FDA label 8b63a918-2f07-88ca-d484-a1b070d6ea7b

WARNINGS Continuous infusions of ULTIVA should be administered only by an infusion device. IV bolus administration of ULTIVA should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of ULTIVA should be administered over 30 to 60 seconds. Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia. Injections of ULTIVA should be made into IV tubing at or close to the venous cannula. Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later point in time. Failure to adequately clear the IV tubing to remove residual ULTIVA has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing. USE OF ULTIVA IS ASSOCIATED WITH APNEA AND RESPIRATORY DEPRESSION. ULTIVA SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF ANESTHETIC DRUGS AND THE MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS, INCLUDING RESPIRATORY AND CARDIAC RESUSCITATION OF PATIENTS IN THE AGE GROUP BEING TREATED. SUCH TRAINING MUST INCLUDE THE ESTABLISHMENT AND MAINTENANCE OF A PATENT AIRWAY AND ASSISTED VENTILATION. ULTIVA SHOULD NOT BE USED IN DIAGNOSTIC OR THERAPEUTIC PROCEDURES OUTSIDE THE MONITORED ANESTHESIA CARE SETTING. PATIENTS RECEIVING MONITORED ANESTHESIA CARE SHOULD BE CONTINUOUSLY MONITORED BY PERSONS NOT INVOLVED IN THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE. OXYGEN SATURATION SHOULD BE MONITORED ON A CONTINUOUS BASIS. RESUSCITATIVE AND INTUBATION EQUIPMENT, OXYGEN, AND AN OPIOID ANTAGONIST MUST BE READILY AVAILABLE. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of ULTIVA by 50% or by temporarily discontinuing the infusion. Skeletal muscle rigidity can be caused by ULTIVA and is related to the dose and speed of administration. ULTIVA may cause chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg administered over 30 to 60 seconds, or after infusion rates > 0.1 mcg/kg/min. Single doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of ULTIVA. Muscle rigidity induced by ULTIVA should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications. Muscle rigidity seen during the use of ULTIVA in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of ULTIVA. Resolution of muscle rigidity after discontinuing the infusion of ULTIVA occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered. ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.

ADVERSE EVENTS ULTIVA produces adverse events that are characteristic of µ-opioids, such as respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. These adverse events dissipate within minutes of discontinuing or decreasing the infusion rate of ULTIVA. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of these events. Adverse event information is derived from controlled clinical trials that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease. Adults Approximately 2770 adult patients were exposed to ULTIVA in controlled clinical trials. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 3. Each patient was counted once for each type of adverse event. Table 3. Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies* at the Recommended Doses † of ULTIVA Induction/Maintenance Postoperative Analgesia After Discontinuation ULTIVA Alfentanil/ Fentanyl ULTIVA Morphine ULTIVA Alfentanil /Fentanyl Adverse Event (n = 921) (n = 466) (n = 281) (n = 98) (n = 929) (n = 466) Nausea 8 (< 1%) 0 61 (22%) 15 (15%) 339 (36%) 202 (43%) Hypotension 178 (19%) 30 (6%) 0 0 16 (2%) 9 (2%) Vomiting 4 (< 1%) 1 (< 1%) 22 (8%) 5 (5%) 150 (16%) 91 (20%) Muscle rigidity 98 (11%)‡ 37 (8%) 7 (2%) 0 2 (< 1%) 1 (< 1%) Bradycardia 62 (7%) 24 (5%) 3 (1%) 3 (3%) 11 (1%) 6 (1%) Shivering 3 (< 1%) 0 15 (5%) 9 (9%) 49 (5%) 10 (2%) Fever 1 (< 1%) 0 2 (< 1%) 0 44 (5%) 9 (2%) Dizziness 0 0 1 (< 1%) 0 27 (3%) 9 (2%) Visual disturbance 0 0 0 0 24 (3%) 14 (3%) Headache 0 0 1 (< 1%) 1 (1%) 21 (2%) 8 (2%) Respiratory depression 1 (< 1%) 0 19 (7%) 4 (4%) 17 (2%) 20 (4%) Apnea 0 1 (< 1%) 9 (3%) 2 (2%) 2 (< 1%) 1 (< 1%) Pruritus 2 (< 1%) 0 7 (2%) 1 (1%) 22 (2%) 7 (2%) Tachycardia 6 (< 1%) 7 (2%) 0 0 10 (1%) 8 (2%) Postoperative pain 0 0 7 (2%) 0 4 (< 1%) 5 (1%) Hypertension 10 (1%) 7 (2%) 5 (2%) 3 (3%) 12 (1%) 8 (2%) Agitation 2 (< 1%) 0 3 (1%) 1 (1%) 6 (< 1%) 1 (< 1%) Hypoxia 0 0 1 (< 1%) 0 10 (1%) 7 (2%) * Does not include adverse events from cardiac studies or the neonatal study. See Tables 6, 7, and 8 for cardiac information. † See Table 10 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. Administration of ULTIVA in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%). ‡ Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is < 1% when remifentanil is administered concurrently or after a hypnotic induction agent. In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower. Table 4. Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies* at the Recommended Doses † of ULTIVA Induction/Maintenance Postoperative Analgesia After Discontinuation ULTIVA Alfentanil/ Fentanyl ULTIVA Morphine ULTIVA Alfentanil/ Fentanyl Adverse Event n Male 326 Female 595 Male 183 Female 283 Male 85 Female 196 Male 36 Female 62 Male 332 Female 597 Male 183 Female 283 Nausea 2% < 1% 0 0 12% 26% 8% 19% 22% 45% 30% 52% Hypotension 29% 14% 7% 6% 0 0 0 0 2% 2% 2% 2% Vomiting < 1% < 1% 0 < 1% 4% 10% 0 8% 5% 22% 8% 27% Muscle rigidity 17% 7% 14% 4% 6% 1% 0 0 < 1% < 1% 0 < 1% * Does not include adverse events from cardiac studies or the neonatal study. † See Table 10 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in monitored anesthesia care are given in Table 5. Table 5. Adverse Events Reported in ≥ 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses* of ULTIVA Adverse Event ULTIVA (n = 159) ULTIVA + 2 mg Midazolam † (n = 103) Propofol (0.5 mg/kg then 50 mcg/kg/min) (n = 63) Nausea 70 (44%) 19 (18%) 20 (32%) Vomiting 35 (22%) 5 (5%) 13 (21%) Pruritus 28 (18%) 16 (16%) 0 Headache 28 (18%) 12 (12%) 6 (10%) Sweating 10 (6%) 0 1 (2%) Shivering 8 (5%) 1 (< 1%) 1 (2%) Dizziness 8 (5%) 5 (5%) 1 (2%) Hypotension 7 (4%) 0 6 (10%) Bradycardia 6 (4%) 0 7 (11%) Respiratory depression 4 (3%) 1 (< 1%)* 0 Muscle rigidity 4 (3%) 0 1 (2%) Chills 2 (1%) 0 2 (3%) Flushing 2 (1%) 0 0 Warm sensation 2 (1%) 0 0 Pain at study IV site 2 (1%) 0 11 (17%) * See Table 12 for recommended doses. Administration of ULTIVA in excess of the recommended infusion rate (i.e., starting doses > 0.1 mcg/kg/min) resulted in a higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%). † With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. Other Adverse Events in Adults Patients The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below. Event frequencies are calculated as the number of patients who were administered ULTIVA and reported an event divided by the total number of patients exposed to ULTIVA in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1883 general anesthesia, n = 609 monitored anesthesia care). Incidence Less than 1% Digestive constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, heartburn, ileus. Cardiovascular various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope. Musculoskeletal muscle stiffness, musculoskeletal chest pain. Respiratory cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea. Nervous anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, sleep disorder, seizure, amnesia. Body as a Whole decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block. Skin rash, urticaria. Urogenital urine retention, oliguria, dysuria, urine incontinence. Infusion Site Reaction erythema, pruritus, rash. Metabolic and Nutrition abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level. Hematologic and Lymphatic anemia, lymphopenia, leukocytosis, thrombocytopenia. The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA in cardiac surgery are given in Tables 6, 7, and 8. These tables represent adverse events collected during discrete phases of cardiac surgery. Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur. Table 6. Adverse Events Reported in ≥ 1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA Induction/Intubation Maintenance Adverse Event ULTIVA (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) ULTIVA (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) Hypotension 18 (8%) 6 (3%) 7 (17%) 26 (11%) 6 (3%) 1 (2%) Bradycardia 9 (4%) 5 (3%) 0 3 (1%) 1 (< 1%) 1 (2%) Hypertension 3 (1%) 2 (1%) 2 (5%) 8 (4%) 6 (3%) 1 (2%) Constipation 9 (4%) 1 (< 1%) 3 (7%) 0 0 1 (2%) Muscle rigidity 2 (< 1%) 2 (1%) 0 5 (2%) 8 (5%) 0 Premature ventricular beats 1 (< 1%) 0 0 3 (1%) 1 (< 1%) 0 Myocardial ischemia 0 0 0 7 (3%) 8 (5%) 1 (2%) Atrial fibrillation 0 0 0 7 (3%) 3 (2%) 1 (2%) Decreased cardiac output 0 0 0 5 (2%) 1 (< 1%) 1 (2%) Tachycardia 0 1 (< 1%) 0 4 (2%) 2 (1%) 0 Coagulation disorder 0 0 0 4 (2%) 0 1 (2%) Arrhythmia 0 0 0 3 (1%) 0 0 Ventricular fibrillation 0 0 0 3 (1%) 1 (< 1%) 1 (2%) Postoperative complication 0 0 0 3 (1%) 0 0 Third degree heart block 0 0 0 2 (< 1%) 0 1 (2%) Hemorrhage 0 0 0 2 (< 1%) 0 1 (2%) Perioperative complication 0 0 0 2 (< 1%) 1 (< 1%) 1 (2%) Involuntary movement(s) 0 0 0 2 (< 1%) 3 (2%) 0 Thrombocytopenia 0 0 1 (2%) 0 0 0 Oliguria 0 0 0 0 3 (2%) 0 Anemia 0 0 0 2 (< 1%) 2 (1%) 0 * See Table 13 for recommended doses. Table 7. Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA Adverse Event ULTIVA n = 227 Fentanyl n = 176 Sufentanil n = 41 Hypertension 14 (6%) 8 (5%) 2 (5%) Hypotension 12 (5%) 3 (2%) 1 (2%) Tachycardia 9 (4%) 5 (3%) 0 Shivering 8 (4%) 3 (2%) 1 (2%) Nausea 8 (4%) 3 (2%) 0 Hemorrhage 4 (2%) 1 (< 1%) 1 (2%) Postoperative complication 4 (2%) 5 (3%) 2 (5%) Agitation 4 (2%) 1 (< 1%) 1 (2%) Ache 4 (2%) 0 0 Decreased cardiac output 3 (1%) 0 0 Arrhythmia 3 (1%) 0 0 Muscle rigidity 2 (< 1%) 1 (< 1%) 2 (5%) Bradycardia 2 (< 1%) 2 (1%) 0 Vomiting 1 (< 1%) 2 (1%) 0 Premature ventricular beats 1 (< 1%) 2 (1%) 0 Anemia 0 3 (2%) 0 Somnolence 0 0 1 (2%) Fever 0 2 (1%) 0 * See Table 13 for recommended doses. Table 8. Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses* of ULTIVA Adverse Event ULTIVA n = 227 Fentanyl n = 176 Sufentanil n = 41 Nausea 90 (40%) 63 (36%) 16 (39%) Vomiting 33 (15%) 26 (15%) 3 (7%) Fever 30 (13%) 15 (9%) 0 Atrial fibrillation 27 (12%) 33 (19%) 4 (10%) Constipation 20 (9%) 35 (20%) 3 (7%) Pleural effusion 11 (5%) 2 (1%) 2 (5%) Hypotension 8 (4%) 8 (5%) 1 (2%) Tachycardia 9 (4%) 15 (9%) 0 Postoperative complication 10 (4%) 6 (3%) 2 (5%) Oliguria 7 (3%) 7 (4%) 1 (2%) Confusion 7 (3%) 10 (6%) 5 (12%) Ache 6 (3%) 2 (1%) 0 Anxiety 6 (3%) 6 (3%) 0 Headache 6 (3%) 2 (1%) 0 Perioperative complication 5 (2%) 7 (4%) 1 (2%) Anemia 5 (2%) 5 (3%) 1 (2%) Agitation 5 (2%) 3 (2%) 1 (2%) Diarrhea 5 (2%) 1 (< 1%) 1 (2%) Edema 4 (2%) 6 (3%) 0 Dizziness 4 (2%) 3 (2%) 1 (2%) Postoperative infection 5 (2%) 7 (4%) 0 Hypoxia 4 (2%) 5 (3%) 0 Apnea 4 (2%) 1 (< 1%) 1 (2%) Hypertension 3 (1%) 3 (2%) 0 Shivering 3 (1%) 1 (< 1%) 0 Heartburn 3 (1%) 3 (2%) 0 Atrial flutter 3 (1%) 1 (< 1%) 0 Arrhythmia 3 (1%) 5 (3%) 0 Hallucinations 3 (1%) 3 (2%) 0 Pneumonia 3 (1%) 3 (2%) 1 (2%) Pharyngitis 3 (1%) 1 (< 1%) 1 (2%) Decreased mental acuity 3 (1%) 1 (< 1%) 0 Dyspnea 3 (1%) 1 (< 1%) 0 Cough 3 (1%) 0 0 Decreased cardiac output 1 (< 1%) 0 3 (7%) Renal insufficiency 1 (< 1%) 5 (3%) 0 Bradycardia 1 (< 1%) 1 (< 1%) 1 (2%) Urine retention 2 (< 1%) 3 (2%) 0 Cerebral infarction 2 (< 1%) 2 (1%) 1 (2%) Premature ventricular beats 2 (< 1%) 3 (2%) 0 Cerebral ischemia 1 (< 1%) 1 (< 1%) 1 (2%) Paresthesia 2 (< 1%) 2 (1%) 0 Seizure 2 (< 1%) 1 (< 1%) 1 (2%) Sleep disorder 1 (< 1%) 1 (< 1%) 1 (2%) Bronchospasm 1 (< 1%) 6 (3%) 0 Atelectasis 2 (< 1%) 3 (2%) 0 Respiratory depression 2 (< 1%) 3 (2%) 0 Pulmonary edema 1 (< 1%) 2 (1%) 0 Respiratory distress 2 (< 1%) 0 1 (2%) Hyperkalemia 2 (< 1%) 3 (2%) 0 Electrolyte disorder 0 3 (2%) 0 Chest congestion 0 3 (2%) 0 Hemoptysis 0 2 (1%) 0 Facial ptosis 0 2 (1%) 0 Hemorrhage 0 2 (1%) 0 Hematuria 0 1 (< 1%) 1 (2%) Visual disturbance(s) 0 1 (< 1%) 1 (2%) Hypokalemia 0 2 (1%) 0 Exacerbation of renal failure 0 0 1 (2%) Blood in stool 0 0 1 (2%) First degree heart block 0 0 1 (2%) Pericarditis 0 0 1 (2%) * See Table 13 for recommended doses. Pediatrics ULTIVA has been studied in 342 pediatric patients in controlled clinical trials for maintenance of general anesthesia. In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA are given in Table 9. Each patient was counted once for each type of adverse event. There were no adverse events ≥ 1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies. Table 9. Adverse Events Reported in ≥ 1% of Pediatric Patients Receiving ULTIVA in General Anesthesia Studies at the Recommended Doses* of ULTIVA Recovery Follow-up ** Adverse Event ULTIVA (n = 342) Fentanyl (n = 103) Bupivacaine (n = 86) ULTIVA (n = 342) Fentanyl (n = 103) Bupivacaine (n = 86) Vomiting 40 (12%) 9 (9%) 10 (12%) 56 (16%) 8 (8%) 12 (14%) Nausea 23 (8%) 7 (7%) 1 (1%) 17 (6%) 6 (6%) 5 (6%) Shivering 9 (3%) 0 0 0 0 0 Rhonchi 8 (3%) 2 (2%) 0 0 0 0 Postoperative complication 5 (2%) 2 (2%) 0 4 ( 1%) 0 0 Stridor 4 (1%) 2 (2%) 0 0 0 0 Cough 4 (1%) 1 (< 1%) 0 0 0 0 * See Table 11 for recommended doses. ** In subjects receiving halothane (n=22), 10 (45%) experienced vomiting. Observed During Clinical Practice In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of remifentanil in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to remifentanil. Cardiovascular Asystole. Non-site Specific Anaphylactic/anaphylactoid responses, which in some cases have been severe (e.g., shock).

<table ID="table_3" width="100%"> <caption>Table 3. Adverse Events Reported in &#x2265; 1% of Adult Patients in General Anesthesia Studies* at the Recommended Doses^&#x2020; of ULTIVA</caption> <colgroup> <col width="17%"/> <col width="12%"/> <col width="14%"/> <col width="15%"/> <col width="14%"/> <col width="13%"/> <col width="13%"/> </colgroup> <tbody> <tr valign="bottom"> <td styleCode="Toprule" align="center"> </td> <td styleCode="Toprule" colspan="2" align="center"> <content styleCode="bold">Induction/Maintenance</content> </td> <td styleCode="Toprule" colspan="2" align="center"> <content styleCode="bold">Postoperative Analgesia</content> </td> <td styleCode="Toprule" colspan="2" align="center"> <content styleCode="bold">After Discontinuation</content> </td> </tr> <tr valign="top"> <td styleCode="Toprule" align="center"> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">ULTIVA</content> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">Alfentanil/ Fentanyl</content> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">ULTIVA</content> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">Morphine</content> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">ULTIVA</content> </td> <td styleCode="Toprule" align="center"> <content styleCode="bold">Alfentanil /Fentanyl</content> </td> </tr> <tr valign="top"> <td> <content styleCode="bold">Adverse Event</content> </td> <td align="center"> <content styleCode="bold">(n = 921)</content> </td> <td align="center"> <content styleCode="bold">(n = 466)</content> </td> <td align="center"> <content styleCode="bold">(n = 281)</content> </td> <td align="center"> <content styleCode="bold">(n = 98)</content> </td> <td align="center"> <content styleCode="bold">(n = 929)</content> </td> <td align="center"> <content styleCode="bold">(n = 466)</content> </td> </tr> <tr> <td>Nausea</td> <td align="center">8 (&lt; 1%)</td> <td align="center">0</td> <td align="center">61 (22%)</td> <td align="center">15 (15%)</td> <td align="center">339 (36%)</td> <td align="center">202 (43%)</td> </tr> <tr> <td>Hypotension</td> <td align="center">178 (19%)</td> <td align="center">30 (6%)</td> <td align="center">0</td> <td align="center">0</td> <td align="center">16 (2%)</td> <td align="center">9 (2%)</td> </tr> <tr> <td>Vomiting</td> <td align="center">4 (&lt; 1%)</td> <td align="center">1 (&lt; 1%)</td> <td align="center">22 (8%)</td> <td align="center">5 (5%)</td> <td align="center">150 (16%)</td> <td align="center">91 (20%)</td> </tr> <tr> <td>Muscle rigidity</td> <td align="center">98 (11%)&#x2021;</td> <td align="center">37 (8%)</td> <td align="center">7 (2%)</td> <td align="center">0</td> <td align="center">2 (&lt; 1%)</td> <td align="center">1 (&lt; 1%)</td> </tr> <tr> <td>Bradycardia</td> <td align="center">62 (7%)</td> <td align="center">24 (5%)</td> <td align="center">3 (1%)</td> <td align="center">3 (3%)</td> <td align="center">11 (1%)</td> <td align="center">6 (1%)</td> </tr> <tr> <td>Shivering</td> <td align="center">3 (&lt; 1%)</td> <td align="center">0</td> <td align="center">15 (5%)</td> <td align="center">9 (9%)</td> <td align="center">49 (5%)</td> <td align="center">10 (2%)</td> </tr> <tr> <td>Fever</td> <td align="center">1 (&lt; 1%)</td> <td align="center">0</td> <td align="center">2 (&lt; 1%)</td> <td align="center">0</td> <td align="center">44 (5%)</td> <td align="center">9 (2%)</td> </tr> <tr> <td>Dizziness</td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (&lt; 1%)</td> <td align="center">0</td> <td align="center">27 (3%)</td> <td align="center">9 (2%)</td> </tr> <tr> <td>Visual disturbance</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">24 (3%)</td> <td align="center">14 (3%)</td> </tr> <tr> <td>Headache </td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (&lt; 1%)</td> <td align="center">1 (1%)</td> <td align="center">21 (2%)</td> <td align="center">8 (2%)</td> </tr> <tr> <td>Respiratory depression</td> <td align="center">1 (&lt; 1%)</td> <td align="center">0</td> <td align="center">19 (7%)</td> <td align="center">4 (4%)</td> <td align="center">17 (2%)</td> <td align="center">20 (4%)</td> </tr> <tr> <td>Apnea</td> <td align="center">0</td> <td align="center">1 (&lt; 1%)</td> <td align="center">9 (3%)</td> <td align="center">2 (2%)</td> <td align="center">2 (&lt; 1%)</td> <td align="center">1 (&lt; 1%)</td> </tr> <tr> <td>Pruritus</td> <td align="center">2 (&lt; 1%)</td> <td align="center">0</td> <td align="center">7 (2%)</td> <td align="center">1 (1%)</td> <td align="center">22 (2%)</td> <td align="center">7 (2%)</td> </tr> <tr> <td>Tachycardia</td> <td align="center">6 (&lt; 1%)</td> <td align="center">7 (2%)</td> <td align="center">0</td> <td align="center">0</td> <td align="center">10 (1%)</td> <td align="center">8 (2%)</td> </tr> <tr> <td>Postoperative pain</td> <td align="center">0</td> <td align="center">0</td> <td align="center">7 (2%)</td> <td align="center">0</td> <td align="center">4 (&lt; 1%)</td> <td align="center">5 (1%)</td> </tr> <tr> <td>Hypertension</td> <td align="center">10 (1%)</td> <td align="center">7 (2%)</td> <td align="center">5 (2%)</td> <td align="center">3 (3%)</td> <td align="center">12 (1%)</td> <td align="center">8 (2%)</td> </tr> <tr> <td>Agitation</td> <td align="center">2 (&lt; 1%)</td> <td align="center">0</td> <td align="center">3 (1%)</td> <td align="center">1 (1%)</td> <td align="center">6 (&lt; 1%)</td> <td align="center">1 (&lt; 1%)</td> </tr> <tr> <td styleCode="Botrule">Hypoxia</td> <td styleCode="Botrule" align="center">0</td> <td styleCode="Botrule" align="center">0</td> <td styleCode="Botrule" align="center">1 (&lt; 1%)</td> <td styleCode="Botrule" align="center">0</td> <td styleCode="Botrule" align="center">10 (1%)</td> <td styleCode="Botrule" align="center">7 (2%)</td> </tr> <tr> <td styleCode="Toprule" colspan="7">* Does not include adverse events from cardiac studies or the neonatal study. See Tables 6, 7, and 8 for cardiac information. &#x2020; See Table 10 for recommended doses. <content styleCode="bold">Not all doses of ULTIVA were equipotent to the comparator opioid. Administration of ULTIVA in excess of the recommended dose (i.e., doses &gt; 1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%). </content> &#x2021; Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is &lt; 1% when remifentanil is administered concurrently or after a hypnotic induction agent.</td> </tr> </tbody> </table>

<table ID="table_4" width="100%"> <caption>Table 4. Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies* at the Recommended Doses^&#x2020; of ULTIVA</caption> <colgroup> <col width="10%"/> <col width="7%"/> <col width="7%"/> <col width="5%"/> <col width="7%"/> <col width="5%"/> <col width="6%"/> <col width="6%"/> <col width="7%"/> <col width="6%"/> <col width="7%"/> <col width="6%"/> <col width="7%"/> </colgroup> <tbody> <tr valign="bottom"> <td styleCode="Toprule Botrule" align="center"> </td> <td styleCode="Toprule Botrule" colspan="4" align="center"> <content styleCode="bold">Induction/Maintenance</content> </td> <td styleCode="Toprule Botrule" colspan="4" align="center"> <content styleCode="bold">Postoperative Analgesia</content> </td> <td styleCode="Toprule Botrule" colspan="4" align="center"> <content styleCode="bold">After Discontinuation</content> </td> </tr> <tr valign="bottom"> <td align="center" valign="top"> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">ULTIVA</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Alfentanil/ Fentanyl</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">ULTIVA </content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Morphine</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">ULTIVA</content> </td> <td colspan="2" align="center" valign="top"> <content styleCode="bold">Alfentanil/ Fentanyl</content> </td> </tr> <tr valign="top"> <td> <content styleCode="bold">Adverse</content> <content styleCode="bold">Event</content> <content styleCode="bold">n</content> </td> <td align="center"> <content styleCode="bold">Male 326</content> </td> <td align="center"> <content styleCode="bold">Female 595</content> </td> <td align="center"> <content styleCode="bold">Male 183</content> </td> <td align="center"> <content styleCode="bold">Female 283</content> </td> <td align="center"> <content styleCode="bold">Male 85</content> </td> <td align="center"> <content styleCode="bold">Female 196</content> </td> <td align="center"> <content styleCode="bold">Male 36</content> </td> <td align="center"> <content styleCode="bold">Female 62</content> </td> <td align="center"> <content styleCode="bold">Male 332</content> </td> <td align="center"> <content styleCode="bold">Female 597</content> </td> <td align="center"> <content styleCode="bold">Male 183</content> </td> <td align="center"> <content styleCode="bold">Female 283</content> </td> </tr> <tr valign="bottom"> <td>Nausea</td> <td align="center">2%</td> <td align="center">&lt; 1%</td> <td align="center">0</td> <td align="center">0</td> <td align="center">12%</td> <td align="center">26%</td> <td align="center">8%</td> <td align="center">19%</td> <td align="center">22%</td> <td align="center">45%</td> <td align="center">30%</td> <td align="center">52%</td> </tr> <tr valign="bottom"> <td>Hypotension</td> <td align="center">29%</td> <td align="center">14%</td> <td align="center">7%</td> <td align="center">6%</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">2%</td> <td align="center">2%</td> <td align="center">2%</td> <td align="center">2%</td> </tr> <tr valign="bottom"> <td>Vomiting</td> <td align="center">&lt; 1%</td> <td align="center">&lt; 1%</td> <td align="center">0</td> <td align="center">&lt; 1%</td> <td align="center">4%</td> <td align="center">10%</td> <td align="center">0</td> <td align="center">8%</td> <td align="center">5%</td> <td align="center">22%</td> <td align="center">8%</td> <td align="center">27%</td> </tr> <tr valign="bottom"> <td>Muscle rigidity</td> <td align="center"> 17%</td> <td align="center"> 7%</td> <td align="center"> 14%</td> <td align="center"> 4%</td> <td align="center"> 6%</td> <td align="center"> 1%</td> <td align="center"> 0</td> <td align="center"> 0</td> <td align="center">&lt; 1%</td> <td align="center">&lt; 1%</td> <td align="center">0</td> <td align="center">&lt; 1%</td> </tr> <tr> <td styleCode="Toprule" colspan="13">* Does not include adverse events from cardiac studies or the neonatal study. &#x2020; See Table 10 for recommended doses. <content styleCode="bold">Not all doses of ULTIVA were equipotent to the comparator opioid.</content> </td> </tr> </tbody> </table>

<table ID="table_5" width="100%"> <caption>Table 5. Adverse Events Reported in &#x2265; 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses* of ULTIVA</caption> <colgroup> <col width="24%"/> <col width="25%"/> <col width="25%"/> <col width="24%"/> </colgroup> <tbody> <tr valign="top"> <td styleCode="Toprule Botrule"> <content styleCode="bold">Adverse Event</content> </td> <td styleCode="Toprule Botrule" align="center"> <content styleCode="bold">ULTIVA (n = 159)</content> </td> <td styleCode="Toprule Botrule" align="center"> <content styleCode="bold">ULTIVA + 2 mg Midazolam^&#x2020; (n = 103)</content> </td> <td styleCode="Toprule Botrule" align="center"> <content styleCode="bold">Propofol (0.5 mg/kg then 50 mcg/kg/min) (n = 63)</content> </td> </tr> <tr> <td>Nausea</td> <td align="center">70 (44%)</td> <td align="center">19 (18%)</td> <td align="center">20 (32%)</td> </tr> <tr> <td>Vomiting</td> <td align="center">35 (22%)</td> <td align="center">5 (5%)</td> <td align="center">13 (21%)</td> </tr> <tr> <td>Pruritus</td> <td align="center">28 (18%)</td> <td align="center">16 (16%)</td> <td align="center">0</td> </tr> <tr> <td>Headache</td> <td align="center">28 (18%)</td> <td align="center">12 (12%)</td> <td align="center">6 (10%)</td> </tr> <tr> <td>Sweating</td> <td align="center">10 (6%)</td> <td align="center">0</td> <td align="center">1 (2%)</td> </tr> <tr> <td>Shivering</td> <td align="center">8 (5%)</td> <td align="center">1 (&lt; 1%)</td> <td align="center">1 (2%)</td> </tr> <tr> <td>Dizziness</td> <td align="center">8 (5%)</td> <td align="center">5 (5%)</td> <td align="center">1 (2%)</td> </tr> <tr> <td>Hypotension</td> <td align="center">7 (4%)</td> <td align="center">0</td> <td align="center">6 (10%)</td> </tr> <tr> <td>Bradycardia</td> <td align="center">6 (4%)</td> <td align="center">0</td> <td align="center">7 (11%)</td> </tr> <tr> <td>Respiratory depression</td> <td align="center">4 (3%)</td> <td align="center">1 (&lt; 1%)*</td> <td align="center">0</td> </tr> <tr> <td>Muscle rigidity</td> <td align="center">4 (3%)</td> <td align="center">0</td> <td align="center">1 (2%)</td> </tr> <tr> <td>Chills</td> <td align="center">2 (1%)</td> <td align="center">0</td> <td align="center">2 (3%)</td> </tr> <tr> <td>Flushing</td> <td align="center">2 (1%)</td> <td align="center">0</td> <td align="center">0</td> </tr> <tr> <td>Warm sensation</td> <td align="center">2 (1%)</td> <td align="center">0</td> <td align="center">0</td> </tr> <tr> <td>Pain at study IV site</td> <td align="center">2 (1%)</td> <td align="center">0</td> <td align="center">11 (17%)</td> </tr> <tr> <td styleCode="Toprule" colspan="4">* See Table 12 for recommended doses. <content styleCode="bold">Administration of ULTIVA in excess of the recommended infusion rate (i.e., starting doses &gt; 0.1 mcg/kg/min) resulted in a higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%).</content> &#x2020; With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.</td> </tr> </tbody> </table>