Sufentanil (Sufentanil Citrate Epidural) - Description and Clinical Pharmacology

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WARNING: MAY BE HABIT FORMING

FOR INTRAVENOUS OR EPIDURAL USE

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Retain in carton until time of use.

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 C₂₂H₃₀N₂O₂S•C₆H₈O₇ and the molecular weight is 578.69. Sufentanil Citrate has the following structural formula:

CLINICAL PHARMACOLOGY

Pharmacology

Sufentanil citrate 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 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.)

Pharmacodynamics

Intravenous Use

At intravenous doses of up to 8 mcg/kg, sufentanil is an analgesic component of general anesthesia; at intravenous doses ≥8 mcg/kg, sufentanil produces a deep level of anesthesia. Sufentanil produces a dose related attenuation of catecholamine release, particularly norepinephrine.

At intravenous dosages of ≥8 mcg/kg, sufentanil produces hypnosis and anesthesia without the use of additional anesthetic agents. A deep level of anesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/kg attenuate the sympathetic response to surgical stress. The catecholamine response, particularly norepinephrine, is further attenuated at doses of sufentanil of 25-30 mcg/kg with hemodynamic stability and preservation of favorable myocardial oxygen balance.

Sufentanil has an immediate onset of action, with relatively limited accumulation. Rapid elimination from tissue storage sites allows for relatively more rapid recovery as compared with equipotent dosages of fentanyl. At dosages of 1-2 mcg/kg, recovery times are comparable to those observed with fentanyl; at dosages of > 2-6 mcg/kg, recovery times are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic dosage range of 8-30 mcg/kg of sufentanil, recovery times are more rapid compared to equipotent fentanyl dosages.

The vagolytic effects of pancuronium may produce a dose dependent elevation in heart rate during sufentanil-oxygen anesthesia. The use of moderate doses of pancuronium or of a less vagolytic neuromuscular blocking agent may be used to maintain a stable lower heart rate and blood pressure during sufentanil-oxygen anesthesia. The vagolytic effects of pancuronium may be reduced in patients administered nitrous oxide with sufentanil.

Preliminary data suggest that in patients administered high doses of sufentanil, initial dosage requirements for neuromuscular blocking agents are generally lower as compared to patients given fentanyl or halothane, and comparable to patients given enflurane.

Bradycardia is infrequently seen in patients administered sufentanil-oxygen anesthesia. The use of nitrous oxide with high doses of sufentanil may decrease mean arterial pressure, heart rate and cardiac output.

Sufentanil at 20 mcg/kg has been shown to provide more adequate reduction in intracranial volume than equivalent doses of fentanyl, based upon requirements for furosemide and anesthesia supplementation in one study of patients undergoing craniotomy. During carotid endarterectomy, sufentanil-nitrous oxide/oxygen produced reductionsin cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen. During cardiovascular surgery, sufentanil-oxygen produced EEG patterns similar to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate general anesthesia.

The intraoperative use of sufentanil at anesthetic dosages maintains cardiac output, with a slight reduction in systemic vascular resistance during the initial postoperative period. The incidence of postoperative hypertension, need for vasoactive agents and requirements for postoperative analgesics are generally reduced in patients administered moderate or high doses of sufentanil as compared to patients given inhalation agents.

Skeletal muscle rigidity is related to the dose and speed of administration of sufentanil. This muscular rigidity may occur unless preventative measures are taken (see WARNINGS).

Decreased respiratory drive and increased airway resistance occur with sufentanil. The duration and degree of respiratory depression are dose related when sufentanil is used at sub-anesthetic dosages. At high doses, a pronounced decrease in pulmonary exchange and apnea may be produced.

Epidural Use in Labor and Delivery

Onset of analgesic effect occurs within approximately 10 minutes of administration of epidural doses of sufentanil and bupivacaine. Duration of analgesia following a single epidural injection of 10-15 mcg sufentanil and bupivacaine 0.125% averaged 1.7 hours.

During labor and vaginal delivery, the addition of 10-15 mcg sufentanil to 10 mL 0.125% bupivacaine provides an increase in the duration of analgesia compared to bupivacaine without an opioid. Analgesia from 15 mcg sufentanil plus 10 mL 0.125% bupivacaine is comparable to analgesia from 10 mL of 0.25% bupivacaine alone. Apgar scores of neonates following epidural administration of both drugs to women in labor were comparable to neonates whose mothers received bupivacaine without an opioid epidurally.

Pharmacokinetics

Intravenous Use

The pharmacokinetics of intravenous sufentanil can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and an elimination half-life of 164 minutes. The liver and small intestine are the major sites of biotransformation. Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug. Plasma protein binding of sufentanil, related to the alpha₁ acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates.

Epidural Use in Labor and Delivery

After epidural administration of incremental doses totaling 5-40 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.

Animal Toxicology:

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 of 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.

CLINICAL STUDIES

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multi-center) 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 -15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1-2 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.