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE Abuse Potential EXALGO contains hydromorphone, an opioid agonist and a 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 EXALGO. 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 EXALGO 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 EXALGO, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions ( 5.2 )] . EXALGO is for use in opioid tolerant patients only. Proper dosing and titration are essential and EXALGO should be prescribed only 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 EXALGO or following a dose increase . Crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of hydromorphone. Accidental Exposure Accidental ingestion of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions ( 5.3 )] . WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, and ACCIDENTAL EXPOSURE See full prescribing information for complete boxed warning . EXALGO contains hydromorphone, a Schedule II controlled substance. Monitor for signs of misuse, abuse, and addiction during EXALGO therapy. ( 5.1 , 9 ) Fatal respiratory depression may occur, with highest risk at initiation and with dose increases; instruct patients on proper administration of EXALGO tablets to reduce risk. EXALGO is for use in opioid-tolerant patients only. Crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of hydromorphone. ( 5.2 ) Accidental ingestion of EXALGO can result in fatal overdose of hydromorphone, especially in children. ( 5.3 )

5 WARNINGS AND PRECAUTIONS Elderly, cachectic, and debilitated patients, and patients with chronic pulmonary disease: Monitor closely because of increased risk of respiratory depression. ( 5.4 , 5.5 ) Interaction with CNS depressants: Consider dose reduction of one or both drugs because of additive effects. ( 5.6 , 7.1 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of EXALGO in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8 ) 5.1 Abuse Potential EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance. Hydromorphone 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 EXALGO 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 EXALGO. 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 EXALGO 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 primary risk of EXALGO. 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 EXALGO, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with EXALGO and following dose increases. Instruct patients against use by individuals other than the patient for whom EXALGO was prescribed and to keep EXALGO 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 EXALGO are essential [see Dosage and Administration ( 2.1 , 2.2 )] . Overestimating the EXALGO 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 EXALGO should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. EXALGO is for use in opioid-tolerant patients only. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients not already tolerant to opioids. Instruct patients to swallow EXALGO tablets intact. The tablets are not to be crushed, dissolved, or chewed. The resulting hydromorphone dose may be fatal. EXALGO 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 EXALGO, especially in children, can result in a fatal overdose of hydromorphone. 5.4 Elderly, Cachectic, and Debilitated Patients Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating EXALGO and when EXALGO is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.6 )]. 5.5 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with EXALGO, as in these patients, even usual therapeutic doses of EXALGO 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. 5.6 Interactions with Alcohol, Other CNS Depressants, and Illicit Drugs Hypotension, profound sedation, coma, or respiratory depression may result if EXALGO is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of EXALGO 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 or illicit drugs that cause CNS depression. If EXALGO therapy is to be initiated in a patient taking a CNS depressant, start with a lower EXALGO 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 ( 7.1 )] . 5.7 Hypotensive Effect EXALGO 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 ( 7.1 ) ] . Monitor these patients for signs of hypotension after initiating or titrating the dose of EXALGO. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking EXALGO 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 EXALGO. EXALGO 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 EXALGO in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions EXALGO is contraindicated in patients with paralytic ileus. Avoid the use of EXALGO in patients with other GI obstruction. Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, EXALGO is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations. It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. The hydromorphone in EXALGO may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.10 Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.11 Use in Patients with Convulsive or Seizure Disorders The hydromorphone in EXALGO 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 EXALGO therapy. 5.12 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 EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions ( 7.2 )] . When discontinuing EXALGO, gradually taper the dose [see Dosage and Administration ( 2.3 )] . Do not abruptly discontinue EXALGO. 5.13 Driving and Operating Machinery EXALGO may impair the mental and/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 EXALGO and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Respiratory Depression [see Warnings and Precautions ( 5.2 )] Chronic Pulmonary Disease [see Warnings and Precautions ( 5.5 )] Head Injuries and Increased Intracranial Pressure [see Warnings and Precautions ( 5.8 )] Interactions with Other CNS Depressants [see Warnings and Precautions ( 5.6 )] Hypotensive Effect [see Warnings and Precautions ( 5.7 )] Gastrointestinal Effects [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (>10%) are: constipation, nausea, vomiting, somnolence, headache, and dizziness ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-778-7898 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. EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year. The most common adverse reactions leading to study discontinuation were nausea, vomiting, constipation, somnolence, and dizziness. The most common treatment-related serious adverse reactions from controlled and uncontrolled chronic pain studies were drug withdrawal syndrome, overdose, confusional state, and constipation. The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients. A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)] . A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 2 . Table 2. Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Titration Phase Double-Blind Treatment Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Asthenia/Fatigue 16 (4) 2 (1) 6 (4) Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) Anorexia/Decreased Appetite 10 (2) 2 (1) 0 (0) Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) Abdominal Pain 9 (2) 4 (3) 3 (2) Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 3 . Table 3. Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia/Fatigue 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia/Decreased Appetite 139 (6) Dry Mouth 121 (5) Abdominal Pain 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia * 88 (4) Depression 81 (3) Dyspnea 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest pain 51 (2) * Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia The following Adverse Reactions occurred in patients with an overall frequency of < 2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paresthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of EXALGO: Skin and subcutaneous tissue disorders: urticaria

<table border="0" cellspacing="0" cellpadding="0"> <col/> <col/> <col/> <col/> <tbody> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Open-Label </content> </paragraph> <paragraph> <content styleCode="bold">Titration Phase</content> </paragraph> </td> <td valign="top" colspan="2" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Double-Blind Treatment Phase</content> </paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "/> <td> <paragraph> <content styleCode="bold">EXALGO (N=447)</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">EXALGO (N=134)</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Placebo (N=134)</content> </paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Constipation</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>69 (15)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>10 (7)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>5 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Nausea</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>53 (12)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>12 (9)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>10 (7)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Somnolence</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>39 (9)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>1 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>0 (0)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Headache</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>35 (8)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>7 (5)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>10 (7)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Vomiting</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>29 (6)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>8 (6)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>6 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Drug Withdrawal Syndrome</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>22 (5)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (10)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>16 (12)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Pruritus</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>21 (5)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>1 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>0 (0)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dizziness</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>17 (4)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Asthenia/Fatigue</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>16 (4)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>6 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Insomnia</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>7 (5)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>5 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Diarrhea</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>5 (4)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>9 (7)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Back Pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>6 (4)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>8 (6)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dry Mouth</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>0 (0)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Edema Peripheral</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>1 (1)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Hyperhidrosis</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>13 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Anorexia/Decreased Appetite</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>10 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>2 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>0 (0)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Arthralgia</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>9 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>8 (6)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Anxiety</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>9 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>0 (0)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>4 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Abdominal Pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>9 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>4 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Muscle Spasms</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>5 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>1 (1)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Weight Decreased</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (1)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>4 (3)</paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>3 (2)</paragraph> </td> </tr> </tbody> </table>

<table border="0" cellspacing="0" cellpadding="0"> <col/> <col/> <tbody> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Preferred Term</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">All Patients (N=2,474)</content> </paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Constipation</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>765 (31)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Nausea</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>684 (28)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Vomiting</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>337 (14)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Somnolence</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>367 (15)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Headache</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>308 (12)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Asthenia/Fatigue</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>272 (11)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dizziness</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>262 (11)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Diarrhea</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>201 (8)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Pruritus</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>193 (8)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Insomnia</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>161 (7)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Hyperhidrosis</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>143 (6)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Edema Peripheral</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>135 (5)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Anorexia/Decreased Appetite</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>139 (6)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dry Mouth</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>121 (5)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Abdominal Pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>115 (5)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Anxiety</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>95 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Back Pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>95 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dyspepsia</content> <content styleCode="bold">*</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>88 (4)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Depression</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>81 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Dyspnea</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>76 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Muscle Spasms</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>74 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Arthralgia</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>72 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Rash</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>64 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Pain in Extremity</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>63 (3)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>58 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Drug Withdrawal Syndrome</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>55 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Pyrexia</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>52 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Fall</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>51 (2)</paragraph> </td> </tr> <tr> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Chest pain</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph>51 (2)</paragraph> </td> </tr> </tbody> </table>