Sufentanil Citrate

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) ] • Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants [see Warnings and Precautions (5.3) ] • Risks of Muscle Rigidity and Skeletal Muscle Movement [see Warnings and Precautions (5.5) ] • Severe Cardiovascular Depression [see Warnings and Precautions (5.6) ] • Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions (5.8) ] • Risks of Use in Patients with ‎Gastrointestinal Conditions [see Warnings and Precautions (5.11) ] • ‎Increased Risk of Seizures in Patients with Seizure Disorders [see Warnings and Precautions (5.12) ] Most common adverse reactions were apnea, rigidity, and bradycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 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. Epidural Use in Labor and Delivery Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself. Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes. There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g., after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sufentanil. 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. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Sufentanil Citrate Injection. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of any duration [see Warnings and Precautions ‎‎(5.7) ]‎ .

4 CONTRAINDICATIONS Sufentanil Citrate Injection is contraindicated in patients with: • Hypersensitivity to sufentanil (e.g., anaphylaxis) [see Adverse Reactions (6.2) ] Hypersensitivity to sufentanil. ( 4 )

11 DESCRIPTION Sufentanil Citrate Injection, USP is a sterile, nonpyrogenic solution of sufentanil citrate in water for injection. Sufentanil Citrate is a potent opioid analgesic which is administered either epidurally or by intravenous injection. Each mL contains sufentanil citrate equivalent to 50 mcg of sufentanil. May contain sodium hydroxide and/or hydrochloric acid for pH adjustment. pH 4.2 (3.5 to 6.0). The solution contains no bacteriostat, antimicrobial agent or added buffer and is intended for use only as a single-use injection. When smaller doses are required, the unused portion should be discarded in an appropriate manner. Sufentanil Citrate, USP, occurs as a white crystalline powder and is chemically designated as N -[-4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]- N -phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1). The molecular formula of sufentanil citrate is C 22 H 30 N 2 O 2 S∙C 6 H 8 O 7 and the molecular weight is 578.69. Sufentanil Citrate has the following structural formula: Chemical Structure

2 DOSAGE AND ADMINISTRATION • Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids. • Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available. ( 2.1 ) • Individualize dosing based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved. ( 2.1 ) • Initiate analgesic treatment with 1 to 2 mcg/kg intravenously. ( 2.2 ) • Initiate epidural injection for labor and delivery at 10 to 15 mcg of sufentanil administered with 10 mL bupivacaine 0.125% with or without epinephrine. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of intravenous or epidural anesthetics and management of the respiratory effects of potent opioids. In patients administered high doses of Sufentanil Citrate Injection, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression. For purposes of administering small volumes of Sufentanil Citrate Injection accurately, the use of a tuberculin syringe or equivalent is recommended. • Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available. • Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved. • Monitor vital signs regularly. • The selection of preanesthetic medications should be based upon the needs of the individual patient. • The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required. As with other potent opioids, the respiratory depressant effect of sufentanil may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia. If Sufentanil Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product's duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available [see Warnings and Precautions (5.3) ] . Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Intravenous use Sufentanil Citrate may be administered intravenously by slow injection or infusion. Adjunct to general anesthesia: • Doses of up to 8 mcg/kg (see Table 1 ) • Total Dosage Requirements of 1 mcg/kg/hr or less are recommended • Dosage should be individualized and adjusted to remaining operative time anticipated. Table 1: Adult Dosage Range Chart, Analgesic Component To General Anesthesia, Intravenous Use Total dosage Maintenance dosage Duration of anesthesia 1 to 2 hours Incremental or Infusion: 1 to 2 mcg/kg Approximately 75% or more of total sufentanil dosage may be administered prior to intubation by either slow injection or infusion titrated to individual patient response. Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required. Incremental: 10 to 25 mcg (0.2 to 0.5 mL) may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to remaining operative time anticipated. Infusion: Intermittent or continuous infusion as needed in response to signs of lightening of analgesia. In absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. Duration of anesthesia 2 to 8 hours Incremental or Infusion: 2 to 8 mcg/kg Approximately 75% or less of the total calculated sufentanil dosage may be administered by slow injection or infusion prior to intubation, titrated to individual patient response. Dosages in this range are generally administered with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures in which endotracheal intubation and mechanical ventilation are required. At dosages in this range, sufentanil has been shown to provide some attenuation of sympathetic reflex activity in response to surgical stimuli, provide hemodynamic stability, and provide relatively rapid recovery. Incremental: 10 to 50 mcg (0.2 to 1 mL) may be administered in increments as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated. Infusion: Intermittent or continuous infusion as needed in response to signs of lightening of analgesia. In the absence of signs of lightening of analgesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. Maintenance infusion rates should be adjusted based upon the induction dose of sufentanil so that the total dose does not exceed 1 mcg/kg/hr of expected surgical time. Induction And Maintenance Of Anesthesia • As the primary anesthetic agent: doses ≥8 mcg/kg (see Dosage Range Chart, Table 2 ). • Dosage should be titrated to individual patient response • In children less than 12 years of age undergoing cardiovascular surgery: 10 to 25 mcg/kg administered with 100% oxygen o Supplemental dosages of up to 25 to 50 mcg are recommended for maintenance, based on response to initial dose and as determined by changes in vital signs indicating surgical stress or lightening of anesthesia. Table 2: Dosage Range Chart, Induction and Maintenance of Anesthesia, Intravenous Use Incremental or Infusion: 8 to 30 mcg/kg Generally administered as a slow injection, as an infusion, or as an injection followed by an infusion. Sufentanil with 100% oxygen and a muscle relaxant has been found to produce sleep at dosages ≥8 mcg/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents. The addition of N 2 O to these dosages will reduce systolic blood pressure. At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated. Dosages of 25 to 30 mcg/kg have been shown to block sympathetic response including catecholamine release. High doses are indicated in patients undergoing major surgical procedures, in which endotracheal intubation and mechanical ventilation are required, such as cardiovascular surgery and neurosurgery in the sitting position with maintenance of favorable myocardial and cerebral oxygen balance. Postoperative observation is essential and postoperative mechanical ventilation may be required at the higher dosage range due to extended postoperative respiratory depression. Incremental: Depending on the initial dose, maintenance doses of 0.5 to 10 mcg/kg may be administered by slow injection in anticipation of surgical stress such as incision, sternotomy or cardiopulmonary bypass. Infusion: Sufentanil citrate may be administered by continuous or intermittent infusion as needed in response to signs of lightening of anesthesia. In the absence of lightening of anesthesia, infusion rates should always be adjusted downward until there is some response to surgical stimulation. The maintenance infusion rate for sufentanil should be based upon the induction dose so that the total dose for the procedure does not exceed 30 mcg/kg. 2.3 Epidural Use in Labor and Delivery Proper placement of the needle or catheter in the epidural space should be verified before sufentanil citrate is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of sufentanil could result in a potentially serious overdose, including acute truncal muscular rigidity and apnea. Unintentional intrathecal injection of the full sufentanil, bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery. • Sufentanil should be administered by slow injection. Respiration should be closely monitored following each administration of an epidural injection of sufentanil. • If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Dosage for Labor and Delivery • 10 to 15 mcg administered with 10 mL bupivacaine 0.125% with or without epinephrine. • Sufentanil and bupivacaine should be mixed together before administration. • Doses can be repeated twice (for a total of three doses) at not less than one-hour intervals until delivery.

1 INDICATIONS AND USAGE Sufentanil Citrate Injection is indicated for intravenous administration in adults and pediatric patients: • as an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated. • as a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, in patients who are intubated and ventilated, such as cardiovascular surgery or neurosurgical procedures in the sitting position, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated. Sufentanil Citrate Injection is indicated for epidural administration: • as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine usually during labor and vaginal delivery. Sufentanil Citrate Injection is an opioid agonist indicated ( 1 ): • as an analgesic adjunct in the maintenance of balanced general anesthesia in patients who are intubated and ventilated. • as a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, in patients who are intubated and ventilated, such as cardiovascular surgery or neurosurgical procedures in the sitting position, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated. • for epidural administration as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine usually during labor and vaginal delivery.

9.2 Abuse Sufentanil Citrate Injection contains sufentanil, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and ‎Precautions (5.1) ] . Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than prescribed by a health care provider or for ‎whom it was not prescribed.‎ Abuse is the intentional, non-therapeutic use of a drug, even once, for its ‎desirable psychological or physiological effects.‎ Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use ‎(e.g., continuing drug use despite harmful consequences, giving a higher ‎priority to drug use than other activities and obligations), and possible ‎tolerance or physical dependence.‎ Misuse and abuse of Sufentanil Citrate Injection increases risk of ‎overdosage, which may lead to central nervous system and respiratory ‎depression, hypotension, seizures, and death. The risk is increased with ‎concurrent abuse of Sufentanil Citrate Injection with alcohol and other ‎central nervous system depressants. Abuse of and addiction to opioids in ‎some individuals may not be accompanied by concurrent tolerance and ‎symptoms of physical dependence. In addition, abuse of opioids can occur ‎in the absence of addiction.‎ All patients treated with opioids require careful and frequent re-evaluation ‎for signs of misuse, abuse, and addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate medical use. ‎Patients at high risk of Sufentanil Citrate Injection abuse include those ‎with a history of prolonged use of products containing sufentanil, those ‎with a history of drug or alcohol abuse, or those who use Sufentanil ‎Citrate Injection in combination with other abused drugs.‎ ‎“Drug-seeking” behavior is very common in persons with substance use ‎disorders. Drug-seeking tactics include emergency calls or visits near the ‎end of office hours, refusal to undergo appropriate examination, testing, or ‎referral, repeated “loss” of prescriptions, tampering with prescriptions, and ‎reluctance to provide prior medical records or contact information for other ‎treating healthcare provider(s). “Doctor shopping” (visiting multiple ‎prescribers to obtain additional prescriptions) is common among people ‎who abuse drugs and people with substance use disorder. Preoccupation ‎with achieving adequate pain relief can be appropriate behavior in a ‎patient with inadequate pain control.‎ Sufentanil Citrate Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-‎evaluation of therapy, and proper dispensing and storage are appropriate ‎measures that help to limit abuse of opioid drugs.‎ Risks Specific to Abuse of Sufentanil Citrate Injection Abuse of Sufentanil Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Sufentanil Citrate Injection with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.1 Controlled Substance Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after ‎repeated administration (i.e., a higher dose of a drug is required to ‎produce the same effect that was once obtained at a lower dose).‎ Physical dependence is a state that develops as a result of a physiological adaptation in ‎response to repeated drug use, manifested by withdrawal signs and ‎symptoms after abrupt discontinuation or a significant dose reduction of a ‎drug.‎ Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Sufentanil Citrate Injection should not be abruptly discontinued in a ‎physically-dependent patient. If Sufentanil Citrate Injection is abruptly ‎discontinued in a physically-dependent patient, a withdrawal syndrome ‎may occur, typically characterized by restlessness, lacrimation, rhinorrhea, ‎perspiration, chills, myalgia, and mydriasis. Other signs and symptoms ‎also may develop, including irritability, anxiety, backache, joint pain, ‎weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, ‎diarrhea, or increased blood pressure, respiratory rate, or heart rate.‎ Infants born to mothers physically-dependent on opioids will also be ‎physically-dependent and may exhibit respiratory difficulties and ‎withdrawal signs [see Use in Specific Populations (8.1) ] .‎

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance. 9.2 Abuse Sufentanil Citrate Injection contains sufentanil, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and ‎Precautions (5.1) ] . Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than prescribed by a health care provider or for ‎whom it was not prescribed.‎ Abuse is the intentional, non-therapeutic use of a drug, even once, for its ‎desirable psychological or physiological effects.‎ Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use ‎(e.g., continuing drug use despite harmful consequences, giving a higher ‎priority to drug use than other activities and obligations), and possible ‎tolerance or physical dependence.‎ Misuse and abuse of Sufentanil Citrate Injection increases risk of ‎overdosage, which may lead to central nervous system and respiratory ‎depression, hypotension, seizures, and death. The risk is increased with ‎concurrent abuse of Sufentanil Citrate Injection with alcohol and other ‎central nervous system depressants. Abuse of and addiction to opioids in ‎some individuals may not be accompanied by concurrent tolerance and ‎symptoms of physical dependence. In addition, abuse of opioids can occur ‎in the absence of addiction.‎ All patients treated with opioids require careful and frequent re-evaluation ‎for signs of misuse, abuse, and addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate medical use. ‎Patients at high risk of Sufentanil Citrate Injection abuse include those ‎with a history of prolonged use of products containing sufentanil, those ‎with a history of drug or alcohol abuse, or those who use Sufentanil ‎Citrate Injection in combination with other abused drugs.‎ ‎“Drug-seeking” behavior is very common in persons with substance use ‎disorders. Drug-seeking tactics include emergency calls or visits near the ‎end of office hours, refusal to undergo appropriate examination, testing, or ‎referral, repeated “loss” of prescriptions, tampering with prescriptions, and ‎reluctance to provide prior medical records or contact information for other ‎treating healthcare provider(s). “Doctor shopping” (visiting multiple ‎prescribers to obtain additional prescriptions) is common among people ‎who abuse drugs and people with substance use disorder. Preoccupation ‎with achieving adequate pain relief can be appropriate behavior in a ‎patient with inadequate pain control.‎ Sufentanil Citrate Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-‎evaluation of therapy, and proper dispensing and storage are appropriate ‎measures that help to limit abuse of opioid drugs.‎ Risks Specific to Abuse of Sufentanil Citrate Injection Abuse of Sufentanil Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Sufentanil Citrate Injection with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after ‎repeated administration (i.e., a higher dose of a drug is required to ‎produce the same effect that was once obtained at a lower dose).‎ Physical dependence is a state that develops as a result of a physiological adaptation in ‎response to repeated drug use, manifested by withdrawal signs and ‎symptoms after abrupt discontinuation or a significant dose reduction of a ‎drug.‎ Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Sufentanil Citrate Injection should not be abruptly discontinued in a ‎physically-dependent patient. If Sufentanil Citrate Injection is abruptly ‎discontinued in a physically-dependent patient, a withdrawal syndrome ‎may occur, typically characterized by restlessness, lacrimation, rhinorrhea, ‎perspiration, chills, myalgia, and mydriasis. Other signs and symptoms ‎also may develop, including irritability, anxiety, backache, joint pain, ‎weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, ‎diarrhea, or increased blood pressure, respiratory rate, or heart rate.‎ Infants born to mothers physically-dependent on opioids will also be ‎physically-dependent and may exhibit respiratory difficulties and ‎withdrawal signs [see Use in Specific Populations (8.1) ] .‎

10 OVERDOSAGE Clinical Presentation Acute overdose with Sufentanil Citrate 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 techniques. 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 sufentanil overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to sufentanil overdose. Because the duration of opioid reversal is expected to be less than the duration of action of sufentanil in Sufentanil Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. 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 initiated with care and by titration with smaller than usual doses of the antagonist.

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Sufentanil Citrate Injection. Table 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved [see Warnings and Precautions (5.4) ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil. Intervention: If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice. CYP3A4 Inducers Clinical Impact: The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions (5.4) ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: The concomitant use of Sufentanil Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: As postoperative analgesia, start with a lower dose of Sufentanil Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [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 (5.8) ]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate 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 Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. Intervention: The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs. Nitrous oxide Clinical Impact: Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection. Intervention: Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected. • Concomitant Use of CNS Depressants : May decrease pulmonary arterial pressure and may cause hypotension. See FPI for management instructions. For postoperative pain, start with the lowest effective dosage and monitor for potentiation of CNS depressant effects. ( 5.3 , 7 ) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Sufentanil Citrate Injection because they may reduce analgesic effect of Sufentanil Citrate Injection or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sufentanil is an opioid agonist. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl. 12.2 Pharmacodynamics Effects on the Central Nervous System Sufentanil produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Sufentanil causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Sufentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Sufentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids [see Dosage and Administration (2.1 , 2.2) ] . The minimum effective analgesic concentration of sufentanil for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance. Concentration–Adverse Reaction Relationships There is a relationship between increasing sufentanil plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . 12.3 Pharmacokinetics Sufentanil Citrate Injection is administered by the intravenous or epidural route. The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model. Absorption After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. Distribution Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes. Elimination The elimination half-life is 164 minutes in adults. The elimination half-life of sufentanil is shorter (e.g., 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g., 434 +/- 160 minutes) compared to that of adolescents and adults. Metabolism The liver and small intestine are the major sites of biotransformation. Excretion Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

12.1 Mechanism of Action Sufentanil is an opioid agonist. When used in balanced general anesthesia, sufentanil has been reported to be as much as 10 times as potent as fentanyl. When administered intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is approximately 5 to 7 times as potent as fentanyl.

12.2 Pharmacodynamics Effects on the Central Nervous System Sufentanil produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation. Sufentanil causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Sufentanil causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Sufentanil produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6.2) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with extended-release agonist opioids [see Dosage and Administration (2.1 , 2.2) ] . The minimum effective analgesic concentration of sufentanil for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance. Concentration–Adverse Reaction Relationships There is a relationship between increasing sufentanil plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.2 , 2.3) ] .

12.3 Pharmacokinetics Sufentanil Citrate Injection is administered by the intravenous or epidural route. The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model. Absorption After epidural administration of incremental doses totaling 5 to 40 mcg sufentanil during labor and delivery, maternal and neonatal sufentanil plasma concentrations were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly higher in mothers than in their infants. Distribution Plasma protein binding of sufentanil, related to the alpha acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Sufentanil has a distribution time of 1.4 minutes and redistribution time of 17.1 minutes. Elimination The elimination half-life is 164 minutes in adults. The elimination half-life of sufentanil is shorter (e.g., 97 +/- 42 minutes) in infants and children, and longer in neonates (e.g., 434 +/- 160 minutes) compared to that of adolescents and adults. Metabolism The liver and small intestine are the major sites of biotransformation. Excretion Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.

20230717

23

3 DOSAGE FORMS AND STRENGTHS Sufentanil Citrate Injection, USP 50 mcg/mL (equivalent to 50 mcg/mL sufentanil base). Solution for injection (sterile): eq. to 50 mcg/mL sufentanil base; 1 mL, 2 mL and 5 mL vials.

Sufentanil Citrate SUFENTANIL CITRATE SUFENTANIL CITRATE SUFENTANIL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay. Impairment of Fertility Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rated were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of sufentanil have not been conducted. Mutagenesis Sufentanil was not genotoxic in the in vitro bacterial reverse mutation assay (Ames assay) or in the in vivo rat bone marrow micronucleous assay. Impairment of Fertility Fertility and early embryonic development studies were conducted in male and female rats treated with 0.005, 0.02 or 0.08 mg/kg sufentanil IV for 56 days and 14 days prior to mating through gestation respectively. Increased mortality was noted in all treatment groups. Lower pregnancy rated were noted following treatment of males at doses of 0.02 and 0.08 mg/kg (0.1 and 0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison), suggesting the potential for an adverse effect on fertility in males. Increased resorption of fetuses and reduced litter size was noted in the high dose females (0.4 times the maximum human total procedural dose of 30 mcg/kg IV, based on a body surface area comparison) suggesting the potential for fetotoxicity, likely due to maternal toxicity.

ANDA074534

Sufentanil Citrate

SUFENTANIL CITRATE

0409-3382

HUMAN PRESCRIPTION DRUG

EPIDURAL,INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 1 mL Vial Label 1 mL Single-dose NDC 0409-3382-11 Preservative-Free Rx only SUFENTANIL CITRATE Injection, USP 50 mcg/mL CII For Intravenous and Epidural Use. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 1 mL Vial Label

Boxed Warning 7/2023‎ Warnings and Precautions; Addiction, Abuse, and Misuse ( 5.1 ) 7/2023‎ Warnings and Precautions; Risks From Concomitant Use With Benzodiazepines Or ‎Other CNS Depressants ( 5.3 ) 7/2023‎ Warnings and Precautions; Opioid-Induced Hyperalgesia and Allodynia ( 5.7 ) 7/2023‎

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1124-5.0 Logo

14 CLINICAL STUDIES Epidural Use in Labor and Delivery Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself. Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes. There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g., after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to sufentanil. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Sufentanil Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6) ] .

8.4 Pediatric Use The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug.

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 Sufentanil Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose. No malformations were observed in either rats or rabbits at doses below the human procedural dose [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% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or non-medical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] . 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. Sufentanil Citrate 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 Sufentanil Citrate 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. The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume). Data Animal Data Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group). Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or 0.9 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group). No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54 times the human procedural dose of 30 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps. Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/day based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups).

8 USE IN SPECIFIC POPULATIONS • Pregnancy : May cause fetal harm. ( 8.1 ) • Lactation : Infants exposed to Sufentanil Citrate Injection through breast milk should be monitored for excess sedation and respiratory depression. ( 8.2 ) 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 Sufentanil Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, embryolethality and maternal toxicity were noted in rabbits when sufentanil was administered intravenously at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose. No malformations were observed in either rats or rabbits at doses below the human procedural dose [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% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or non-medical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ] . 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. Sufentanil Citrate 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 Sufentanil Citrate 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. The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. Sufentanil is not recommended for intravenous use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery. In clinical trials, one case of severe fetal bradycardia associated with maternal hypotension was reported within 8 minutes of maternal administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume). Data Animal Data Pregnant rats were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group). Pregnant rabbits were treated with intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or 0.9 times the human total procedural dose of 30 mcg/kg based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group). No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54 times the human procedural dose of 30 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps. Pregnant rats were treated intravenously with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or 0.4 times the human total procedural dose of 30 mcg/day based on body surface area, respectively) from Gestation Day 16 through Lactation Day 21. Sufentanil reduced birth weights in the mid- and high-dose groups, decreased live fetuses in the high-dose group, and decreased pup survival in all groups in the presence of maternal toxicity (decreased weight gain and increased mortality in all groups). 8.2 Lactation Risk Summary The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sufentanil Citrate Injection and any potential adverse effects on the breastfed infant from Sufentanil Citrate Injection or from the underlying maternal condition. Clinical Considerations Infants exposed to Sufentanil Citrate Injection through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) ]. 8.4 Pediatric Use The safety and efficacy of intravenous sufentanil in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children. The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life of the drug. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to sufentanil. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Sufentanil Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6) ] . 8.6 Hepatic Impairment Sufentanil Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension. 8.7 Renal Impairment Sufentanil Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of sufentanil citrate and its metabolites. Reduce the dosage as needed and monitor for signs of respiratory depression, sedation, and hypotension.

16 HOW SUPPLIED/STORAGE AND HANDLING Sufentanil Citrate Injection, USP equivalent to 50 mcg/mL sufentanil is supplied in the following single-dose containers: Unit of Sale Concentration NDC 0409-3382-21 50 mcg/mL Carton of 10 Single-dose Fliptop Vials NDC 0409-3382-22 100 mcg/2 mL Carton of 10 Single-dose Fliptop Vials (50 mcg/mL) NDC 0409-3382-25 250 mcg/5 mL Carton of 10 Single-dose Fliptop Vials (50 mcg/mL) Protect from light. Retain in carton until time of use. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Protect from light. Retain in carton until time of use. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SUFENTANIL CITRATE ‎INJECTION Addiction, Abuse, and Misuse Because the use of Sufentanil Citrate Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death , assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions ‎[see Warnings and Precautions (5.1) ]‎ . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of ‎Sufentanil Citrate Injection, ‎especially during initiation or following a dose ‎increase. To reduce the risk of respiratory depression, proper dosing ‎and ‎titration of Sufentanil Citrate Injection are essential [see Warnings and ‎Precautions (5.2) ] .‎ Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants ‎‎Concomitant use of opioids with benzodiazepines or other central nervous ‎system (CNS) depressants, including ‎alcohol, may result in profound sedation, ‎respiratory depression, coma, and death. Reserve concomitant prescribing of ‎‎Sufentanil Citrate Injection and benzodiazepines or other CNS depressants for ‎use in patients for whom ‎alternative treatment options are inadequate [see ‎ Warnings and Precautions (5.3) , Drug Interactions (7) ] .‎ Cytochrome P450 3A4 Interaction The concomitant use of Sufentanil Citrate Injection with all cytochrome P450 ‎‎3A4 inhibitors may result in an ‎increase in sufentanil plasma concentrations, ‎which could increase or prolong adverse reactions and may cause ‎potentially ‎fatal respiratory depression. In addition, discontinuation of a concomitantly used ‎cytochrome P450 3A4 ‎inducer may result in an increase in sufentanil plasma ‎concentration. Monitor patients receiving Sufentanil Citrate Injection and any ‎CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4) , Drug ‎Interactions (7) , ‎ Clinical Pharmacology (12.3) ]‎ . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SUFENTANIL CITRATE ‎INJECTION See full prescribing information for complete boxed warning. • Because the use of Sufentanil Citrate Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions. ( 5.1 ) • Serious, life-threatening, or fatal respiratory depression may occur with use of ‎Sufentanil Citrate Injection, ‎especially during initiation or following a dose ‎increase. To reduce the risk of respiratory depression, proper dosing ‎and ‎titration of Sufentanil Citrate Injection are essential. ( 5.2 ) • Concomitant use of opioids with benzodiazepines or other central nervous ‎system (CNS) depressants, including ‎alcohol, may result in profound sedation, ‎respiratory depression, coma, and death. Reserve concomitant prescribing of ‎‎Sufentanil Citrate Injection and benzodiazepines or other CNS depressants for ‎use in patients for whom ‎alternative treatment options are inadequate. ( 5.3 , 7 ) • The concomitant use of Sufentanil Citrate Injection with all cytochrome P450 ‎‎3A4 inhibitors may result in an ‎increase in sufentanil plasma concentrations, ‎which could increase or prolong adverse reactions and may cause ‎potentially ‎fatal respiratory depression. In addition, discontinuation of a concomitantly used ‎cytochrome P450 3A4 ‎inducer may result in an increase in sufentanil plasma ‎concentration. Monitor patients receiving Sufentanil Citrate Injection and any ‎CYP3A4 inhibitor or inducer. ( 5.4 , 7 , 12.3 )