FDA label 29e7bcf3-b975-45e2-9917-4f1d34ea1dbc

WARNING: ADDICTION, ABUSE, AND MISUSE Addiction, Abuse, and Misuse Remifentanil Hydrochloride for injection 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 Remifentanil Hydrochloride for injection [see Warnings and Precautions (5.1) ] . WARNING: ADDICTION, ABUSE, AND MISUSE See full prescribing information for complete boxed warning. REMIFENTANIL HYDROCHLORIDE FOR INJECTION exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Respiratory Depression in Spontaneously Breathing Patients : Monitor closely, particularly during initiation and titration. ( 5.2 ) Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or other CNS Depressants : Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of Remifentanil Hydrochloride for injection with benzodiazepines or other CNS depressants ( 5.3 ) Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Remifentanil Hydrochloride for injection if serotonin syndrome is suspected. ( 5.4 ) Administration : Continuous infusions of Remifentanil Hydrochloride for injection should be administered only by an infusion device. ( 5.5 ) Skeletal Muscle Rigidity : is related to the dose and speed of administration. Muscle rigidity induced by Remifentanil Hydrochloride for injection should be managed in the context of the patient's clinical condition. ( 5.6 ) Potential Inactivation by Nonspecific Esterases in Blood Products : Remifentanil Hydrochloride for injection should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. ( 5.7 ) Bradycardia : Monitor heart rate during dosage initiation and titration. It is responsive to ephedrine or anticholinergic drugs ( 5.8 ) Hypotension : Monitor blood pressure during dosage initiation and titration. It is responsive to decreases in the administration of Remifentanil Hydrochloride for injection or to IV fluids or catecholamine administration ( 5.9 ) Intraoperative Awareness : Inoperative awareness has been reported in patients under 55 years of age when Remifentanil Hydrochloride for injection has been administered with propofol infusion rates of ≤ 75 mcg/kg/min ( 5.10 ) Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. ( 5.11 ) Risks of Use in Patients with Biliary Tract Disease : Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. ( 5.12 ) Increased Risk of Seizures in Patients with Seizure Disorders : Monitor patients with a history of seizure disorders for worsened seizure control during Remifentanil Hydrochloride for injection therapy. ( 5.13 ) Rapid Offset of Action : Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. ( 5.14 ) 5.1 Addiction, Abuse, and Misuse Remifentanil Hydrochloride for injection contains remifentanil, a Schedule II controlled substance. As an opioid, Remifentanil Hydrochloride for injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling Remifentanil Hydrochloride for injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Respiratory Depression in Spontaneously Breathing Patients 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. Remifentanil Hydrochloride for injection 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 respiration 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. Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of Remifentanil Hydrochloride for injection by 50% or by temporarily discontinuing the infusion [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 Remifentanil Hydrochloride for injection, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially when initiating therapy with and following dosage increases of Remifentanil Hydrochloride for injection. Remifentanil Hydrochloride for injection 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. 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 Remifentanil Hydrochloride for injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression. Monitor such patients closely including vital signs, particularly when initiating and titrating Remifentanil Hydrochloride for injection and when Remifentanil Hydrochloride for injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Remifentanil Hydrochloride for injection are essential [see Dosage and Administration (2.11) ]. 5.3 Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of Remifentanil Hydrochloride for injection with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7) ] . 5.4 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Remifentanil Hydrochloride for injection 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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 Remifentanil Hydrochloride for injection if serotonin syndrome is suspected. 5.5 Administration Continuous infusions of Remifentanil Hydrochloride for injection should be administered only by an infusion device. IV bolus administration of Remifentanil Hydrochloride for injection should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of Remifentanil Hydrochloride for injection should be administered over 30 to 60 seconds. Interruption of an infusion of Remifentanil Hydrochloride for injection 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 Remifentanil Hydrochloride for injection at recommended doses. Discontinuation of an infusion of Remifentanil Hydrochloride for injection should be preceded by the establishment of adequate postoperative analgesia. Injections of Remifentanil Hydrochloride for injection should be made into IV tubing at or close to the venous cannula. Upon discontinuation of Remifentanil Hydrochloride for injection, the IV tubing should be cleared to prevent the inadvertent administration of Remifentanil Hydrochloride for injection at a later point in time. Failure to adequately clear the IV tubing to remove residual Remifentanil Hydrochloride for injection 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. 5.6 Skeletal Muscle Rigidity Skeletal muscle rigidity can be caused by Remifentanil Hydrochloride for injection and is related to the dose and speed of administration. Remifentanil Hydrochloride for injection 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 Remifentanil Hydrochloride for injection. Muscle rigidity induced by Remifentanil Hydrochloride for injection 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 and can be treated by decreasing the rate or discontinuing the infusion of Remifentanil Hydrochloride for injection or by administering a neuromuscular blocking agent. The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status. Muscle rigidity seen during the use of Remifentanil Hydrochloride for injection in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of Remifentanil Hydrochloride for injection. Resolution of muscle rigidity after discontinuing the infusion of Remifentanil Hydrochloride for injection occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered. 5.7 Potential Inactivation by Nonspecific Esterases in Blood Products Remifentanil Hydrochloride for injection should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. 5.8 Bradycardia Bradycardia has been reported with Remifentanil Hydrochloride for injection and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate. 5.9 Hypotension Hypotension has been reported with Remifentanil Hydrochloride for injection and is responsive to decreases in the administration of Remifentanil Hydrochloride for injection or to IV fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration. 5.10 Intraoperative Awareness Intraoperative awareness has been reported in patients under 55 years of age when Remifentanil Hydrochloride for injection has been administered with propofol infusion rates of ≤ 75 mcg/kg/min. 5.11 Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Remifentanil Hydrochloride for injection may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Remifentanil Hydrochloride for injection. Opioids may also obscure the clinical course in a patient with a head injury. 5.12 Risks of Use in Patients with Biliary Tract Disease The remifentanil in Remifentanil Hydrochloride for injection 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. 5.13 Increased Risk of Seizures in Patients with Seizure Disorders The remifentanil in Remifentanil Hydrochloride for injection 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 Remifentanil Hydrochloride for injection therapy. 5.14 Rapid Offset of Action Analgesic activity will subside within 5 to 10 minutes after discontinuation of administration of Remifentanil Hydrochloride for injection. However, respiratory depression may continue in some patients for up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of Remifentanil Hydrochloride for injection.

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Respiratory Depression in Spontaneously Breathing Patients [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions (5.3) ] Serotonin Syndrome [see Warnings and Precautions (5.4) ] Skeletal Muscle Rigidity [see Warnings and Precautions (5.6) ] Bradycardia [see Warnings and Precautions (5.8) ] Hypotension [see Warnings and Precautions (5.9) ] Biliary Tract Disease [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Navinta LLC at +1-609-883-1135 or FDA at +1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Adverse event information is derived from controlled clinical studies 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 2,770 adult patients were exposed to Remifentanil Hydrochloride for injection in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of Remifentanil Hydrochloride for injection are given in Table 11. Each patient was counted once for each type of adverse event. Table 11: Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies Does not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information. at the Recommended Doses See Table 1 for recommended doses. Not all doses of Remifentanil Hydrochloride for injection were equipotent to the comparator opioid. Administration of Remifentanil Hydrochloride for injection in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg) resulted in higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%). of Remifentanil Hydrochloride for injection Adverse Event Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil Hydrochloride for injection (n = 921) Alfentanil/ Fentanyl (n = 466) Remifentanil Hydrochloride for injection (n = 281) Morphine (n = 98) Remifentanil Hydrochloride for injection (n = 929) Alfentanil /Fentanyl (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%) 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. 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%) In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower. Table 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies Does not include adverse events from cardiac studies or the neonatal study. at the Recommended Doses See Table 1 for recommended doses. Not all doses of Remifentanil Hydrochloride for injection were equipotent to the comparator opioid. of Remifentanil Hydrochloride for injection Adverse Event n Induction Maintenance Postoperative Analgesia After Discontinuation Remifentanil Hydrochloride for injection Alfentanil/ Fentanyl Remifentanil Hydrochloride for injection Morphine Remifentanil Hydrochloride for injection Alfentanil/ Fentanyl 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% The frequencies of adverse events from the clinical studies at the recommended doses of Remifentanil Hydrochloride for injection in monitored anesthesia care are given in Table 13. Table 13: Adverse Events Reported in ≥ 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses See Table 3 for recommended doses. Administration of Remifentanil Hydrochloride for injection 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%). of Remifentanil Hydrochloride for injection Adverse Event Remifentanil Hydrochloride for injection (n = 159) Remifentanil Hydrochloride for injection + 2 mg Midazolam With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. (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%) Other Adverse Events in Adult 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 Remifentanil Hydrochloride for injection and reported an event divided by the total number of patients exposed to Remifentanil Hydrochloride for injection in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1,883 general anesthesia, n = 609 monitored anesthesia care). Incidence Less than 1% Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, 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, 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 Remifentanil Hydrochloride for injection in cardiac surgery are given in Tables 14, 15, and 16. 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 14: Adverse Events Reported in ≥ 1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses See Table 4 for recommended doses. of Remifentanil Hydrochloride for injection Induction/Intubation Maintenance Adverse Event Remifentanil Hydrochloride for injection (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) Remifentanil Hydrochloride for injection (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 Table 15: Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses See Table 4 for recommended doses. of Remifentanil Hydrochloride for injection Adverse Event Remifentanil Hydrochloride for injection 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 Hemorrahage 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 Table 16: Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses See Table 4 for recommended doses. of Remifentanil Hydrochloride for injection Adverse Event Remifentanil Hydrochloride for injection 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%) Pediatrics Remifentanil Hydrochloride for injection has been studied in 342 pediatric patients in controlled clinical studies 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 Remifentanil Hydrochloride for injection are given in Table 17. 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 17: Adverse Events Reported in ≥ 1% of Pediatric Patients Receiving Remifentanil Hydrochloride for injection in General Anesthesia Studies at the Recommended Doses See Table 2 for recommended doses. of Remifentanil Hydrochloride for injection Recovery Follow-up In subjects receiving halothane (n = 22), 10 (4 5%) experienced vomiting. Adverse Event Remifentanil Hydrochloride for injection (n =342) Fentanyl (n = 103) Bupivacaine (n = 86) Remifentanil Hydrochloride for injection (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 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of remifentanil. 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 causal relationship to drug exposure. Cardiovascular: Asystole Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Remifentanil Hydrochloride for injection.

<table ID="ID411" width="100%" styleCode="Noautorules"><caption> Table 11: Adverse Events Reported in &#x2265; 1% of Adult Patients in General Anesthesia Studies<footnote ID="ID4110"> Does not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information.</footnote> at the Recommended Doses<footnote ID="ID4111">See Table 1 for recommended doses. Not all doses of Remifentanil Hydrochloride for injection were equipotent to the comparator opioid. Administration of Remifentanil Hydrochloride for injection in excess of the recommended dose (i.e., doses &gt; 1 and up to 20 mcg/kg) resulted in higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%).</footnote><sup/>of Remifentanil Hydrochloride for injection </caption><col width="15%"/><col width="17%"/><col width="12%"/><col width="15%"/><col width="11%"/><col width="15%"/><col width="13%"/><tbody><tr><td rowspan="2" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse</content> <content styleCode="bold"> Event</content> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Induction/Maintenance</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Postoperative Analgesia</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> After Discontinuation</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection</content> <content styleCode="bold"> (n = 921)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Alfentanil/</content> <content styleCode="bold"> Fentanyl</content> <content styleCode="bold"> (n = 466)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection</content> <content styleCode="bold"> (n = 281)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Morphine</content> <content styleCode="bold"> (n = 98)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection (n = 929)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Alfentanil /Fentanyl</content> <content styleCode="bold"> (n = 466)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 61 (22%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15 (15%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 339 (36%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 202 (43%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 178 (19%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30 (6%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 22 (8%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 150 (16%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 91 (20%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Muscle rigidity </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 98 (11%)<footnote ID="ID4112"> 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.</footnote> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 37 (8%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 62 (7%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 24 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (1%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Shivering </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 (9%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 49 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fever </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 44 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dizziness </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Visual disturbance </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 24 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 (3%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Headache </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 21 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory depression </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 (7%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 (4%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 17 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 20 (4%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Apnea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pruritus </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 22 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Postoperative pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (1%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (2%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypoxia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (2%) </td></tr></tbody></table>

<table ID="ID413" width="100%" styleCode="Noautorules"><caption> Table 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies<footnote ID="ID4130"><sup/>Does not include adverse events from cardiac studies or the neonatal study.</footnote> at the Recommended Doses<footnote ID="ID4131">See Table 1 for recommended doses. <content styleCode="bold"> Not all doses of Remifentanil Hydrochloride for injection were equipotent to the comparator opioid.</content></footnote> of Remifentanil Hydrochloride for injection</caption><col width="12%"/><col width="6%"/><col width="8%"/><col width="6%"/><col width="8%"/><col width="6%"/><col width="8%"/><col width="6%"/><col width="8%"/><col width="6%"/><col width="8%"/><col width="6%"/><col width="8%"/><tbody><tr><td rowspan="3" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse</content> <content styleCode="bold"> Event</content> <content styleCode="bold"> n</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Induction Maintenance</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Postoperative Analgesia</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> After Discontinuation</content> </td></tr><tr><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Alfentanil/</content> <content styleCode="bold"> Fentanyl</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Morphine</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Alfentanil/</content> <content styleCode="bold"> Fentanyl</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male 326</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female 595</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male 183</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female</content> <content styleCode="bold"> 283</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male 85</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female 196</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male 36</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female 62</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male </content> <content styleCode="bold"> 332</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female 597</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Male 183</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Female 283</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 26% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 22% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 52% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 29% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 22% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Muscle rigidity </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 17% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1% </td></tr></tbody></table>

<table ID="ID415" width="100%" styleCode="Noautorules"><caption> Table 13: Adverse Events Reported in &#x2265; 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses<footnote ID="ID4150">See Table 3 for recommended doses. Administration of Remifentanil Hydrochloride for injection 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%).</footnote> of Remifentanil Hydrochloride for injection </caption><col width="20%"/><col width="27%"/><col width="30%"/><col width="21%"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse</content> <content styleCode="bold"> Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection (n = 159)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Remifentanil Hydrochloride for injection + 2 mg Midazolam</content><footnote ID="ID4151"><sup/>With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.</footnote> <content styleCode="bold"> (n = 103)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Propofol (0.5 mg/kg</content> <content styleCode="bold"> then 50 mcg/kg/min)</content> <content styleCode="bold"> (n = 63)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 70 (44%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 (18%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 20 (32%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 35 (22%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13 (21%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pruritus </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 (18%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16 (16%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Headache </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 (18%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12 (12%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (10%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Sweating </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10 (6%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Shivering </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dizziness </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (5%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (4%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (10%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6 (4%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7 (11%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory Depression </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (&lt;1%)<footnoteRef IDREF="ID4150"/> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Muscle rigidity </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Chills </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (3%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Flushing </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Warm sensation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pain at study IV site </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 (1%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 (17%) </td></tr></tbody></table>