Remifentanil Hydrochloride

1 INDICATIONS AND USAGE ULTIVA is indicated for intravenous (IV) administration: • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures. • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. • As an analgesic component of monitored anesthesia care in adult patients. ULTIVA is an opioid agonist indicated for intravenous administration: • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures. ( 1 ) • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. ( 1 ) • As an analgesic component of monitored anesthesia care in adult patients. ( 1 )

2 DOSAGE AND ADMINISTRATION • Monitor patients closely for respiratory depression when initiating therapy and following dosage increases and adjust the dosage accordingly. ( 2.1 ) • Initial Dosage in Adults : See full prescribing information for recommended doses in adult patients. ( 2.2 , 2.3 ) • Initial Dosage in Pediatric Patients : See full prescribing information for recommended doses in pediatric patients. ( 2.2 ) • Geriatric Patients : The starting doses should be decreased by 50% in elderly patients (> 65 years). ( 2.6 ) 2.1 Important Dosage and Administration Instructions Monitor patients closely for respiratory depression when initiating therapy and following dosage increases with ULTIVA and adjust the dosage accordingly [see Warnings and Precautions (5.2) ]. ULTIVA is for IV use only. Continuous infusions of ULTIVA should be administered only by an infusion device. The injection site should be close to the venous cannula and all IV tubing should be cleared at the time of discontinuation of infusion. ULTIVA should not be administered without dilution. Consider an alternative to ULTIVA for patients taking mixed agonist/antagonist and partial agonist opioid analgesics due to reduced analgesic effect or potential withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTIVA if patient is not responding appropriately to treatment. Discard unused portion. 2.2 General Anesthesia ULTIVA is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. ULTIVA is synergistic with other anesthetics; therefore, clinicians may need to reduce doses of thiopental, propofol, isoflurane, and midazolam by up to 75% with the coadministration of ULTIVA. The administration of ULTIVA must be individualized based on the patient's response. Induction of Anesthesia ULTIVA should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of ULTIVA, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. ULTIVA should not be used as a sole agent for induction of anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. Maintenance of Anesthesia After endotracheal intubation, the infusion rate of ULTIVA should be decreased in accordance with the dosing guidelines in Tables 1 (adults, predominately ASA physical status I, II, or III) and 2 (pediatric patients). • Due to the fast onset and short duration of action of ULTIVA, the rate of administration during anesthesia can be titrated upward in 25% to 100% increments in adult patients or up to 50% increments in pediatric patients, or downward in 25% to 50% decrements every 2 to 5 minutes to attain the desired level of µ-opioid effect. • In response to light anesthesia or transient episodes of intense surgical stress, supplemental bolus doses of 1 mcg/kg may be administered every 2 to 5 minutes. • At infusion rates > 1 mcg/kg/min, increases in the concomitant anesthetic agents should be considered to increase the depth of anesthesia. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 (2.2) .] Table 1: Dosing Guidelines in Adults – General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care Setting An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Induction of Anesthesia (through intubation) 0.5 – 1 Maintenance of anesthesia with: Nitrous oxide (66%) 0.4 0.1 – 2 1 Isoflurane (0.4 to 1.5 MAC) 0.25 0.05 – 2 1 Propofol (100 to 200 mcg/kg/min) 0.25 0.05 – 2 1 Continuation as an analgesic into the immediate postoperative period 0.1 0.025 – 0.2 not recommended Table 2 summarizes the recommended doses in pediatric patients, predominantly ASA physical status I, II, or III. In pediatric patients, remifentanil was administered with nitrous oxide or nitrous oxide in combination with halothane, sevoflurane, or isoflurane. The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA. Table 2: Dosing Guidelines in Pediatric Patients – Maintenance of Anesthesia Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Maintenance of anesthesia in patients aged 1 to 12 years old with An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. : Halothane (0.3 to 1.5 MAC) 0.25 0.05 – 1.3 1 Sevoflurane (0.3 to 1.5 MAC) 0.25 0.05 – 1.3 1 Isoflurane (0.4 to 1.5 MAC) 0.25 0.05 – 1.3 1 Maintenance of anesthesia for patients from birth to 2 months of age with: Nitrous oxide (70%) The clearance rate in neonates is highly variable, on average two times higher than in the young healthy adult population. Therefore, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required. The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Clinical Studies (14.4) .] 0.4 0.4 – 1.0 1 Boluses of 1 mcg/kg were studied in ASA 1 and 2, full-term patients weighing at least 2500 gm, undergoing pyloromyotomy who received pretreatment with atropine. Neonates receiving supplementation with potent inhalation agents or neuraxial anesthesia, those with significant co-morbidities or undergoing significant fluid shifts, or those who have not been pretreated with atropine, may require smaller bolus doses to avoid hypotension and/or bradycardia. 2.3 Continuation as an Analgesic into the Immediate Postoperative Period Under the Direct Supervision of an Anesthesia Practitioner Infusions of ULTIVA may be continued into the immediate postoperative period for select patients for whom later transition to longer acting analgesics may be desired. • ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period. • The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended. • When used as an IV analgesic in the immediate postoperative period, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min. • The infusion rate may be adjusted every 5 minutes in 0.025 mcg/kg/min increments to balance the patient's level of analgesia and respiratory rate. • Infusion rates greater than 0.2 mcg/kg/min are associated with respiratory depression (respiratory rate less than 8 breaths/min). Due to the rapid offset of action of ULTIVA, no residual analgesic activity will be present within 5 to 10 minutes after discontinuation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14) ] . 2.4 Analgesic Component of Monitored Anesthesia Care It is strongly recommended that supplemental oxygen be supplied to the patient whenever ULTIVA is administered. • ULTIVA has not been studied for use in children in monitored anesthesia care. Single Dose A single IV dose of 0.5 to 1 mcg/kg over 30 to 60 seconds of ULTIVA may be given 90 seconds before the placement of the local or regional anesthetic block [see Warnings and Precautions (5.7) ] . Continuous Infusion When used alone as an IV analgesic component of monitored anesthesia care, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min beginning 5 minutes before placement of the local or regional anesthetic block. • Because of the risk for hypoventilation, the infusion rate of ULTIVA should be decreased to 0.05 mcg/kg/min following placement of the block. • Thereafter, rate adjustments of 0.025 mcg/kg/min at 5 minute intervals may be used to balance the patient's level of analgesia and respiratory rate. • Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min). • Bolus doses of ULTIVA administered simultaneously with a continuous infusion of ULTIVA to spontaneously breathing patients are not recommended. Table 3 summarizes the recommended doses for monitored anesthesia care in adult patients, predominately ASA physical status I, II, or III. Table 3: Dosing Guidelines in Adults – Monitored Anesthesia Care Method Timing ULTIVA Alone ULTIVA + 2 mg Midazolam Single IV Dose Given 90 seconds before local anesthetic 1 mcg/kg over 30 to 60 seconds 0.5 mcg/kg over 30 to 60 seconds Continuous IV Infusion Beginning 5 minutes before local anesthetic 0.1 mcg/kg/min 0.05 mcg/kg/min After local anesthetic 0.05 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min) 0.025 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min) 2.5 Discontinuation Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later time. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14) ] . 2.6 Dosage Modifications in Geriatric Patients The starting doses of ULTIVA should be decreased by 50% in elderly patients (> 65 years). ULTIVA should then be cautiously titrated to effect [see Use in Specific Populations (8.5) ] . 2.7 Dosage Modifications in Pediatric Patients See Table 2 for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 and Maintenance of Anesthesia (2.2) .] ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period or for use as a component of monitored anesthesia care . 2.8 Dosage Modifications in Coronary Artery Bypass Surgery Table 4 summarizes the recommended doses for induction, maintenance, and continuation as an analgesic into the ICU in adult patients, predominantly ASA physical status III or IV. To avoid hypotension during the induction phase, it is important to consider the concomitant medication regimens . [See Clinical Studies: Coronary Artery Bypass Surgery (14.5) .] Table 4: Dosing Recommendations See Clinical Studies: Coronary Artery Bypass Surgery subsection (14.5) for concomitant medication regimens. – Coronary Artery Bypass Surgery Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Range of Infusion Dose ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) Induction of Anesthesia (through intubation) 1 Maintenance of Anesthesia 1 0.125 to 4 0.5 to 1 Continuation as an analgesic into ICU 1 0.05 to 1 2.9 Dosage Modifications in Obese Patients The starting doses of ULTIVA should be based on ideal body weight (IBW) in obese patients (greater than 30% over their IBW) [see Use in Specific Populations (8.6) ] . 2.10 Dosage Modifications in Preanesthetic Medication The need for premedication and the choice of anesthetic agents must be individualized. In clinical studies, patients who received ULTIVA frequently received a benzodiazepine premedication. 2.11 Preparation for Administration To reconstitute solution, add 1 mL of diluent per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL. • ULTIVA should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 5). ULTIVA should not be administered without dilution. Table 5: Reconstitution and Dilution of ULTIVA Final Concentration Amount of ULTIVA in Each Vial Final Volume After Reconstitution and Dilution 20 mcg/mL 1 mg 50 mL 2 mg 100 mL 5 mg 250 mL 25 mcg/mL 1 mg 40 mL 2 mg 80 mL 5 mg 200 mL 50 mcg/mL 1 mg 20 mL 2 mg 40 mL 5 mg 100 mL 250 mcg/mL 5 mg 20 mL Continuous IV infusions of ULTIVA should be administered only by an infusion device. Infusion rates of ULTIVA can be individualized for each patient using Table 6: Table 6: IV Infusion Rates of ULTIVA (mL/kg/h) Drug Delivery Rate (mcg/kg/min) Infusion Delivery Rate (mL/kg/h) 20 mcg/mL 25 mcg/mL 50 mcg/mL 250 mcg/mL 0.0125 0.038 0.03 0.015 not recommended 0.025 0.075 0.06 0.03 not recommended 0.05 0.15 0.12 0.06 0.012 0.075 0.23 0.18 0.09 0.018 0.1 0.3 0.24 0.12 0.024 0.15 0.45 0.36 0.18 0.036 0.2 0.6 0.48 0.24 0.048 0.25 0.75 0.6 0.3 0.06 0.5 1.5 1.2 0.6 0.12 0.75 2.25 1.8 0.9 0.18 1.0 3.0 2.4 1.2 0.24 1.25 3.75 3.0 1.5 0.3 1.5 4.5 3.6 1.8 0.36 1.75 5.25 4.2 2.1 0.42 2.0 6.0 4.8 2.4 0.48 When ULTIVA is used as an analgesic component of monitored analgesia care, a final concentration of 25 mcg/mL is recommended. When ULTIVA is used for pediatric patients 1 year of age and older, a final concentration of 20 or 25 mcg/mL is recommended. Table 7 is a guideline for milliliter-per-hour delivery for a solution of 20 mcg/mL with an infusion device. Table 7: IV Infusion Rates of ULTIVA (mL/h) for a 20 mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 5 10 20 30 40 50 60 0.0125 0.188 0.375 0.75 1.125 1.5 1.875 2.25 0.025 0.375 0.75 1.5 2.25 3.0 3.75 4.5 0.05 0.75 1.5 3.0 4.5 6.0 7.5 9.0 0.075 1.125 2.25 4.5 6.75 9.0 11.25 13.5 0.1 1.5 3.0 6.0 9.0 12.0 15.0 18.0 0.15 2.25 4.5 9.0 13.5 18.0 22.5 27.0 0.2 3.0 6.0 12.0 18.0 24.0 30.0 36.0 0.25 3.75 7.5 15.0 22.5 30.0 37.5 45.0 0.3 4.5 9.0 18.0 27.0 36.0 45.0 54.0 0.35 5.25 10.5 21.0 31.5 42.0 52.5 63.0 0.4 6.0 12.0 24.0 36.0 48.0 60.0 72.0 Table 8 is a guideline for milliliter-per-hour delivery for a solution of 25 mcg/mL with an infusion device. Table 8: IV Infusion Rates of ULTIVA (mL/h) for a 25 mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 10 20 30 40 50 60 70 80 90 100 0.0125 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4 2.7 3.0 0.025 0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 0.05 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 0.075 1.8 3.6 5.4 7.2 9.0 10.8 12.6 14.4 16.2 18.0 0.1 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2 21.6 24.0 0.15 3.6 7.2 10.8 14.4 18.0 21.6 25.2 28.8 32.4 36.0 0.2 4.8 9.6 14.4 19.2 24.0 28.8 33.6 38.4 43.2 48.0 Table 9 is a guideline for milliliter-per-hour delivery for a solution of 50 mcg/mL with an infusion device. Table 9: IV Infusion Rates of ULTIVA (mL/h) for a 50 mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 30 40 50 60 70 80 90 100 0.025 2.1 2.4 2.7 3.0 0.05 2.4 3.0 3.6 4.2 4.8 5.4 6.0 0.075 2.7 3.6 4.5 5.4 6.3 7.2 8.1 9.0 0.1 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 0.15 5.4 7.2 9.0 10.8 12.6 14.4 16.2 18.0 0.2 7.2 9.6 12.0 14.4 16.8 19.2 21.6 24.0 0.25 9.0 12.0 15.0 18.0 21.0 24.0 27.0 30.0 0.5 18.0 24.0 30.0 36.0 42.0 48.0 54.0 60.0 0.75 27.0 36.0 45.0 54.0 63.0 72.0 81.0 90.0 1.0 36.0 48.0 60.0 72.0 84.0 96.0 108.0 120.0 1.25 45.0 60.0 75.0 90.0 105.0 120.0 135.0 150.0 1.5 54.0 72.0 90.0 108.0 126.0 144.0 162.0 180.0 1.75 63.0 84.0 105.0 126.0 147.0 168.0 189.0 210.0 2.0 72.0 96.0 120.0 144.0 168.0 192.0 216.0 240.0 Table 10 is a guideline for milliliter-per-hour delivery for a solution of 250 mcg/mL with an infusion device. Table 10: IV Infusion Rates of ULTIVA (mL/h) for a 250 mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 30 40 50 60 70 80 90 100 0.1 0.72 0.96 1.20 1.44 1.68 1.92 2.16 2.40 0.15 1.08 1.44 1.80 2.16 2.52 2.88 3.24 3.60 0.2 1.44 1.92 2.40 2.88 3.36 3.84 4.32 4.80 0.25 1.80 2.40 3.00 3.60 4.20 4.80 5.40 6.00 0.5 3.60 4.80 6.00 7.20 8.40 9.60 10.80 12.00 0.75 5.40 7.20 9.00 10.80 12.60 14.40 16.20 18.00 1.0 7.20 9.60 12.00 14.40 16.80 19.20 21.60 24.00 1.25 9.00 12.00 15.00 18.00 21.00 24.00 27.00 30.00 1.5 10.80 14.40 18.00 21.60 25.20 28.80 32.40 36.00 1.75 12.60 16.80 21.00 25.20 29.40 33.60 37.80 42.00 2.0 14.40 19.20 24.00 28.80 33.60 38.40 43.20 48.00 2.12 Compatibility and Stability Reconstitution and Dilution Prior to Administration ULTIVA is stable for 24 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with the IV fluids listed below. Sterile Water for Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP Lactated Ringer's and 5% Dextrose Injection, USP ULTIVA is stable for 4 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with Lactated Ringer's Injection, USP. ULTIVA has been shown to be compatible with these IV fluids when coadministered into a running IV administration set. Compatibility with Other Therapeutic Agents ULTIVA has been shown to be compatible with Diprivan ® (propofol) Injection when coadministered into a running IV administration set. The compatibility of ULTIVA with other therapeutic agents has not been evaluated. Incompatibilities Nonspecific esterases in blood products may lead to the hydrolysis of remifentanil to its carboxylic acid metabolite. Therefore, administration of ULTIVA into the same IV tubing with blood is not recommended. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product should be a clear, colorless liquid after reconstitution and free of visible particulate matter. ULTIVA does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

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) ] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] • Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions (5.3) ] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.4) ] • Serotonin Syndrome [see Warnings and Precautions (5.5) ] • Skeletal Muscle Rigidity [see Warnings and Precautions (5.7) ] • Bradycardia [see Warnings and Precautions (5.9) ] • Hypotension [see Warnings and Precautions (5.10) ] • Biliary Tract Disease [see Warnings and Precautions (5.13) ] • Seizures [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 ULTIVA in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA 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 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%). of ULTIVA Adverse Event Induction/Maintenance Postoperative Analgesia After Discontinuation ULTIVA (n = 921) Alfentanil/Fentanyl (n = 466) ULTIVA (n = 281) Morphine (n = 98) ULTIVA (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 ULTIVA were equipotent to the comparator opioid. of ULTIVA Adverse Event n Induction Maintenance Postoperative Analgesia After Discontinuation ULTIVA Alfentanil/Fentanyl ULTIVA Morphine ULTIVA 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 ULTIVA 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 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%). of ULTIVA Adverse Event ULTIVA (n = 159) ULTIVA + 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 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 = 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 ULTIVA 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 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 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 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 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 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%) Pediatrics ULTIVA 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 ULTIVA 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 ULTIVA in General Anesthesia Studies at the Recommended Doses See Table 2 for recommended doses. of ULTIVA Recovery Follow-up In subjects receiving halothane (n = 22), 10 (45%) experienced vomiting. 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 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 ULTIVA. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.4) ] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

12.3 Pharmacokinetics After IV doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three-compartment model with a rapid distribution half-life of one minute, a slower distribution half-life of 6 minutes, and a terminal elimination half-life of 10 to 20 minutes. Since the terminal elimination component contributes less than 10% of the overall area under the concentration versus time curve (AUC), the effective biological half-life of ULTIVA is 3 to 10 minutes. This is similar to the 3- to 10-minute half-life measured after termination of prolonged infusions (up to 4 hours; see Figure 2) and correlates with recovery times observed in the clinical setting after infusions up to 12 hours. Concentrations of remifentanil are proportional to the dose administered throughout the recommended dose range. The pharmacokinetics of remifentanil are unaffected by the presence of renal or hepatic impairment. Distribution The initial volume of distribution (V d ) of remifentanil is approximately 100 mL/kg and represents distribution throughout the blood and rapidly perfused tissues. Remifentanil subsequently distributes into peripheral tissues with a steady-state volume of distribution of approximately 350 mL/kg. These two distribution volumes generally correlate with total body weight (except in severely obese patients when they correlate better with ideal body weight [IBW]). Remifentanil is approximately 70% bound to plasma proteins of which two-thirds is binding to alpha-1-acid-glycoprotein. Elimination The clearance of remifentanil in young, healthy adults is approximately 40 mL/min/kg. Clearance generally correlates with total body weight (except in severely obese patients when it correlates better with IBW). The high clearance of remifentanil combined with a relatively small volume of distribution produces a short elimination half-life of approximately 3 to 10 minutes (see Figure 2). This value is consistent with the time taken for blood or effect site concentrations to fall by 50% (context-sensitive half-times) which is approximately 3 to 6 minutes. Unlike other fentanyl analogs, the duration of action does not increase with prolonged administration. Figure 2: Mean Concentration (sd) versus Time Figure 2: Mean Concentration (sd) versus Time Titration to Effect The rapid elimination of remifentanil permits the titration of infusion rate without concern for prolonged duration. In general, every 0.1 mcg/kg/min change in the IV infusion rate will lead to a corresponding 2.5 ng/mL change in blood remifentanil concentration within 5 to 10 minutes. In intubated patients only, a more rapid increase (within 3 to 5 minutes) to a new steady state can be achieved with a 1.0 mcg/kg bolus dose in conjunction with an infusion rate increase. Metabolism Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders this compound susceptible to hydrolysis by nonspecific esterases in blood and tissues. This hydrolysis results in the production of the carboxylic acid metabolite (3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid), and represents the principal metabolic pathway for remifentanil (> 95%). The carboxylic acid metabolite is essentially inactive (1/4600 as potent as remifentanil in dogs). Remifentanil is not metabolized by plasma cholinesterase (pseudocholinesterase) and is not appreciably metabolized by the liver or lung. Excretion The carboxylic acid metabolite is excreted by the kidneys with an elimination half-life of approximately 90 minutes. Specific Populations Age: Geriatric Population The clearance of remifentanil is reduced (approximately 25%) in the elderly (> 65 years of age) compared to young adults (average 25 years of age). However, remifentanil blood concentrations fall as rapidly after termination of administration in the elderly as in young adults. Age: Pediatric Population In pediatric patients, 5 days to 17 years of age (n = 47), the clearance and volume of distribution of remifentanil were increased in younger children and declined to young healthy adult values by age 17. The average clearance of remifentanil in neonates (less than 2 months of age) was approximately 90.5 ± 36.8 mL/min/kg (mean ± SD) while in adolescents (13 to 16 years) this value was 57.2 ± 21.1 mL/min/kg. The total (steady-state) volume of distribution in neonates was 452 ± 144 mL/kg versus 223 ± 30.6 mL/kg in adolescents. The half-life of remifentanil was the same in neonates and adolescents. Clearance of remifentanil was maintained at or above normal adult values in patients 5 days to 17 years of age. Sex There is no significant difference in the pharmacokinetics of remifentanil in male and female patients after correcting for differences in weight. Hepatic Impairment The pharmacokinetics of remifentanil and its carboxylic acid metabolite are unchanged in patients with severe hepatic impairment. Renal Impairment The pharmacokinetic profile of ULTIVA is not changed in patients with end stage renal disease (creatinine clearance < 10 mL/min). In anephric patients, the half-life of the carboxylic acid metabolite increases from 90 minutes to 30 hours. The metabolite is removed by hemodialysis with a dialysis extraction ratio of approximately 30%. Obesity There is no difference in the pharmacokinetics of remifentanil in non-obese versus obese (greater than 30% over IBW) patients when normalized to IBW. Cardiopulmonary Bypass (CPB) Remifentanil clearance is reduced by approximately 20% during hypothermic CPB. Drug Interaction Studies Remifentanil clearance is not altered by concomitant administration of thiopental, isoflurane, propofol, or temazepam during anesthesia. In vitro studies with atracurium, mivacurium, esmolol, echothiophate, neostigmine, physostigmine, and midazolam revealed no inhibition of remifentanil hydrolysis in whole human blood by these drugs.