FDA label 319f79f5-a83e-4c51-b362-c01eb43d5ed6

WARNING: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE Reports of serious adverse events, including deaths in patients treated with OTFC have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of OTFC for any other fentanyl product may result in fatal overdose. OTFC is indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. OTFC is not indicated for use in opioid non-tolerant patients including those with only as needed (PRN) prior exposure. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients OTFC is contraindicated in the management of acute or postoperative pain including headache/migraine. When prescribing, do not convert patients on a mcg per mcg basis to OTFC from other fentanyl products. When dispensing, do not substitute an OTFC prescription for other fentanyl products. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of OTFC for any other fentanyl product may result in fatal overdose. Special care must be used when dosing OTFC. If the breakthrough pain episode is not relieved 15 minutes after completion of the OTFC unit, patients may take ONLY ONE additional dose using the same strength and then must wait at least 4 hours before taking another dose [see Dosage And Administration ( 2.2 )] . OTFC contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. OTFC can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing OTFC in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression Patients and their caregivers must be instructed that OTFC contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested OTFC. All units must be kept out of the reach of children and opened units properly discarded. [see Warnings And Precautions ( 5.3 ), Patient Counseling Information ( 17.5 , 17.6 ), and How Supplied/Storage And Handling ( 16.2 )] . OTFC is intended to be used only in the care of cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. The concomitant use of OTFC with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see Drug Interactions ( 7 )] . WARNINGS: IMPORTANCE OF PROPER PATIENT SELECTION and POTENTIAL FOR ABUSE See full prescribing information for complete boxed warning. Must not be used in opioid non-tolerant patients. ( 1 ) Life-threatening hypoventilation could occur at any dose in patients not taking chronic opiates. ( 5.2 ) Contraindicated in management of acute or postoperative pain including headache/migraines. ( 4 ) Contains fentanyl, a Schedule II controlled substance with abuse liability similar to other opioid analgesics. ( 9.1 ) Contains medicine in an amount that can be fatal to a child. Keep out of reach of children and discard opened units properly. ( 5.3 ) Use with strong and moderate CYP450 3A4 inhibitors may result in potentially fatal respiratory depression. ( 7 )

WARNING: Do not use Oral Transmucosal Fentanyl Citrate (OTFC) unless you are regularly using other opioid pain medicines around-the-clock for your constant cancer pain and your body is used to these medicines. You MUST keep OTFC in a safe place out of the reach of children. Accidental ingestion by a child is a medical emergency and can result in death. Death has been reported in children who have accidentally taken OTFC. If a child accidentally takes OTFC, get emergency help right away.

5. WARNINGS AND PRECAUTIONS See Boxed Warning - WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, DOSING, and POTENTIAL FOR ABUSE Clinically significant respiratory and CNS depression can occur. Monitor patients accordingly. ( 5.2 ) Full and partially consumed OTFC units contain medicine that can be fatal to a child. Ensure proper storage and disposal. Interim safe storage container available (“OTFC Child Safety Kit”) ( 5.3 ) Use with other CNS depressants and potent cytochrome P450 3A4 inhibitors may increase depressant effects including respiratory depression, hypotension, and profound sedation. Consider dosage adjustments if warranted. ( 5.4 ) Titrate OTFC cautiously in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. ( 5.6 ) Administer OTFC with extreme caution in patients susceptible to intracranial effects of CO 2 retention. ( 5.7 ) 5.1 Important Information Regarding Prescribing and Dispensing When prescribing, DO NOT convert a patient to OTFC from any other fentanyl product on a mcg per mcg basis as OTFC and other fentanyl products are not equivalent on a microgram per microgram basis. OTFC is NOT a generic version of Fentora ® . When dispensing, DO NOT substitute an OTFC prescription for a Fentora prescription under any circumstances. Fentora and OTFC are not equivalent. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products including Fentora that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of OTFC for any other fentanyl product may result in a fatal overdose. There are no safe conversion directions available for patients on any other fentanyl products. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of OTFC should always be 200 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects [see Dosage And Administration ( 2.2 )] . 5.2 Respiratory Depression As with all opioids, there is a risk of clinically significant respiratory depression in patients using OTFC. Accordingly, follow all patients for symptoms of respiratory depression. Respiratory depression may occur more readily when opioids are given in conjunction with other agents that depress respiration. 5.3 Patient/Caregiver Instructions Patients and their caregivers must be instructed that OTFC contains a medicine in an amount which can be fatal to a child. Death has been reported in children who have accidentally ingested OTFC. Patients and their caregivers must be instructed to keep both used and unused dosage units out of the reach of children. While all units should be disposed of immediately after use, partially consumed units represent a special risk to children. In the event that a unit is not completely consumed it must be properly disposed as soon as possible [see How Supplied/Storage And Handling ( 16.1 , 16.2 ), and Patient Counseling Information ( 17.1 ) and the Medication Guide ] . Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home (on a full time or visiting basis) and counsel them regarding the dangers to children from inadvertent exposure. OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant. 5.4 Additive CNS Depressant Effects The concomitant use of OTFC with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., respiratory depression, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see Drug Interactions ( 7 )] . Patients on concomitant CNS depressants must be monitored for a change in opioid effects. Consideration should be given to adjusting the dose of OTFC if warranted. 5.5 Effects on Ability to Drive and Use Machines Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking OTFC of these dangers and counsel them accordingly. 5.6 Chronic Pulmonary Disease Because potent opioids can cause respiratory depression, titrate OTFC with caution in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of OTFC may further decrease respiratory drive to the point of respiratory failure. 5.7 Head Injuries and Increased Intracranial Pressure Administer OTFC with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted. 5.8 Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use OTFC with caution in patients with bradyarrhythmias. 5.9 MAO Inhibitors OTFC 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 Most common adverse reactions during titration phase (frequency ≥5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache. ( 6.1 ) Most common adverse reactions during treatment (frequency ≥5%): dyspnea, constipation, anxiety, confusion, depression, rash, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cephalon, Inc., at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience The safety of OTFC (oral transmucosal fentanyl citrate) has been evaluated in 257 opioid-tolerant chronic cancer pain patients. The duration of OTFC use varied during the open-label study. Some patients were followed for over 21 months. The average duration of therapy in the open-label study was 129 days. The adverse reactions seen with OTFC are typical opioid side effects. Frequently, these adverse reactions will cease or decrease in intensity with continued use of OTFC, as the patient is titrated to the proper dose. Expect opioid side effects and manage them accordingly. The most serious adverse reactions associated with all opioids including OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. Follow all patients for symptoms of respiratory depression. Because the clinical trials of OTFC were designed to evaluate safety and efficacy in treating breakthrough cancer pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent cancer pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received OTFC for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of OTFC therapy, or cancer-related symptoms. Adverse reactions are included regardless of causality or severity. 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. Three short-term clinical trials with similar titration schemes were conducted in 257 patients with malignancy and breakthrough cancer pain. Data are available for 254 of these patients. The goal of titration in these trials was to find the dose of OTFC that provided adequate analgesia with acceptable side effects (successful dose). Patients were titrated from a low dose to a successful dose in a manner similar to current titration dosing guidelines. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration and are commonly associated with opioid administration or are of particular clinical interest. The ability to assign a dose-response relationship to these adverse reactions is limited by the titration schemes used in these studies. Adverse reactions are listed in descending order of frequency within each body system. Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients) Dose Group Percentage of Patients Reporting Event 200-600 mcg 800-1400 mcg 1600 mcg >1600 mcg Any Dose * (n=230) (n=138) (n=54) (n=41) (n=254) * Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once Body As A Whole Asthenia 6 4 0 7 9 Headache 3 4 6 5 6 Accidental Injury 1 1 4 0 2 Digestive Nausea 14 15 11 22 23 Vomiting 7 6 6 15 12 Constipation 1 4 2 0 4 Nervous Dizziness 10 16 6 15 17 Somnolence 9 9 11 20 17 Confusion 1 6 2 0 4 Anxiety 3 0 2 0 3 Abnormal Gait 0 1 4 0 2 Dry Mouth 1 1 2 0 2 Nervousness 1 1 0 0 2 Vasodilatation 2 0 2 0 2 Hallucinations 0 1 2 2 1 Insomnia 0 1 2 0 1 Thinking Abnormal 0 1 2 0 1 Vertigo 1 0 0 0 1 Respiratory Dyspnea 2 3 6 5 4 Skin Pruritus 1 0 0 5 2 Rash 1 1 0 2 2 Sweating 1 1 2 2 2 Special Senses Abnormal Vision 1 0 2 0 2 The following adverse reactions not reflected in Table 1 occurred during titration with an overall frequency of 1% or greater and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, abdominal pain, chills, back pain, chest pain, infection Cardiovascular: Migraine Digestive: Diarrhea, dyspepsia, flatulence Metabolic and Nutritional: Peripheral edema, dehydration Nervous: Hypesthesia Respiratory: Pharyngitis, cough increased The following reactions occurred during titration with an overall frequency of less than 1% and are listed in descending order of frequency within each body system. Body as a Whole: Flu syndrome, abscess, bone pain Cardiovascular: Deep thrombophlebitis, hypertension, hypotension Digestive: Anorexia, eructation, esophageal stenosis, fecal impaction, gum hemorrhage, mouth ulceration, oral moniliasis Hemic and Lymphatic: Anemia, leukopenia Metabolic and Nutritional: Edema, hypercalcemia, weight loss Musculoskeletal: Myalgia, pathological fracture, myasthenia Nervous: Abnormal dreams, urinary retention, agitation, amnesia, emotional lability, euphoria, incoordination, libido decreased, neuropathy, paresthesia, speech disorder Respiratory: Hemoptysis, pleural effusion, rhinitis, asthma, hiccup, pneumonia, respiratory insufficiency, sputum increased Skin and Appendages: Alopecia, exfoliative dermatitis Special Senses: Taste perversion Urogenital: Vaginal hemorrhage, dysuria, hematuria, urinary incontinence, urinary tract infection A long-term extension study was conducted in 156 patients with malignancy and breakthrough cancer pain who were treated for an average of 129 days. Data are available for 152 of these patients. Table 2 lists by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during the long-term extension study and are commonly associated with opioid administration or are of particular clinical interest. Adverse reactions are listed in descending order of frequency within each body system. Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients) Dose Group Percentage of Patients Reporting Event 200-600 mcg 800-1400 mcg 1600 mcg >1600 mcg Any Dose* (n=98) (n=83) (n=53) (n=27) (n=152) Body As A Whole Asthenia 25 30 17 15 38 Headache 12 17 13 4 20 Accidental Injury 4 6 4 7 9 Hypertonia 2 2 2 0 3 Digestive Nausea 31 36 25 26 45 Vomiting 21 28 15 7 31 Constipation 14 11 13 4 20 Intestinal Obstruction 0 2 4 0 3 Cardiovascular Hypertension 1 1 0 0 1 Nervous Dizziness 12 10 9 0 16 Anxiety 9 8 8 7 15 Somnolence 8 13 8 7 15 Confusion 2 5 13 7 10 Depression 9 4 2 7 9 Insomnia 5 1 8 4 7 Abnormal Gait 5 1 0 0 4 Dry Mouth 3 1 2 4 4 Nervousness 2 2 0 4 3 Stupor 4 1 0 0 3 Vasodilatation 1 1 4 0 3 Thinking Abnormal 2 1 0 0 2 Abnormal Dreams 1 1 0 0 1 Convulsion 0 1 2 0 1 Myoclonus 0 0 4 0 1 Tremor 0 1 2 0 1 Vertigo 0 0 4 0 1 Respiratory Dyspnea 15 16 8 7 22 Skin Rash 3 5 8 4 8 Sweating 3 2 2 0 4 Pruritus 2 0 2 0 2 Special Senses Abnormal Vision 2 2 0 0 3 Urogenital Urinary Retention 1 2 0 0 2 The following reactions not reflected in Table 2 occurred with an overall frequency of 1% or greater in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Pain, fever, back pain, abdominal pain, chest pain, flu syndrome, chills, infection, abdomen enlarged, bone pain, ascites, sepsis, neck pain, viral infection, fungal infection, cachexia, cellulitis, malaise, pelvic pain Cardiovascular: Deep thrombophlebitis, migraine, palpitation, vascular disorder Digestive: Diarrhea, anorexia, dyspepsia, dysphagia, oral moniliasis, mouth ulceration, rectal disorder, stomatitis, flatulence, gastrointestinal hemorrhage, gingivitis, jaundice, periodontal abscess, eructation, glossitis, rectal hemorrhage Hemic and Lymphatic: Anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy, lymphedema, pancytopenia Metabolic and Nutritional: Peripheral edema, edema, dehydration, weight loss, hyperglycemia, hypokalemia, hypercalcemia, hypomagnesemia Musculoskeletal: Myalgia, pathological fracture, joint disorder, leg cramps, arthralgia, bone disorder Nervous: Hypesthesia, paresthesia, hypokinesia, neuropathy, speech disorder Respiratory: Cough increased, pharyngitis, pneumonia, rhinitis, sinusitis, bronchitis, epistaxis, asthma, hemoptysis, sputum increased Skin and Appendages: Skin ulcer, alopecia Special Senses: Tinnitus, conjunctivitis, ear disorder, taste perversion Urogenital: Urinary tract infection, urinary incontinence, breast pain, dysuria, hematuria, scrotal edema, hydronephrosis, kidney failure, urinary urgency, urination impaired, breast neoplasm, vaginal hemorrhage, vaginitis The following reactions occurred with a frequency of less than 1% in the long-term extension study and are listed in descending order of frequency within each body system. Body as a Whole: Allergic reaction, cyst, face edema, flank pain, granuloma, bacterial infection, injection site pain, mucous membrane disorder, neck rigidity Cardiovascular: Angina pectoris, hemorrhage, hypotension, peripheral vascular disorder, postural hypotension, tachycardia Digestive: Cheilitis, esophagitis, fecal incontinence, gastroenteritis, gastrointestinal disorder, gum hemorrhage, hemorrhage of colon, hepatorenal syndrome, liver tenderness, tooth caries, tooth disorder Hemic and Lymphatic: Bleeding time increased Metabolic and Nutritional: Acidosis, generalized edema, hypocalcemia, hypoglycemia, hyponatremia, hypoproteinemia, thirst Musculoskeletal: Arthritis, muscle atrophy, myopathy, synovitis, tendon disorder Nervous: Acute brain syndrome, agitation, cerebral ischemia, facial paralysis, foot drop, hallucinations, hemiplegia, miosis, subdural hematoma Respiratory: Hiccup, hyperventilation, lung disorder, pneumothorax, respiratory failure, voice alteration Skin and Appendages: Herpes zoster, maculopapular rash, skin discoloration, urticaria, vesiculobullous rash Special Senses: Ear pain, eye hemorrhage, lacrimation disorder, partial permanent deafness, partial transitory deafness Urogenital: Kidney pain, nocturia, oliguria, polyuria, pyelonephritis 6.2 Post-Marketing Experience Adverse reactions are reported voluntarily from a population of uncertain size, and, therefore, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to OTFC. The following adverse reactions have been identified during postapproval use of OTFC (which contains approximately 2 grams of sugar per unit): Digestive: Dental decay of varying severity including dental caries, tooth loss, and gum line erosion. General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer.

<table cellpadding="5" ID="i4737a5da-9c18-489e-877a-691898796926"> <caption>Table 1. Percent of Patients with Specific Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Titration (Events in 1% or More of Patients)</caption> <col align="left" width="40"/> <col align="left"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center" span="1"/> <thead> <tr> <td align="center" colspan="2" rowspan="3">Dose Group</td> <th align="center" colspan="5">Percentage of Patients Reporting Event </th> </tr> <tr align="center"> <td>200-600 mcg</td> <td>800-1400 mcg</td> <td>1600 mcg</td> <td>&gt;1600 mcg</td> <td>Any Dose^* </td> </tr> <tr align="center"> <th align="center" colspan="1" rowspan="1">(n=230)</th> <th align="center">(n=138)</th> <th align="center">(n=54)</th> <th align="center">(n=41)</th> <th align="center">(n=254)</th> </tr> </thead> <tfoot> <tr> <td colspan="7" rowspan="1"> ^* Any Dose = A patient who experienced the same adverse event at multiple doses was only counted once</td> </tr> </tfoot> <tbody align="center"> <tr> <td colspan="7">Body As A Whole</td> </tr> <tr> <td/> <td>Asthenia</td> <td>6</td> <td>4</td> <td>0</td> <td>7</td> <td>9</td> </tr> <tr> <td/> <td>Headache</td> <td>3</td> <td>4</td> <td>6</td> <td>5</td> <td>6</td> </tr> <tr> <td/> <td>Accidental Injury</td> <td>1</td> <td>1</td> <td>4</td> <td>0</td> <td>2</td> </tr> <tr> <td colspan="7">Digestive</td> </tr> <tr> <td/> <td>Nausea</td> <td>14</td> <td>15</td> <td>11</td> <td>22</td> <td>23</td> </tr> <tr> <td/> <td>Vomiting</td> <td>7</td> <td>6</td> <td>6</td> <td>15</td> <td>12</td> </tr> <tr> <td/> <td>Constipation</td> <td>1</td> <td>4</td> <td>2</td> <td>0</td> <td>4</td> </tr> <tr> <td colspan="7">Nervous</td> </tr> <tr> <td/> <td>Dizziness</td> <td>10</td> <td>16</td> <td>6</td> <td>15</td> <td>17</td> </tr> <tr> <td/> <td>Somnolence</td> <td>9</td> <td>9</td> <td>11</td> <td>20</td> <td>17</td> </tr> <tr> <td/> <td>Confusion</td> <td>1</td> <td>6</td> <td>2</td> <td>0</td> <td>4</td> </tr> <tr> <td/> <td>Anxiety</td> <td>3</td> <td>0</td> <td>2</td> <td>0</td> <td>3</td> </tr> <tr> <td/> <td>Abnormal Gait</td> <td>0</td> <td>1</td> <td>4</td> <td>0</td> <td>2</td> </tr> <tr> <td/> <td>Dry Mouth</td> <td>1</td> <td>1</td> <td>2</td> <td>0</td> <td>2</td> </tr> <tr> <td/> <td>Nervousness</td> <td>1</td> <td>1</td> <td>0</td> <td>0</td> <td>2</td> </tr> <tr> <td/> <td>Vasodilatation</td> <td>2</td> <td>0</td> <td>2</td> <td>0</td> <td>2</td> </tr> <tr> <td/> <td>Hallucinations</td> <td>0</td> <td>1</td> <td>2</td> <td>2</td> <td>1</td> </tr> <tr> <td/> <td>Insomnia</td> <td>0</td> <td>1</td> <td>2</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Thinking Abnormal</td> <td>0</td> <td>1</td> <td>2</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Vertigo</td> <td>1</td> <td>0</td> <td>0</td> <td>0</td> <td>1</td> </tr> <tr> <td colspan="7">Respiratory</td> </tr> <tr> <td/> <td rowspan="1">Dyspnea</td> <td>2</td> <td>3</td> <td>6</td> <td>5</td> <td>4</td> </tr> <tr> <td colspan="7">Skin</td> </tr> <tr> <td/> <td>Pruritus</td> <td>1</td> <td>0</td> <td>0</td> <td>5</td> <td>2</td> </tr> <tr> <td/> <td>Rash</td> <td>1</td> <td>1</td> <td>0</td> <td>2</td> <td>2</td> </tr> <tr> <td/> <td>Sweating</td> <td>1</td> <td>1</td> <td>2</td> <td>2</td> <td>2</td> </tr> <tr> <td colspan="7">Special Senses</td> </tr> <tr> <td/> <td>Abnormal Vision</td> <td>1</td> <td>0</td> <td>2</td> <td>0</td> <td>2</td> </tr> </tbody> </table>

<table cellpadding="5" ID="i7342066d-fdd3-4b23-8b24-a1a649583059"> <caption>Table 2. Percent of Patients with Adverse Events Commonly Associated with Opioid Administration or of Particular Clinical Interest Which Occurred During Long Term Treatment (Events in 1% or More of Patients)</caption> <col align="left" width="40"/> <col align="left"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <col align="center"/> <thead> <tr> <th colspan="2" rowspan="3">Dose Group</th> <th align="center" colspan="5">Percentage of Patients Reporting Event</th> </tr> <tr> <th align="center">200-600 mcg</th> <th align="center">800-1400 mcg</th> <th align="center">1600 mcg</th> <th align="center">&gt;1600 mcg</th> <th align="center">Any Dose*</th> </tr> <tr> <th align="center">(n=98)</th> <th align="center">(n=83)</th> <th align="center">(n=53)</th> <th align="center">(n=27)</th> <th align="center">(n=152)</th> </tr> </thead> <tbody align="center"> <tr> <td colspan="2">Body As A Whole</td> </tr> <tr> <td/> <td>Asthenia</td> <td>25</td> <td>30</td> <td>17</td> <td>15</td> <td>38</td> </tr> <tr> <td/> <td>Headache</td> <td>12</td> <td>17</td> <td>13</td> <td>4</td> <td>20</td> </tr> <tr> <td/> <td>Accidental Injury</td> <td>4</td> <td>6</td> <td>4</td> <td>7</td> <td>9</td> </tr> <tr> <td/> <td>Hypertonia</td> <td>2</td> <td>2</td> <td>2</td> <td>0</td> <td>3</td> </tr> <tr> <td colspan="2">Digestive</td> </tr> <tr> <td/> <td>Nausea</td> <td>31</td> <td>36</td> <td>25</td> <td>26</td> <td>45</td> </tr> <tr> <td/> <td>Vomiting</td> <td>21</td> <td>28</td> <td>15</td> <td>7</td> <td>31</td> </tr> <tr> <td/> <td>Constipation</td> <td>14</td> <td>11</td> <td>13</td> <td>4</td> <td>20</td> </tr> <tr> <td/> <td>Intestinal Obstruction</td> <td>0</td> <td>2</td> <td>4</td> <td>0</td> <td>3</td> </tr> <tr> <td colspan="2">Cardiovascular</td> </tr> <tr> <td/> <td>Hypertension</td> <td>1</td> <td>1</td> <td>0</td> <td>0</td> <td>1</td> </tr> <tr> <td colspan="2">Nervous</td> </tr> <tr> <td/> <td>Dizziness</td> <td>12</td> <td>10</td> <td>9</td> <td>0</td> <td>16</td> </tr> <tr> <td/> <td>Anxiety</td> <td>9</td> <td>8</td> <td>8</td> <td>7</td> <td>15</td> </tr> <tr> <td/> <td>Somnolence</td> <td>8</td> <td>13</td> <td>8</td> <td>7</td> <td>15</td> </tr> <tr> <td/> <td>Confusion</td> <td>2</td> <td>5</td> <td>13</td> <td>7</td> <td>10</td> </tr> <tr> <td/> <td>Depression</td> <td>9</td> <td>4</td> <td>2</td> <td>7</td> <td>9</td> </tr> <tr> <td/> <td>Insomnia</td> <td>5</td> <td>1</td> <td>8</td> <td>4</td> <td>7</td> </tr> <tr> <td/> <td>Abnormal Gait</td> <td>5</td> <td>1</td> <td>0</td> <td>0</td> <td>4</td> </tr> <tr> <td/> <td>Dry Mouth</td> <td>3</td> <td>1</td> <td>2</td> <td>4</td> <td>4</td> </tr> <tr> <td/> <td>Nervousness</td> <td>2</td> <td>2</td> <td>0</td> <td>4</td> <td>3</td> </tr> <tr> <td/> <td>Stupor</td> <td>4</td> <td>1</td> <td>0</td> <td>0</td> <td>3</td> </tr> <tr> <td/> <td>Vasodilatation</td> <td>1</td> <td>1</td> <td>4</td> <td>0</td> <td>3</td> </tr> <tr> <td/> <td>Thinking Abnormal</td> <td>2</td> <td>1</td> <td>0</td> <td>0</td> <td>2</td> </tr> <tr> <td/> <td>Abnormal Dreams</td> <td>1</td> <td>1</td> <td>0</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Convulsion</td> <td>0</td> <td>1</td> <td>2</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Myoclonus</td> <td>0</td> <td>0</td> <td>4</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Tremor</td> <td>0</td> <td>1</td> <td>2</td> <td>0</td> <td>1</td> </tr> <tr> <td/> <td>Vertigo</td> <td>0</td> <td>0</td> <td>4</td> <td>0</td> <td>1</td> </tr> <tr> <td colspan="2">Respiratory</td> </tr> <tr> <td/> <td>Dyspnea</td> <td>15</td> <td>16</td> <td>8</td> <td>7</td> <td>22</td> </tr> <tr> <td colspan="2">Skin</td> </tr> <tr> <td/> <td>Rash</td> <td>3</td> <td>5</td> <td>8</td> <td>4</td> <td>8</td> </tr> <tr> <td/> <td>Sweating</td> <td>3</td> <td>2</td> <td>2</td> <td>0</td> <td>4</td> </tr> <tr> <td/> <td>Pruritus</td> <td>2</td> <td>0</td> <td>2</td> <td>0</td> <td>2</td> </tr> <tr> <td colspan="2">Special Senses</td> </tr> <tr> <td/> <td>Abnormal Vision</td> <td>2</td> <td>2</td> <td>0</td> <td>0</td> <td>3</td> </tr> <tr> <td colspan="2">Urogenital</td> </tr> <tr> <td/> <td>Urinary Retention</td> <td>1</td> <td>2</td> <td>0</td> <td>0</td> <td>2</td> </tr> </tbody> </table>