Remifentanil Hydrochloride

Boxed Warning 01/2024 Warnings and Precautions (5.3, 5.4) 01/2024 Boxed Warning 01/2024 Warnings and Precautions ( 5.3 , 5.4 ) 01/2024

1 INDICATIONS AND USAGE 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 )

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 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 …

3 DOSAGE FORMS AND STRENGTHS For injection: 1 mg, 2 mg, and 5 mg: 3 mL Vial 1 mg lyophilized powder 5 mL Vial 2 mg lyophilized powder 10 mL Vial 5 mg lyophilized powder For injection: 1 mg, 2 mg, and 5 mg for intravenous administration after reconstitution and dilution. ( 3 )

4 CONTRAINDICATIONS Remifentanil Hydrochloride for injection 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 )

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) ] 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 Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or 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. 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 ( 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% 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 …

7 DRUG INTERACTIONS Table 18 includes clinically significant drug interactions with remifentanil Hydrochloride for injection. Table 18: Clinically Significant Drug Interactions with Remifentanil Hydrochloride for Injection 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 (5.5) ] . Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Remifentanil Hydrochloride for injection 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 (5.5) ] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. If urgent use of Remifentanil Hydrochloride for injection 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 Hydrochloride for injection 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 Hydrochloride for injection 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 Hydrochloride for injection 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 )

Drug Interactions In animals the duration of muscle paralysis from succinylcholine is not prolonged by remifentanil.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Labor or Delivery: Respiratory depression and other opioid effects may occur in newborns whose mothers are given Remifentanil Hydrochloride for injection, shortly before delivery. ( 8.1 ) Lactation: Infants exposed to Remifentanil Hydrochloride for injection through breast milk should be monitored for excess sedation and respiratory depression. ( 8.2 ) Pediatric Use: Remifentanil Hydrochloride for injection has not been studied in pediatric patients for use as a postoperative analgesic or as an analgesic component of monitored anesthesia care. ( 8.4 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with remifentanil hydrochloride in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours. There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min for a surgical procedure lasting 3 hours [ see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Remifentanil Hydrochloride for injection, is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Remifentanil Hydrochloride for injection can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In a human clinical trial, the average maternal remifentanil concentrations were approximately twice those seen in the fetus. In some cases, however, fetal concentrations were similar to those in the mother. The umbilical arteriovenous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate. Animal Data Pregnant rats were treated from Gestation Day 6 to 15 with intravenous remifentanil doses of 0.5, 1.6, or 5 mg/kg/day (0.2, 0.7, or 2.2 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively). Reduced fetal weights were reported in the high dose group; however, no malformations were reported in surviving fetuses despite a non-dose dependent increase in maternal mortality. Pregnant rabbits were treated from Gestation Day 6 to 18 with intravenous remifentanil doses of 0.1, 0.5, or 0.8 mg/kg/day (0.09, 0.4, or 0.7 times a human intravenous infusion of an induction dose of 1 mcg/kg with a maintenance dose of 2 mcg/kg/min based on body surfa …

12.1 Mechanism of Action Remifentanil Hydrochloride for injection is a μ-opioid agonist with rapid onset and peak effect, and short duration of action. The μ- opioid activity of Remifentanil Hydrochloride for injection is antagonized by opioid antagonists such as naloxone. Unlike other opioids, Remifentanil Hydrochloride for injection is rapidly metabolized by hydrolysis of the propanoic acid-methyl ester linkage by nonspecific blood and tissue esterases. Remifentanil Hydrochloride for injection is not a substrate for plasma cholinesterase (pseudocholinesterase) and, therefore, patients with atypical cholinesterase are expected to have a normal duration of action.

11 DESCRIPTION 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 and 3 mg of glycine, 2 mg of remifentanil base and 6 mg of glycine or 5 mg of remifentanil base and 15 mg of glycine; and hydrochloric acid to buffer the solutions to a nominal pH of 3 after reconstitution. When reconstituted as directed, solutions of Remifentanil Hydrochloride for injection are clear and colorless and contain remifentanil hydrochloride (HCl) equivalent to 1 mg/mL of remifentanil base. The pH of reconstituted solutions of Remifentanil Hydrochloride for injection ranges from 2.5 to 3.5. Remifentanil hydrochloride has a pKa of 7.07. Remifentanil hydrochloride has an n-octanol: water partition coefficient of 17.9 at pH 7.3. Image

10 OVERDOSAGE Clinical Presentation Acute overdose with Remifentanil Hydrochloride for injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to remifentanil overdose, stop the infusion or administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to remifentanil overdose. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

16 HOW SUPPLIED/STORAGE AND HANDLING Remifentanil HCl for injection should be stored at 2° to 25°C (36° to 77°F). Remifentanil HCl for IV use is supplied as follows: Product Code Unit of Sale Strength Each PRX723103 NDC 63323-723-06 Unit of 10 1 mg per vial NDC 63323-723-04 3 mL Single Dose Vial Discard unused portion. The container closure is not made with natural rubber latex. The brand names mentioned in this document are the trademarks of their respective owners. PREMIERProRx ® is a registered trademark of Premier Healthcare Alliance, L.P., used under license. Manufactured by: Fresenius Kabi Lake Zurich, IL 60047 www.fresenius-kabi.com/us 451651A Fresenius Kabi Logo