FDA label 5c1d0931-163d-4a51-8680-633d73f81eb8

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROME Addiction, Abuse, and Misuse Hydromorphone hydrochloride extended-release tablets expose 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 hydromorphone hydrochloride extended-release tablets, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions ( 5.1 )]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone hydrochloride extended-release tablets. Monitor for respiratory depression, especially during initiation of hydromorphone hydrochloride extended-release tablets or following a dose increase. Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole; crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets can cause rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions ( 5.2 )]. Accidental Ingestion Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions ( 5.2 )]. Neonatal Opioid Withdrawal Syndrome Prolonged use of hydromorphone hydrochloride extended-release tablets 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 )]. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; and NEONATAL OPIOID WITHDRAWAL SYNDROME See full prescribing information for complete boxed warning. Hydromorphone hydrochloride extended-release tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole to avoid exposure to a potentially fatal dose of hydromorphone. ( 5.2 ) Accidental ingestion of hydromorphone hydrochloride extended-release tablets, especially in children, can result in fatal overdose of hydromorphone. ( 5.2 ) Prolonged use of hydromorphone hydrochloride extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available ( 5.3 ).

5 WARNINGS AND PRECAUTIONS Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects. ( 5.4 ) Elderly, cachectic, debilitated patients and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. ( 5.5 , 5.6 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of hydromorphone hydrochloride extended-release tablets in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8 ) 5.1 Addiction, Abuse, and Misuse Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . As modified-release products such as hydromorphone hydrochloride extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and monitor all patients receiving hydromorphone hydrochloride extended-release tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death [see Overdosage ( 10 )]. Opioid agonists such as hydromorphone hydrochloride extended-release tablets are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information ( 17 )]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydromorphone hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with hydromorphone hydrochloride extended-release tablets and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential [see Dosage and Administration ( 2 )] . Overestimating the hydromorphone hydrochloride extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of hydromorphone hydrochloride extended-release tablets during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if hydromorphone hydrochloride extended-release tablets are used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of hydromorphone hydrochloride extended-release tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin hydromorphone hydrochloride extended-release tablets is made, start with one third to one half the calculated starting dose, 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 )]. 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating hydromorphone hydrochloride extended-release tablets and when hydromorphone hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 )] . 5.6 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 hydromorphone hydrochloride extended-release tablets, as in these patients, even usual therapeutic doses of hydromorphone hydrochloride extended-release tablets may decrease respiratory drive to the point of apnea [see Warnings and Precautions ( 5.2 )] . Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Hypotensive Effect Hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets. Hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions Hydromorphone hydrochloride extended-release tablets are contraindicated in patients with paralytic ileus. Avoid the use of hydromorphone hydrochloride extended-release tablets in patients with other GI obstruction. Because the hydromorphone hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the GI tract, hydromorphone hydrochloride extended-release tablets are 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 hydromorphone hydrochloride extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. The hydromorphone in hydromorphone hydrochloride extended-release tablets may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.10 Sulfites Hydromorphone hydrochloride extended-release tablets contain 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 hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including hydromorphone hydrochloride extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions ( 7.2 )] . When discontinuing hydromorphone hydrochloride extended-release tablets, gradually taper the dose [see Dosage and Administration ( 2.3 )] . Do not abruptly discontinue hydromorphone hydrochloride extended-release tablets. 5.13 Driving and Operating Machinery Hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.3 )] Interactions with Other CNS Depressants [see Warnings and Precautions ( 5.4 )] 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 Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Hydromorphone hydrochloride extended-release tablets were administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to hydromorphone hydrochloride extended-release tablets 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 Hydromorphone Hydrochloride Extended-Release Tablets (N=447) Hydromorphone Hydrochloride Extended-Release Tablets (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) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Insomnia 13 (3) 7 (5) 5 (4) 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) 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 Hydromorphone Hydrochloride Extended-Release Tablets 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 of body temperature change, feeling jittery, hangover, gait disturbance, feeling drunk, body temperature decreased 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 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, crying, 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, 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 reactions have been identified during post-approval use of hydromorphone hydrochloride extended-release tablets: Immune system disorders: hypersensitivity Skin and subcutaneous tissue disorders: angioedema, urticaria

<table> <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> <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">Hydromorphone Hydrochloride Extended-Release Tablets</content> <content styleCode="bold"> (N=447)</content> </paragraph> </td> <td valign="top" styleCode=" Botrule Toprule Lrule Rrule "> <paragraph> <content styleCode="bold">Hydromorphone Hydrochloride Extended-Release Tablets</content> <content styleCode="bold"> (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">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">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">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">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> <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> </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>