Sufentanil Citrate

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.

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 overdose reversal agent, 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 overdose reversal agent (e.g., naloxone, nalmefene) , 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 shoul…

5 WARNINGS AND PRECAUTIONS • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.2 ) • Risks of Skeletal Muscle Rigidity and Skeletal Muscle Movement : Manage with neuromuscular blocking agent. See full prescribing information for more detail on managing these risks. ( 5.5 ) • Severe Cardiovascular Depression : Monitor during dosage initiation and titration. ( 5.6 ) • Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced ‎Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an increase in pain, or an increase in ‎sensitivity to pain. If OIH is suspected, carefully consider appropriately ‎decreasing the dose of the current opioid analgesic, or ‎opioid rotation. ( 5.7 )‎ • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected. ( 5.8 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury : Monitor for sedation and respiratory depression. ( 5.10 ) 5.1 Addiction, Abuse, and Misuse Sufentanil Citrate Injection contains sufentanil, a Schedule II controlled substance. As an opioid, Sufentanil Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Consider these risks when handling Sufentanil Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Sufentanil Citrate Injection should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Sufentanil Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene) , depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. As with other potent opioids, the respiratory depressant effect of Sufentanil Citrate Injection 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. Certain forms of conduction anesthesia, such as spinal anesthesia and some epidural anesthetics, can alter respiration by blocking intercostal nerves [see Clinical Pharmacology (12.2) ]. Sufentanil Citrate Injection can also alter respiration. Therefore, when Sufentanil Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these fo…

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 )

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 at frequent intervals for respiratory depression and sedation. 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 may 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 [see Warnings and Precautions (5.2 , 5.3 )] . 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, gabapentinoids (gabapentin or pregabalin), 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 reupt…

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 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 nonmedical 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 overdose reversal agent, such as naloxone or nalmefene, 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 de…

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) ] • Skeletal Muscle Rigidity and Skeletal Muscle Movement [see Warnings and Precautions (5.5) ] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] • Severe Cardiovascular Depression [see Warnings and Precautions (5.6) ] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7) ]‎ • Serotonin Syndrome [see Warnings and Precautions (5.8) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11) ] • ‎ Seizures [see Warnings and Precautions (5.12) ] Most common adverse reactions were apnea, rigidity, and bradycardia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 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 Warn…