Fentanyl Citrate

RECENT MAJOR CHANGES Dosage and Administration ( 2.1 ) 12/2025 Warnings and Precautions ( 5.2 , 5.3 , 5.11 ) 12/2025

1 INDICATIONS AND USAGE Fentanyl Citrate Injection is indicated for: analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises. use as a narcotic analgesic supplement in general or regional anesthesia. administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. use as an anesthetic agent with oxygen in selected high-risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures. Fentanyl Citrate Injection is indicated for: analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises. use as an opioid analgesic supplement in general or regional anesthesia. administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. use as an anesthetic agent with oxygen in selected high-risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

2 DOSAGE AND ADMINISTRATION Fentanyl 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 the 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 treatment in adults with 50 mcg to 100 mcg. ( 2.2 ) Initiate treatment in children 2 to 12 years of age, with a reduced dose as low as 2 mcg/kg to 3 mcg/kg. ( 2.2 ) 2.1 Important Dosage and Administration Instructions Fentanyl 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 (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 routinely. As with other potent opioids, the respiratory depressant effect of fentanyl 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 Fentanyl 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 (5.4) ] . Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Dosage Premedication in Adults 50 mcg to 100 mcg may be administered intramuscularly 30 to 60 minutes prior to surgery. Adjunct to General Anesthesia See Dosage Range Charts below. Table 1: Dosage Range Chart Total Dosage (expressed as fentanyl base) Low Dose —2 mcg/kg For use in minor, but painful, surgical procedures. May also provide some pain relief in the immediate postoperative period. Moderate Dose —2 mcg/kg to 20 mcg/kg For use in more major surgical procedures, in addition to adequate analgesia, may abolish some of the stress response. Expect respiratory depression requiring artificial ventilation during anesthesia and careful observation of ventilation postoperatively is essential. High dose —20 mcg/kg to 50 mcg/kg For open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and the stress response to surgery would be detrimental to the well-being of the patient. In conjunction with nitrous oxide/oxygen has been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin. Expect the need of postoperative ventilation and observation due to extended post-operative respiratory depression. Maintenance Dose (expressed as fentanyl base) Low Dose —2 mcg/kg Additional dosages infrequently needed in these minor procedures. Moderate Dose —2 mcg/kg to 20 mcg/kg 25 mcg to 100 mcg Administer intravenously or intramuscularly as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. High Dose —20 mcg/kg to 50 mcg/kg Maintenance dosage [ranging from 25 mcg to one half the initial loading dose] as needed based on vital signs indicative of stress and lightening of analgesia. Individualize the dosage especially if the anticipated remaining operative time is short. Adjunct to Regio …

3 DOSAGE FORMS AND STRENGTHS Single-Dose Vials and Prefilled Syringes: Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 1 mL, 2 mL, 5 mL, 20 mL, 50 mL single-dose glass vials and 0.5 mL and 1 mL single-dose, prefilled, glass syringes. Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 1 mL, 2 mL, 5 mL, 20 mL, 50 mL single-dose glass vials and 0.5 mL and 1 mL single-dose prefilled, glass syringes ( 3 )

4 CONTRAINDICATIONS Fentanyl Citrate Injection is contraindicated in patients with: Hypersensitivity to fentanyl (e.g., anaphylaxis) [See Adverse Reactions (6) ] Hypersensitivity to fentanyl (4)

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4) ] 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) ] The following adverse reactions associated with the use of fentanyl were identified in clinical studies or postmarketing reports. Because some of these reactions were 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. As with other opioid agonists, the most common serious adverse reactions reported to occur with fentanyl are respiratory depression, apnea, rigidity and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm, diaphoresis, serotonin syndrome, adrenal insufficiency, and anaphylaxis. It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. When a tranquilizer is used with Fentanyl Citrate Injection, the following adverse reactions can occur: chills and/or shivering, restlessness and postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression); extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with fentanyl citrate. Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of fentanyl citrate with a neuroleptic agent. 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 Fentanyl 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) ] . Hypoglycemia : Causes of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.11) ]. Most common serious adverse reactions were respiratory depression, apnea, rigidity, and bradycardia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with Fentanyl Citrate Injection. Table 2: Clinically Significant Drug Interactions with Fentanyl Citrate Injection Inhibitors of CYP3A4 Clinical Impact : The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved [see Warnings and Precautions (5.3) ] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl 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 fentanyl. Intervention: If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved [see Dosage and Administration (2.1) ] . Monitor patients for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl 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 Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3) ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl 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 Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl 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 Fentanyl 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 Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl 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 Fentanyl 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 (5.4) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, 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 Fentanyl Citrate Injection if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephr …

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. (8.1) Lactation : Infants exposed to Fentanyl Citrate Injection through breast milk should be monitored for excess sedation and respiratory depression. (8.2) Geriatric Patients : Titrate slowly and monitor for CNS and respiratory depression. (8.5) 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 Fentanyl Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations) . In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [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. Labor or Delivery There are insufficient data to support the use of fentanyl in labor or delivery. Therefore, such use is not recommended. 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. Fentanyl 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 Fentanyl 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. Data Animal Data Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m 2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m 2 basis). There was no evidence of teratogenicity reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m 2 basis. 8.2 Lactation Risk Summary Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.38%. However, …

12.1 Mechanism of Action Fentanyl Citrate Injection is an opioid agonist, whose principal actions of therapeutic value are analgesia and sedation.

11 DESCRIPTION Fentanyl Citrate Injection is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration. Fentanyl citrate is chemically identified as N- (1-Phenethyl-4-piperidyl)propionanilide citrate (1:1) with the following structural formula: C 22 H 28 N 2 O • C 6 H 8 O 7 Molecular Weight is 528.59 Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection. Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment. The pH range is 4.0 – 7.5. Contains no preservative. structural formula

10 OVERDOSAGE Clinical Presentation Acute overdose with fentanyl 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, hypoglycemia, 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) ] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid overdose reversal agent such as naloxone of nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the overdose reversal agent 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 reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

16 HOW SUPPLIED/STORAGE AND HANDLING Fentanyl Citrate Injection, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows: NDC 0641-6247-25 1 mL Single Dose vials packaged in 25s NDC 0641-6027-25 2 mL Single Dose vials packaged in 25s NDC 0641-6028-10 5 mL Single Dose vials packaged in 10s NDC 0641-6248-10 1 mL Single Dose prefilled syringes in 10s NDC 0641-6249-10 0.5 mL Single Dose prefilled syringes in 10s For Intravenous Use by Hospital Personnel Specifically Trained in the Use of Narcotic Analgesics: NDC 0641-6029-01 20 mL Single Dose vials packaged individually NDC 0641-6030-01 50 mL Single Dose vials packaged individually PROTECT FROM LIGHT. Keep covered in carton until time of use. Store at 20 ̊C to 25 ̊C (68 ̊F to 77 ̊F), excursions permitted to 15 ̊C to 30 ̊C (59 ̊F to 86 ̊F) [See USP Controlled Room Temperature]. Contains no preservative. DISCARD UNUSED PORTION. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Product Inquiry call 1-877-845-0689.