FDA label 85716ea8-a146-4620-a5f6-0f4264282d9e

BOXED WARNING Reports of serious adverse events, including deaths in patients treated with fentanyl buccal tablets 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 fentanyl buccal tablets for any other fentanyl product may result in fatal overdose. Fentanyl buccal tablets are indicated only for the management of breakthrough pain in patients with cancer 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 oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer. Fentanyl buccal tablets are not indicated for use in opioid non-tolerant patients including those with only as needed (PRN) prior exposure. Fentanyl buccal tablets are contraindicated in the management of acute or postoperative pain including headache/migraine. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients. When prescribing, do not convert patients on a mcg per mcg basis from Actiq®‡ to fentanyl buccal tablets. Carefully consult the Initial Dosing Recommendations table. (See DOSAGE AND ADMINISTRATION, Table 7 .) When dispensing, do not substitute a fentanyl buccal tablets prescription for other fentanyl products. Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablets 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 fentanyl buccal tablets for any other fentanyl product may result in fatal overdose. Special care must be used when dosing fentanyl buccal tablets. If the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY one additional dose using the same strength and must wait at least 4 hours before taking another dose. (See DOSAGE AND ADMINISTRATION .) Fentanyl buccal tablets contain fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Fentanyl buccal tablets can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing fentanyl buccal tablets 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 fentanyl buccal tablets contain a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep all tablets out of the reach of children. (See Information for Patients and Caregivers for disposal instructions.) Fentanyl buccal tablets are intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. The concomitant use of fentanyl buccal tablets with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.

WARNINGS See BOXED WARNING When prescribing, DO NOT convert a patient from Actiq ®‡ to fentanyl buccal tablets without following the instructions found in the prescribing information as Actiq ®‡ and fentanyl buccal tablets are not equivalent on a microgram per microgram basis. Fentanyl buccal tablets are NOT a generic version of Actiq ®‡ . When dispensing, DO NOT substitute a fentanyl buccal tablets prescription for an Actiq ®‡ prescription under any circumstances. Fentanyl buccal tablets and Actiq ®‡ are not equivalent. Substantial differences exist in the pharmacokinetic profile of fentanyl buccal tablets compared to other fentanyl products including Actiq ®‡ that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of fentanyl buccal tablets for the same dose of Actiq ®‡ or 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 fentanyl buccal tablets should be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. (See DOSAGE AND ADMINISTRATION . ) Use with CNS Depressants The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation, hypotension, and profound sedation may occur. Fentanyl buccal tablets are 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. Pediatric Use: The safety and efficacy of fentanyl buccal tablets have not been established in pediatric patients below the age of 18 years. Patients and their caregivers must be instructed that fentanyl buccal tablets contain a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children. (See SAFETY AND HANDLING , PRECAUTIONS , and MEDICATION GUIDE for specific patient instructions.) Drug Abuse, Addiction and Diversion of Opioids Fentanyl buccal tablets contain fentanyl, a mu-opioid agonist and a Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and is subject to misuse, and criminal diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers. Fentanyl buccal tablets should be prescribed with caution to patients who have a higher risk of substance abuse, including patients with bipolar disorder and/or schizophrenia. Patients with chronic pain may be at a higher risk for suicide. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since fentanyl buccal tablets may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of patients, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Fentanyl buccal tablets should be handled appropriately to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Physical Dependence and Withdrawal The administration of fentanyl buccal tablets should be guided by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with cancer and chronic pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain. Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. Respiratory Depression Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in fentanyl buccal tablets. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

ADVERSE REACTIONS Pre-Marketing Clinical Trial Experience The safety of fentanyl buccal tablets has been evaluated in 304 opioid tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months. The most commonly observed adverse events seen with fentanyl buccal tablets are typical of opioid side effects. Opioid side effects should be expected and managed accordingly. The clinical trials of fentanyl buccal tablets were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received fentanyl buccal tablets for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of fentanyl buccal tablets therapy or cancer-related symptoms. Table 5 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Table 5. Adverse Events Which Occurred During Titration at a Frequency of ≥ 5% System Organ Class MeDRA preferred term, n (%) 100 mcg (N=45) 200 mcg (N=34) 400 mcg (N=53) 600 mcg (N=56) 800 mcg (N=113) Total (N=304)* * Three hundred and two (302) patients were included in the safety analysis. Gastrointestinal disorders Nausea 4 (9) 5 (15) 10 (19) 13 (23) 18 (16) 50 (17) Vomiting 0 2 (6) 2 (4) 7 (13) 3 (3) 14 (5) General disorders and administration site conditions Fatigue 3 (7) 1 (3) 9 (17) 1 (2) 5 (4) 19 (6) Nervous system disorders Dizziness 5 (11) 2 (6) 12 (23) 18 (32) 21 (19) 58 (19) Somnolence 2 (4) 2 (6) 6 (12) 7 (13) 3 (3) 20 (7) Headache 1 (2) 3 (9) 4 (8) 8 (14) 10 (9) 26 (9) Table 6 lists, by successful dose, adverse events with an overall frequency of ≥ 5% within the total population that occurred after a successful dose had been determined. Table 6. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of ≥ 5% System Organ Class MeDRA preferred term, n (%) 100 mcg (N=19) 200 mcg (N=31) 400 mcg (N=44) 600 mcg (N=48) 800 mcg (N=58) Total (N=200) Blood and lymphatic system disorders Anemia 6 (32) 4 (13) 4 (9) 5 (10) 7 (13) 26 (13) Neutropenia 0 2 (6) 1 (2) 4 (8) 4 (7) 11 (6) Gastrointestinal disorders Nausea 8 (42) 5 (16) 14 (32) 13 (27) 17 (31) 57 (29) Vomiting 7 (37) 5 (16) 9 (20) 8 (17) 11 (20) 40 (20) Constipation 5 (26) 4 (13) 5 (11) 4 (8) 6 (11) 24 (12) Diarrhea 3 (16) 0 4 (9) 3 (6) 5 (9) 15 (8) Abdominal pain 2 (11) 1 (3) 4 (9) 7 (15) 4 (7) 18 (9) General disorders and administration site conditions Edema peripheral 6 (32) 5 (16) 4 (9) 5 (10) 3 (5) 23 (12) Asthenia 3 (16) 5 (16) 2 (5) 3 (6) 8 (15) 21 (11) Fatigue 3 (16) 3 (10) 9 (20) 9 (19) 8 (15) 32 (16) Infections and infestations Pneumonia 1 (5) 5 (16) 1 (2) 1 (2) 4 (7) 12 (6) Investigations Weight decreased 1 (5) 1 (3) 3 (7) 2 (4) 6 (11) 13 (7) Metabolism and nutrition disorders Dehydration 4 (21) 0 4 (9) 6 (13) 7 (13) 21 (11) Anorexia 1 (5) 2 (6) 4 (9) 3 (6) 6 (11) 16 (8) Hypokalemia 0 2 (6) 0 1 (2) 8 (15) 11 (6) Musculoskeletal and connective tissue disorders Back pain 2 (11) 0 2 (5) 3 (6) 2 (4) 9 (5) Arthralgia 0 1 (3) 3 (7) 4 (8) 3 (5) 11 (6) Neoplasms benign, malignant and unspecified (including cysts and polyps) Cancer pain 3 (16) 1 (3) 3 (7) 2 (4) 1 (2) 10 (5) Nervous system disorders Dizziness 5 (26) 3 (10) 5 (11) 6 (13) 6 (11) 25 (13) Headache 2 (11) 1 (3) 4 (9) 5 (10) 8 (15) 20 (10) Somnolence 0 1 (3) 4 (9) 4 (8) 8 (15) 17 (9) Psychiatric disorders Confusional state 3 (16) 1 (3) 2 (5) 3 (6) 5 (9) 14 (7) Depression 2 (11) 1 (3) 4 (9) 3 (6) 5 (9) 15 (8) Insomnia 2 (11) 1 (3) 3 (7) 2 (4) 4 (7) 12 (6) Respiratory, thoracic, and mediastinal disorders Cough 1 (5) 1 (3) 2 (5) 4 (8) 5 (9) 13 (7) Dyspnea 1 (5) 6 (19) 0 7 (15) 4 (7) 18 (9) In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of fentanyl buccal tablets. There was no evidence of excess toxicity in this subset of patients. The duration of exposure to fentanyl buccal tablets varied greatly, and included open-label and double-blind studies. The frequencies listed below represent the ≥1% of patients from three clinical trials (titration and post-titration periods combined) who experienced that event while receiving fentanyl buccal tablets. Events are classified by system organ class. Adverse Events (≥1%) Blood and Lymphatic System Disorders: Anemia, Neutropenia, Thrombocytopenia, Leukopenia Cardiac Disorders: Tachycardia Gastrointestinal Disorders: Nausea, Vomiting, Constipation, Abdominal Pain, Diarrhea, Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration General Disorders and Administration Site Conditions: Fatigue, Edema Peripheral, Asthenia, Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain Hepatobiliary Disorders: Jaundice Infections and Infestations: Pneumonia, Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture Investigations: Decreased Weight, Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count Metabolism and Nutrition Disorders: Dehydration, Anorexia, Hypokalemia, Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back Pain, Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain Nervous System Disorders: Dizziness, Headache, Somnolence, Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy Psychiatric Disorders: Confusional State, Depression, Insomnia, Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness Renal and Urinary Disorders: Renal Failure Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Cough, Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis

<table frame="void"> <caption>Table 5. Adverse Events Which Occurred During Titration at a Frequency of &#x2265; 5%</caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <thead> <tr> <td valign="top"> <content styleCode="bold">System Organ Class MeDRA preferred term, n (%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">100 mcg (N=45) </content> </td> <td align="center" valign="top"> <content styleCode="bold">200 mcg (N=34) </content> </td> <td align="center" valign="top"> <content styleCode="bold">400 mcg (N=53) </content> </td> <td align="center" valign="top"> <content styleCode="bold">600 mcg (N=56) </content> </td> <td align="center" valign="top"> <content styleCode="bold">800 mcg (N=113) </content> </td> <td align="center" valign="top"> <content styleCode="bold">Total </content> <content styleCode="bold"> </content> <content styleCode="bold">(N=304)* </content> </td> </tr> </thead> <tfoot> <tr> <td valign="top" colspan="7"> * Three hundred and two (302) patients were included in the safety analysis.</td> </tr> </tfoot> <tbody> <tr> <td valign="top" colspan="7"> <content styleCode="bold">Gastrointestinal disorders </content> </td> </tr> <tr> <td valign="top"> Nausea </td> <td align="center" valign="top"> 4 (9)</td> <td align="center" valign="top"> 5 (15) </td> <td align="center" valign="top"> 10 (19) </td> <td align="center" valign="top"> 13 (23) </td> <td align="center" valign="top"> 18 (16)</td> <td align="center" valign="top"> 50 (17) </td> </tr> <tr> <td valign="top"> Vomiting </td> <td align="center" valign="top"> 0 </td> <td align="center" valign="top"> 2 (6) </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 7 (13) </td> <td align="center" valign="top"> 3 (3) </td> <td align="center" valign="top"> 14 (5) </td> </tr> <tr> <td valign="top" colspan="7"> <content styleCode="bold">General disorders and administration site conditions </content> </td> </tr> <tr> <td valign="top"> Fatigue </td> <td align="center" valign="top"> 3 (7) </td> <td align="center" valign="top"> 1 (3) </td> <td align="center" valign="top"> 9 (17) </td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 5 (4) </td> <td align="center" valign="top"> 19 (6) </td> </tr> <tr> <td valign="top" colspan="7"> <content styleCode="bold">Nervous system disorders</content> </td> </tr> <tr> <td valign="top"> Dizziness </td> <td align="center" valign="top"> 5 (11) </td> <td align="center" valign="top"> 2 (6) </td> <td align="center" valign="top"> 12 (23) </td> <td align="center" valign="top"> 18 (32) </td> <td align="center" valign="top"> 21 (19) </td> <td align="center" valign="top"> 58 (19) </td> </tr> <tr> <td valign="top"> Somnolence </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 2 (6) </td> <td align="center" valign="top"> 6 (12) </td> <td align="center" valign="top"> 7 (13) </td> <td align="center" valign="top"> 3 (3) </td> <td align="center" valign="top"> 20 (7) </td> </tr> <tr> <td valign="top"> Headache </td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 3 (9) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 8 (14) </td> <td align="center" valign="top"> 10 (9) </td> <td align="center" valign="top"> 26 (9) </td> </tr> </tbody> </table>

<table frame="void"> <caption>Table 6. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of &#x2265; 5%</caption> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <thead> <tr> <td valign="top" colspan="2"> <content styleCode="bold">System Organ Class </content> <content styleCode="bold"> </content> <content styleCode="bold">MeDRA preferred </content> <content styleCode="bold"> </content> <content styleCode="bold">term, n (%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">100 mcg</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=19)</content> </td> <td align="center" valign="top" colspan="2"> <content styleCode="bold">200 mcg</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=31)</content> </td> <td align="center" valign="top"> <content styleCode="bold">400 mcg</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=44) </content> </td> <td align="center" valign="top"> <content styleCode="bold">600 mcg </content> <content styleCode="bold"> </content> <content styleCode="bold">(N=48) </content> </td> <td align="center" valign="top"> <content styleCode="bold">800 mcg </content> <content styleCode="bold"> </content> <content styleCode="bold">(N=58) </content> </td> <td align="center" valign="top"> <content styleCode="bold">Total</content> <content styleCode="bold"> </content> <content styleCode="bold">(N=200)</content> </td> </tr> </thead> <tbody> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Blood and lymphatic system disorders </content> </td> </tr> <tr> <td valign="top" colspan="2"> Anemia </td> <td align="center" valign="top"> 6 (32)</td> <td align="center" valign="top" colspan="2"> 4 (13)</td> <td align="center" valign="top"> 4 (9)</td> <td align="center" valign="top"> 5 (10)</td> <td align="center" valign="top"> 7 (13)</td> <td align="center" valign="top"> 26 (13) </td> </tr> <tr> <td valign="top" colspan="2"> Neutropenia </td> <td align="center" valign="top"> 0</td> <td align="center" valign="top" colspan="2"> 2 (6)</td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 4 (7) </td> <td align="center" valign="top"> 11 (6) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Gastrointestinal disorders </content> </td> </tr> <tr> <td valign="top" colspan="2"> Nausea </td> <td align="center" valign="top"> 8 (42)</td> <td align="center" valign="top" colspan="2"> 5 (16)</td> <td align="center" valign="top"> 14 (32) </td> <td align="center" valign="top"> 13 (27) </td> <td align="center" valign="top"> 17 (31) </td> <td align="center" valign="top"> 57 (29) </td> </tr> <tr> <td valign="top" colspan="2"> Vomiting </td> <td align="center" valign="top"> 7 (37)</td> <td align="center" valign="top" colspan="2"> 5 (16)</td> <td align="center" valign="top"> 9 (20) </td> <td align="center" valign="top"> 8 (17) </td> <td align="center" valign="top"> 11 (20) </td> <td align="center" valign="top"> 40 (20) </td> </tr> <tr> <td valign="top" colspan="2"> Constipation </td> <td align="center" valign="top"> 5 (26)</td> <td align="center" valign="top" colspan="2"> 4 (13)</td> <td align="center" valign="top"> 5 (11) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 6 (11) </td> <td align="center" valign="top"> 24 (12) </td> </tr> <tr> <td valign="top" colspan="2"> Diarrhea </td> <td align="center" valign="top"> 3 (16)</td> <td align="center" valign="top" colspan="2"> 0</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 5 (9) </td> <td align="center" valign="top"> 15 (8)</td> </tr> <tr> <td valign="top" colspan="2"> Abdominal pain </td> <td align="center" valign="top"> 2 (11)</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 7 (15) </td> <td align="center" valign="top"> 4 (7) </td> <td align="center" valign="top"> 18 (9) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">General disorders and administration site conditions </content> </td> </tr> <tr> <td valign="top" colspan="2"> Edema peripheral </td> <td align="center" valign="top"> 6 (32)</td> <td align="center" valign="top" colspan="2"> 5 (16)</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 5 (10) </td> <td align="center" valign="top"> 3 (5) </td> <td align="center" valign="top"> 23 (12) </td> </tr> <tr> <td valign="top" colspan="2"> Asthenia </td> <td align="center" valign="top"> 3 (16)</td> <td align="center" valign="top" colspan="2"> 5 (16)</td> <td align="center" valign="top"> 2 (5) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 8 (15) </td> <td align="center" valign="top"> 21 (11) </td> </tr> <tr> <td valign="top" colspan="2"> Fatigue </td> <td align="center" valign="top"> 3 (16)</td> <td align="center" valign="top" colspan="2"> 3 (10)</td> <td align="center" valign="top"> 9 (20) </td> <td align="center" valign="top"> 9 (19) </td> <td align="center" valign="top"> 8 (15) </td> <td align="center" valign="top"> 32 (16) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Infections and infestations </content> </td> </tr> <tr> <td valign="top" colspan="2"> Pneumonia </td> <td align="center" valign="top"> 1 (5)</td> <td align="center" valign="top" colspan="2"> 5 (16)</td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 4 (7) </td> <td align="center" valign="top"> 12 (6) </td> </tr> <tr> <td valign="top" colspan="2"> <content styleCode="bold">Investigations </content> </td> <td align="center" valign="top"> </td> <td align="center" valign="top" colspan="2"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> <td align="center" valign="top"> </td> </tr> <tr> <td valign="top" colspan="2"> Weight decreased </td> <td align="center" valign="top"> 1 (5)</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 3 (7) </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 6 (11) </td> <td align="center" valign="top"> 13 (7) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Metabolism and nutrition disorders </content> </td> </tr> <tr> <td valign="top" colspan="2"> Dehydration </td> <td align="center" valign="top"> 4 (21)</td> <td align="center" valign="top" colspan="2"> 0</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 6 (13) </td> <td align="center" valign="top"> 7 (13) </td> <td align="center" valign="top"> 21 (11) </td> </tr> <tr> <td valign="top" colspan="2"> Anorexia </td> <td align="center" valign="top"> 1 (5)</td> <td align="center" valign="top" colspan="2"> 2 (6)</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 6 (11) </td> <td align="center" valign="top"> 16 (8) </td> </tr> <tr> <td valign="top" colspan="2"> Hypokalemia </td> <td align="center" valign="top"> 0</td> <td align="center" valign="top" colspan="2"> 2 (6)</td> <td align="center" valign="top"> 0 </td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 8 (15) </td> <td align="center" valign="top"> 11 (6) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Musculoskeletal and connective tissue disorders </content> </td> </tr> <tr> <td valign="top" colspan="2"> Back pain </td> <td align="center" valign="top"> 2 (11)</td> <td align="center" valign="top" colspan="2"> 0</td> <td align="center" valign="top"> 2 (5) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 9 (5) </td> </tr> <tr> <td valign="top" colspan="2"> Arthralgia </td> <td align="center" valign="top"> 0</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 3 (7) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 3 (5) </td> <td align="center" valign="top"> 11 (6) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Neoplasms benign, malignant and unspecified (including cysts and polyps)</content> </td> </tr> <tr> <td valign="top" colspan="2"> Cancer pain </td> <td align="center" valign="top"> 3 (16)</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 3 (7) </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 1 (2) </td> <td align="center" valign="top"> 10 (5) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Nervous system disorders</content> </td> </tr> <tr> <td valign="top" colspan="2"> Dizziness </td> <td align="center" valign="top"> 5 (26)</td> <td align="center" valign="top" colspan="2"> 3 (10)</td> <td align="center" valign="top"> 5 (11) </td> <td align="center" valign="top"> 6 (13) </td> <td align="center" valign="top"> 6 (11) </td> <td align="center" valign="top"> 25 (13) </td> </tr> <tr> <td valign="top" colspan="2"> Headache </td> <td align="center" valign="top"> 2 (11)</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 5 (10) </td> <td align="center" valign="top"> 8 (15) </td> <td align="center" valign="top"> 20 (10) </td> </tr> <tr> <td valign="top" colspan="2"> Somnolence </td> <td align="center" valign="top"> 0</td> <td align="center" valign="top" colspan="2"> 1 (3)</td> <td align="center" valign="top"> 4 (9) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 8 (15) </td> <td align="center" valign="top"> 17 (9) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Psychiatric disorders </content> </td> </tr> <tr> <td valign="top"> Confusional state </td> <td align="center" valign="top" colspan="2"> 3 (16)</td> <td align="center" valign="top"> 1 (3)</td> <td align="center" valign="top" colspan="2"> 2 (5) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 5 (9) </td> <td align="center" valign="top"> 14 (7)</td> </tr> <tr> <td valign="top"> Depression </td> <td align="center" valign="top" colspan="2"> 2 (11)</td> <td align="center" valign="top"> 1 (3)</td> <td align="center" valign="top" colspan="2"> 4 (9) </td> <td align="center" valign="top"> 3 (6) </td> <td align="center" valign="top"> 5 (9) </td> <td align="center" valign="top"> 15 (8)</td> </tr> <tr> <td valign="top"> Insomnia </td> <td align="center" valign="top" colspan="2"> 2 (11)</td> <td align="center" valign="top"> 1 (3)</td> <td align="center" valign="top" colspan="2"> 3 (7) </td> <td align="center" valign="top"> 2 (4) </td> <td align="center" valign="top"> 4 (7) </td> <td align="center" valign="top"> 12 (6) </td> </tr> <tr> <td valign="top" colspan="9"> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </td> </tr> <tr> <td valign="top"> Cough </td> <td align="center" valign="top" colspan="2"> 1 (5)</td> <td align="center" valign="top"> 1 (3)</td> <td align="center" valign="top" colspan="2"> 2 (5) </td> <td align="center" valign="top"> 4 (8) </td> <td align="center" valign="top"> 5 (9) </td> <td align="center" valign="top"> 13 (7) </td> </tr> <tr> <td valign="top"> Dyspnea </td> <td align="center" valign="top" colspan="2"> 1 (5)</td> <td align="center" valign="top"> 6 (19)</td> <td align="center" valign="top" colspan="2"> 0 </td> <td align="center" valign="top"> 7 (15) </td> <td align="center" valign="top"> 4 (7) </td> <td align="center" valign="top"> 18 (9) </td> </tr> </tbody> </table>