REMIFENTANIL HYDROCHLORIDE

Remifentanil hydrochloride for injection is an opioid agonist. The chemical name is 3-[4-methoxycarbonyl-4-[(1-oxopropyl) phenylamino]-1-piperidine] propanoic acid methyl ester, hydrochloride salt. The molecular weight is 412.91. Its molecular formula is C 20 H 28 N 2 O 5 • HCl, and it has the following chemical structure. Remifentanil hydrochloride for injection is a sterile, nonpyrogenic, preservative-free, white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. Each vial contains 1 mg of remifentanil base; 15 mg glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of remifentanil HCl are clear and colorless and contain remifentanil hydrochloride (HCl) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of remifentanil HCl ranges from 2.5 to 3.5. Remifentanil HCl has a pKa of 7.07. Remifentanil HCl has an n-octanol:water partition coefficient of 17.9 at pH 7.3. remif-struc-01.jpg

Remifentanil hydrochloride (HCl) for injection 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. Remifentanil hydrochloride for injection 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 )

• 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 remifentanil HCl and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )]. Remifentanil HCl is for intravenous use only. Continuous infusions of remifentanil HCl 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. Remifentanil HCl should not be administered without dilution. Consider an alternative to remifentanil HCl 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 remifentanil HCl if patient is not responding appropriately to treatment. Discard unused portion. 2.2 General Anesthesia Remifentanil HCl 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. Remifentanil HCl 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 remifentanil HCl. The administration of remifentanil HCl must be individualized based on the patient's response. Induction of Anesthesia Remifentanil HCl 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 remifentanil HCl, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. Remifentanil HCl 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 remifentanil HCl 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 remifentanil HCl, 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 a Phase Continuous IV Infusion of Remifentanil HCl (mcg/kg/min) Range of Infusion Dose Remifentanil HCl (mcg/kg/min) Supplemental IV Bolus Dose of Remifentanil HCl (mcg/kg) Induction of Anesthesia (through intubation) 0.5 – 1 a 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 a An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. 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 remifentanil HCl. Table 2: Dosing Guidelines in Pediatric Patients – Maintenance of Anesthesia Phase Continuous IV Infusion of Remifentanil HCl (mcg/kg/min) Range of Infusion Dose Remifentanil HCl (mcg/kg/min) Supplemental IV Bolus Dose of Remifentanil HCl (mcg/kg) Maintenance of anesthesia in patients aged 1 to 12 years old with a : 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%) b 0.4 0.4 – 1.0 1 c a An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. b 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 remifentanil HCl. [See Clinical Pharmacology: Specific Populations: Pediatric Population ( 12.3 ) and Clinical Studies ( 14.4 ).] c 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 remifentanil HCl may be continued into the immediate postoperative period for select patients for whom later transition to longer acting analgesics may be desired. • Remifentanil HCl has not been studied in pediatric patients for use in the immediate postoperative period. • The use of bolus injections of remifentanil HCl to treat pain during the postoperative period is not recommended. • When used as an IV analgesic in the immediate postoperative period, remifentanil HCl 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 remifentanil HCl, 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 remifentanil HCl. 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 remifentanil HCl is administered. • Remifentanil HCl 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 remifentanil HCl may be given 90 seconds before the placement of the local or regional anesthetic block [see Warnings and Precautions ( 5.6 )] . Continuous Infusion When used alone as an IV analgesic component of monitored anesthesia care, remifentanil HCl 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 remifentanil HCl 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 remifentanil HCl administered simultaneously with a continuous infusion of remifentanil HCl 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 Remifentanil HCl Alone Remifentanil HCl + 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 remifentanil HCl, the IV tubing should be cleared to prevent the inadvertent administration of remifentanil HCl at a later time. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of remifentanil HCl. 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 remifentanil HCl should be decreased by 50% in elderly patients (> 65 years). Remifentanil HCl 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 remifentanil HCl 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 ).] Remifentanil HCl 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 a – Coronary Artery Bypass Surgery Phase Continuous IV Infusion of Remifentanil HCl (mcg/kg/min) Range of Infusion Dose Remifentanil HCl (mcg/kg/min) Supplemental IV Bolus Dose of Remifentanil HCl (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 a See Clinical Studies: Coronary Artery Bypass Surgery subsection ( 14.5 ) for concomitant medication regimens. 2.9 Dosage Modifications in Obese Patients The starting doses of remifentanil HCl 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 remifentanil HCl 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. • Remifentanil HCl should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 5). Remifentanil HCl should not be administered without dilution. Table 5: Reconstitution and Dilution of Remifentanil HCl Final Concentration Amount of Remifentanil HCl in Each Vial Final Volume After Reconstitution and Dilution 20 mcg/mL 1 mg 50 mL 25 mcg/mL 1 mg 40 mL 50 mcg/mL 1 mg 20 mL Continuous IV infusions of remifentanil HCl should be administered only by an infusion device. Infusion rates of remifentanil HCl can be individualized for each patient using Table 6: Table 6: IV Infusion Rates of Remifentanil HCl (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 remifentanil HCl is used as an analgesic component of monitored analgesia care, a final concentration of 25 mcg/mL is recommended. When remifentanil HCl 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 Remifentanil HCl (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 Remifentanil HCl (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 Remifentanil HCl (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 Remifentanil HCl (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 Remifentanil HCl 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 Remifentanil HCl 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. Remifentanil HCl has been shown to be compatible with these IV fluids when coadministered into a running IV administration set. Compatibility with Other Therapeutic Agents Remifentanil HCl has been shown to be compatible with Diprivan ® (propofol) Injection when coadministered into a running IV administration set. The compatibility of remifentanil HCl 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 remifentanil HCl 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. Remifentanil HCl does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

Remifentanil HCl is contraindicated: • For epidural or intrathecal administration due to the presence of glycine in the formulation [see Nonclinical Toxicology ( 13 )] . • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis) [see Adverse Reactions ( 6.2 )] . Remifentanil hydrochloride for injection is contraindicated: • For epidural or intrathecal administration due to the presence of glycine in the formulation. ( 4 ) • In patients with hypersensitivity to remifentanil (e.g., anaphylaxis). ( 4 )

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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 HCl in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil HCl 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 a at the Recommended Doses b of Remifentanil HCl Adverse Event Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl (n = 921) Alfentanil/ Fentanyl (n = 466) Remifentanil HCl (n = 281) Morphine (n = 98) Remifentanil HCl (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%) c 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%) a Does not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information. b See Table 1 for recommended doses. Not all doses of remifentanil HCl were equipotent to the comparator opioid. Administration of remifentanil HCl 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%). c Included in the muscle rigidity incidence is chest wall rigidity (5%). The overall muscle rigidity incidence is < 1% when remifentanil is administered concurrently or after a hypnotic induction agent. In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower. Table 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies a at the Recommended Doses b of Remifentanil HCl Adverse Event n Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl Alfentanil/Fentanyl Remifentanil HCl Morphine Remifentanil HCl 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% a Does not include adverse events from cardiac studies or the neonatal study. b See Table 1 for recommended doses. Not all doses of remifentanil HCl were equipotent to the comparator opioid. The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil HCl 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 a of Remifentanil HCl Adverse Event Remifentanil HCl (n = 159) Remifentanil HCl + 2 mg Midazolam b (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%) a 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%) a See Table 3 for recommended doses. Administration of remifentanil HCl 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%). b With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. 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 HCl and reported an event divided by the total number of patients exposed to remifentanil HCl 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 HCl 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 a of Remifentanil HCl Induction/Intubation Maintenance Adverse Event Remifentanil HCl (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) Remifentanil HCl (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 a See Table 4 for recommended doses. Table 15: Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl 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 a See Table 4 for recommended doses. Table 16: Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl 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%) a See Table 4 for recommended doses. Pediatrics Remifentanil HCl 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 HCl 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 HCl in General Anesthesia Studies at the Recommended Doses a of Remifentanil HCl Recovery Follow-up b Adverse Event Remifentanil HCl (n = 342) Fentanyl (n = 103) Bupivacaine (n = 86) Remifentanil HCl (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 a See Table 2 for recommended doses. b In subjects receiving halothane (n = 22), 10 (45%) experienced vomiting. 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 HCl.

Table 18 includes clinically significant drug interactions with remifentanil HCl. Table 18: Clinically Significant Drug Interactions with Remifentanil HCl Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. Patients should be advised to avoid alcohol for 24 hours after surgery [see Warnings and Precautions ( 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.4 )]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue remifentanil HCl if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.4 )] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )]. If urgent use of remifentanil HCl is necessary, use test doses and frequent titration of small doses while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of remifentanil HCl is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of remifentanil HCl and/or precipitate withdrawal symptoms. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Consider discontinuing remifentanil HCl if patient is not responding appropriately to treatment and institute alternative analgesic treatment. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : May reduce the analgesic effect of Remifentanil hydrochloride for injection and/or precipitate withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. ( 7 )