Sufentanil Citrate Injection, USP
CII

Sufentanil Citrate Injection, USP is a sterile, nonpyrogenic, aqueous solution for intravenous and epidural injection. Each mL contains sufentanil citrate equivalent to 50 mcg (0.05 mg) of sufentanil in Water for Injection. pH 3.5–6.0; citric acid added, if needed, for pH adjustment. Contains no preservative. Sufentanil Citrate is a potent opioid analgesic chemically designated as N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate (1:1) with the following structural formula:

Sufentanil is an opioid analgesic. 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.

Assays of histamine in patients administered sufentanil citrate have shown no elevation in plasma histamine levels and no indication of histamine release.

(See dosage chart for more complete information on the intravenous use of Sufentanil Citrate Injection.)

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 bupivacaine, usually 12.5 mg per administration, during labor and vaginal delivery.

SEE DOSAGE AND ADMINISTRATION SECTION FOR MORE COMPLETE INFORMATION ON THE USE OF SUFENTANIL.

Sufentanil Citrate Injection is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists.

SUFENTANIL CITRATE INJECTION SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS AND EPIDURAL ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT OPIOIDS.

AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE.

PRIOR TO CATHETER INSERTION, THE PHYSICIAN SHOULD BE FAMILIAR WITH PATIENT CONDITIONS (SUCH AS INFECTION AT THE INJECTION SITE, BLEEDING DIATHESIS, ANTICOAGULANT THERAPY, ETC.) WHICH CALL FOR SPECIAL EVALUATION OF THE BENEFIT VERSUS RISK POTENTIAL.

Intravenous administration or unintentional intravascular injection during epidural administration of sufentanil citrate may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is dose related. Administration of sufentanil may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. As with fentanyl, muscular rigidity has been reported to occur or recur infrequently in the extended postoperative period. The incidence of muscular rigidity associated with intravenous sufentanil can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of sufentanil at dosages up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when sufentanil is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion or 3) simultaneous administration of sufentanil and a full paralyzing dose of a neuromuscular blocking agent when sufentanil is used in rapidly administered anesthetic dosages (above 8 mcg/kg).

The neuromuscular blocking agents used should be compatible with the patient’s cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.

The initial dose of sufentanil should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses.

Vital signs should be monitored routinely.

Nitrous oxide may produce cardiovascular depression when given with high doses of sufentanil (see CLINICAL PHARMACOLOGY).

Bradycardia has been reported infrequently with sufentanil-oxygen anesthesia and has been responsive to atropine.

Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by sufentanil may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO₂ stimulation which may persist into or recur in the postoperative period. Respiratory depression may be enhanced when sufentanil is administered in combination with volatile inhalational agents and/or other central nervous system depressants such as barbiturates, tranquilizers and other opioids. Appropriate postoperative monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained prior to discharging the patient from the recovery area. Respiration should be closely monitored following each administration of an epidural injection of sufentanil.

Proper placement of the needle or catheter in the epidural space should be verified before sufentanil 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. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medications. Sufentanil should be administered epidurally by slow injection.

The use of epidurally administered sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.) 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).

It is not known whether sufentanil is excreted in human milk. Because fentanyl analogs are excreted in human milk, caution should be exercised when sufentanil citrate is administered to a nursing woman.

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.

The intravenous LD₅₀ of sufentanil is 16.8 to 18.0 mg/kg in mice, 11.8 to 13.0 mg/kg in guinea pigs and 10.1 to 19.5 mg/kg in dogs. Reproduction studies performed in rats and rabbits given doses up to 2.5 times the upper human intravenous dose for a period of 10 to over 30 days revealed high maternal mortality rates due to decreased food consumption and anoxia, which preclude any meaningful interpretation of the results. Epidural and intrathecal injections of sufentanil in dogs and epidural injections in rats were not associated with neurotoxicity.

The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Sufentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See CLINICAL PHARMACOLOGY,WARNINGS and PRECAUTIONS on the management of respiratory depression and skeletal muscle rigidity. Urinary retention has been associated with the use of epidural opioids but was not reported in the clinical trials of epidurally administered sufentanil due to the use of indwelling catheters. The incidence of urinary retention in patients without urinary catheters receiving epidural sufentanil is unknown; return of normal bladder activity may be delayed.

The following adverse reaction information is derived from controlled clinical trials in 320 patients who received intravenous sufentanil during surgical anesthesia and in 340 patients who received epidural sufentanil plus bupivacaine 0.125% for analgesia during labor. Based on the observed frequency, none of the reactions occurring with an incidence less than 1% were observed during clinical trials of epidural sufentanil used during labor and delivery (N=340).

In general, cardiovascular and musculoskeletal adverse experiences were not observed in clinical trials of epidural sufentanil. Hypotension was observed 7 times more frequently in intravenous trials than in epidural trials. The incidence of central nervous system, dermatological and gastrointestinal adverse experiences was approximately 4 to 25 times higher in studies of epidural use in labor and delivery.

Probably Causally Related: Incidence greater than 1% – Derived from clinical trials

(See preceding p)

Cardiovascular – bradycardia*, hypertension*, hypotension*

Musculoskeletal – chest wall rigidity*

Central Nervous System – somnolence*

Dermatological – pruritus (25%)

Gastrointestinal – nausea*, vomiting*

*Incidence 3% to 9%

Probably Causally Related: Incidence less than 1% – Derived from clinical trials

(Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized)

Body as a whole – anaphylaxis

Cardiovascular – arrhythmia*, tachycardia*, cardiac arrest

Central Nervous System – chills*

Dermatological – erythema*

Musculoskeletal – skeletal muscle rigidity of neck and extremities

Respiratory – apnea*, bronchospasm*, postoperative respiratory depression*

Miscellaneous – intraoperative muscle movement*

*Incidence 0.3 to 1%

Sufentanil Citrate Injection is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused.

Overdosage is manifested by an extension of the pharmacological actions of sufentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. The most serious and significant effect of overdose for both intravenous and epidural administration of sufentanil is respiratory depression. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with sufentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude more immediate countermeasures. In the event of overdosage, oxygen should be administered and ventilation assisted or controlled as indicated for hypoventilation or apnea. A patent airway must be maintained, and a nasopharyngeal airway or endotracheal tube may be indicated. If depressed respiration is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed.

The dosage of sufentanil should be individualized in each case according to body weight, physical status, underlying pathological condition, use of other drugs, and type of surgical procedure and anesthesia. In obese patients (more than 20% above ideal total body weight), the dosage of sufentanil should be determined on the basis of lean body weight. Dosage should be reduced in elderly and debilitated patients (see PRECAUTIONS).

Vital signs should be monitored routinely.

Because the clearance of sufentanil is reduced in neonates, especially those with cardiovascular disease, the dose of sufentanil should be reduced accordingly (see PRECAUTIONS).

Sufentanil citrate may be administered intravenously by slow injection or infusion 1) in doses up to 8 mcg/kg as an analgesic adjunct to general anesthesia and 2) in doses ≥ 8 mcg/kg as a primary anesthetic agent for induction and maintenance of anesthesia (seeDosage Range Chart). If benzodiazepines, barbiturates, inhalation agents, other opioids or other central nervous system depressants are used concomitantly, the dose of sufentanil and/or these agents should be reduced (see PRECAUTIONS). In all cases, dosage should be titrated to individual patient response.

Sufentanil Citrate Injection, USP, equivalent to 50 mcg (0.05 mg) sufentanil per mL, is available in the following:

1 mL (50 mcg) DOSETTE ampuls packaged in 10s (NDC 10019-050-43)

2 mL (100 mcg) DOSETTE ampuls packaged in 10s (NDC 10019-050-21)

5 mL (250 mcg) DOSETTE ampuls packaged in 10s (NDC 10019-050-06)

PROTECT FROM LIGHT: Keep covered in carton until time of use.

Store at 20˚-25˚C (68˚-77˚F), excursions permitted to 15˚-30˚C (59˚-86˚F) [see USP Controlled Room Temperature].

Baxter and Dosette are trademarks of Baxter International Inc., or its subsidiaries.

Manufactured by

Baxter Healthcare Corporation

Deerfield, IL 60015 USA

For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)

MLT-7/1.0