FDA label 76e8e776-4029-4db8-b604-b50cf576f34e

WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME Life-Threatening Respiratory Depression Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with OTFC, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of OTFC or following a dose increase [ see Warnings and Precautions ( 5.1 )] . The substitution of OTFC for any other fentanyl product may result in fatal overdose [se e Warnings and Precautions ( 5.2 )] . Due to the risk of respiratory depression, OTFC is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients [ see Contraindications ( 4 )]. Accidental Ingestion Accidental ingestion of even one dose of OTFC, especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions ( 5.2 )]. Death has been reported in children who have accidentally ingested OTFC. OTFC must be kept out of reach of children [ see Patient Counseling Information and How Supplied/Storage and Handling ( 16 ) ]. Cytochrome P450 3A4 Interaction The concomitant use of OTFC with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving OTFC and any CYP3A4 inhibitor or inducer [ see Warnings and Precautions ( 5.3 ), Drug Interactions (7), Clinical Pharmacology ( 12.3 )]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [ see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] . • Reserve concomitant prescribing of OTFC and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. • Limit dosages and durations to the minimum required. • Follow patients for signs and symptoms of respiratory depression and sedation. Risk of Medication Errors 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 and that could result in fatal overdose [ see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.5 )]. • When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to OTFC [ see Dosage and Administration ( 2.1 )]. • When dispensing, do not substitute an OTFC prescription for other fentanyl products. Addiction, Abuse, and Misuse OTFC exposes 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 OTFC, and monitor all patients regularly for the development of these behaviors and conditions [se e Warnings and Precautions ( 5.6 )]. Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for misuse, abuse, addiction, and overdose, OTFC is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program [ see Warnings and Precautions ( 5.7 )]. Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483. Neonatal Opioid Withdrawal Syndrome Prolonged use of OTFC 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 ( 5.8 )]. WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME See full prescribing information for complete boxed warning. • Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. Due to the risk of fatal respiratory depression, OTFC is contraindicated in opioid non-tolerant patients ( 1 ) and in management of acute or postoperative pain, including headache/migraines. ( 5.1 ) • Accidental ingestion of OTFC, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal. ( 2.7 , 5.2 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl. ( 5.3 , 7, 12.3 ) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.4 , 7 ) • When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl product to OTFC. ( 5.5 ) • When dispensing, do not substitute with any other fentanyl products. ( 5.5 ) • OTFC exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor closely for these behaviors and conditions. ( 5.6 ) • OTFC is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program. ( 5.7 ) • Prolonged use of OTFC during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.8 ).

5 WARNINGS AND PRECAUTIONS • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.9 ) • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue OTFC if serotonin syndrome is suspected. ( 5.10 ) • Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) • Severe Hypotension : Monitor during dosage initiation and titration. Avoid use of OTFC in patients with circulatory shock. ( 5.12 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of OTFC in patients with impaired consciousness or coma. ( 5.13 ) 5.1 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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 OTFC, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of OTFC. To reduce the risk of respiratory depression, proper dosing and titration of OTFC are essential [s ee Dosage and Administration ( 2 )] . Overestimating the OTFC dosage can result in a fatal overdose with the first dose. The substitution of OTFC for any other fentanyl product may result in fatal overdose [ see Warnings and Precautions ( 5.5 )]. OTFC could be fatal to individuals for whom it is not prescribed and for those who are not opioid-tolerant. Accidental ingestion of even one dose of OTFC, especially by children, can result in respiratory depression and death due to an overdose of fentanyl [see Warnings and Precautions ( 5.1 , 5.2 )] . 5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion or Exposure Death has been reported in children who have accidentally ingested OTFC. Patients and their caregivers must be informed that OTFC contains a medicine in an amount which can be fatal to a child. Healthcare providers 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. 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 Patient Counseling Information ( 17 )] . Detailed instructions for the proper storage, administration, disposal, and important instructions for managing an overdose of OTFC are provided in the OTFC Medication Guide . Encourage patients to read this information in its entirety and give them an opportunity to have their questions answered. 5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of OTFC with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions ( 5.1 )] , particularly when an inhibitor is added after a stable dose of OTFC is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in OTFC-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using OTFC with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in OTFC-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of OTFC until stable drug effects are achieved [see Drug Interactions ( 7 )] . Concomitant use of OTFC with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using OTFC with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [ see Drug Interactions ( 7 )]. 5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (including Alcohol) Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OTFC with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [s ee Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when OTFC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [ see Drug Interactions ( 7 ) and Patient Counseling Information ( 17 )] . 5.5 Risk of Medication Errors 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 other transmucosal immediate release fentanyl (TIRF) formulations. When dispensing, do not substitute an OTFC prescription for any other TIRF formulation under any circumstances. Other TIRF formulations and OTFC are not equivalent. Substantial differences exist in the pharmacokinetic profile of OTFC compared to other fentanyl products including other TIRF formulations 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 ( 2.3 )] . 5.6 Addiction, Abuse, and Misuse OTFC contains fentanyl, a Schedule II controlled substance. As an opioid, OTFC exposes users to the risks of addiction, abuse, and misuse [se e Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OTFC. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OTFC, and monitor all patients receiving OTFC for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OTFC, but use in such patients necessitates intensive counseling about the risks and proper use of OTFC along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing OTFC. 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. 5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for misuse, abuse, addiction, and overdose [ see Warnings and Precautions ( 5.6 )], OTFC is available only through a restricted program called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe for outpatient use, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of OTFC, patient and prescriber enrollment is not required. Required components of the TIRF REMS Access program are: • Healthcare professionals, who prescribe OTFC for outpatient use, must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements. • To receive OTFC, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement. • Pharmacies that dispense OTFC must enroll in the program, and agree to comply with the REMS requirements. • Wholesalers and distributors that distribute OTFC must enroll in the program, and distribute only to authorized pharmacies. • Further information, including a list of qualified pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483. 5.8 Neonatal Opioid Withdrawal Syndrome Prolonged use of OTFC during pregnancy can result in withdrawal 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [s ee Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )] . 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of OTFC in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: OTFC-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OTFC [see Warnings and Precautions ( 5.1 )]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [s ee Warnings and Precautions ( 5.1 )]. Monitor such patients closely, particularly when initiating and titrating OTFC and when OTFC is given concomitantly with other drugs that depress respiration [ see Warnings and Precautions ( 5.1 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of OTFC with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions ( 7 )] . This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue OTFC if serotonin syndrome is suspected. 5.11 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.12 Severe Hypotension OTFC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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 )] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of OTFC. In patients with circulatory shock, OTFC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OTFC in patients with circulatory shock. 5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OTFC may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OTFC. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OTFC in patients with impaired consciousness or coma. 5.14 Risks of Use in Patients with Gastrointestinal Conditions OTFC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The fentanyl in OTFC may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. 5.15 Increased Risk of Seizures in Patients with Seizure Disorders The fentanyl in OTFC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OTFC therapy. 5.16 Risks of Driving and Operating Machinery OTFC may impair the mental 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 OTFC and know how they will react to the medication. 5.17 Cardiac Disease Intravenous fentanyl may produce bradycardia. Therefore, use OTFC with caution in patients with bradyarrhythmias. 5.18 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 [see Drug Interactions ( 7 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.1 )] • Interactions with Benzodiazepines and Other CNS Depressants [s ee Warnings and Precautions ( 5.4 )] • Addiction, Abuse, and Misuse [s ee Warnings and Precautions ( 5.6 )] • Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions ( 5.8 )] • Serotonin Syndrome [s ee Warnings and Precautions ( 5.10 )] • Adrenal Insufficiency [s ee Warnings and Precautions ( 5.11 )] • Severe Hypotension [see Warnings and Precautions ( 5.12 )] • Gastrointestinal Adverse Reactions [s ee Warnings and Precautions ( 5.14 )] • Seizures [see Warnings and Precautions ( 5.15 )] Most common (frequency ≥ 5%): nausea, dizziness, somnolence, vomiting, asthenia, and headache, dyspnea, constipation, anxiety, confusion, depression, rash and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Oral Transmucosal Fentanyl Citrate (OTFC) 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 most serious adverse reactions associated with OTFC are respiratory depression (potentially leading to apnea or respiratory arrest), circulatory depression, hypotension, and shock. 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. 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. Table 1 lists, by dose groups, adverse reactions with an overall frequency of 1% or greater that occurred during titration. 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 (n=230) 800- 1400 mcg (n=138) 1600 mcg (n=54) > 1600 mcg (n=41) Any Dose* (n=254) 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 Digestive: Diarrhea, dyspepsia, flatulence Metabolic and Nutritional: Peripheral edema, dehydration Nervous: Hypesthesia, migraine 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: bone pain Cardiovascular: Deep thrombophlebitis, hypertension, hypotension Digestive: Anorexia, eructation, 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. 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 (n=98) 800- 1400 mcg (n=83) 1600 mcg (n=53) >1600 mcg (n=27) Any Dose* (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, 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, migraine 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, 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 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OTFC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. Digestive: • Dental decay : Dental decay, including dental caries, tooth loss, and gum line erosion. Nervous System Disorders: • Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Endocrine Disorders: • Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. • Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids. Immune System Disorders: • Anaphylaxis : Anaphylaxis has been reported with ingredients contained in OTFC. General Disorders and Administration Site Conditions: Application site reactions including irritation, pain, and ulcer, and drug withdrawal syndrome.

<table ID="_Refid_00180928-021f-4373-b82d-aaddc9c1f" width="100%"> <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 width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Dose Group</content> </paragraph> </td> <td align="center" colspan="5" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>Percentage of Patients Reporting Event</paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">200-</content> <content styleCode="bold">600 mcg (n=230)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">800-</content> <content styleCode="bold">1400 mcg (n=138)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">1600</content> <content styleCode="bold"> mcg </content> </paragraph> <paragraph> <content styleCode="bold">(n=54)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">&gt; 1600</content> <content styleCode="bold">mcg </content> </paragraph> <paragraph> <content styleCode="bold">(n=41)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Any Dose*</content> </paragraph> <paragraph> <content styleCode="bold">(n=254)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body As A Whole</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Accidental Injury</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Digestive</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Confusion</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Abnormal Gait</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dry Mouth </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nervousness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vasodilatation</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Hallucinations</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Thinking Abnormal </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vertigo</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Pruritus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Sweating</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Special Senses</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Abnormal Vision</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_3b6b93c3-3e65-482e-9ec1-4b5abf856" width="100%"> <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 width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Dose Group</content> </paragraph> </td> <td align="center" colspan="5" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Percentage of Patients Reporting Event</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">200-</content> <content styleCode="bold">600 mcg (n=98)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">800-</content> <content styleCode="bold">1400 mcg (n=83)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">1600</content> <content styleCode="bold"> mcg </content> </paragraph> <paragraph> <content styleCode="bold">(n=53)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">&gt;1600</content> <content styleCode="bold">mcg </content> </paragraph> <paragraph> <content styleCode="bold">(n=27)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Any Dose*</content> </paragraph> <paragraph> <content styleCode="bold">(n=152)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Body As A Whole</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>38</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Accidental Injury</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypertonia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Digestive</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>45</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>31</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Intestinal Obstruction</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Cardiovascular</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypertension</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nervous</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Confusion</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abnormal Gait</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dry Mouth</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nervousness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Stupor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vasodilatation</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Thinking Abnormal</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abnormal Dreams</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Convulsion</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Myoclonus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vertigo</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Respiratory</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>22</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Sweating</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Pruritus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Special Senses</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abnormal Vision</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Urogenital</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Urinary Retention</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> </tbody> </table>