CLINICAL PHARMACOLOGY
Pharmacology
SUFENTA is an opioid analgesic. When used in balanced general anesthesia, SUFENTA 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, SUFENTA is approximately 5 to 7 times as potent as fentanyl.
Assays of histamine in patients administered SUFENTA 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 SUFENTA.)
Pharmacodynamics
Intravenous use
At intravenous doses of up to 8 mcg/kg, SUFENTA is an analgesic component of general anesthesia; at intravenous doses ≥8 mcg/kg, SUFENTA produces a deep level of anesthesia. SUFENTA produces a dose related attenuation of catecholamine release, particularly norepinephrine.
At intravenous dosages of ≥8 mcg/kg, SUFENTA 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 SUFENTA of 25 to 30 mcg/kg, with hemodynamic stability and preservation of favorable myocardial oxygen balance.
SUFENTA 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 to 2 mcg/kg, recovery times are comparable to those observed with fentanyl; at dosages of >2 to 6 mcg/kg, recovery times are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic dosage range of 8 to 30 mcg/kg of SUFENTA, 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 SUFENTA-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 SUFENTA-oxygen anesthesia. The vagolytic effects of pancuronium may be reduced in patients administered nitrous oxide with SUFENTA.
Preliminary data suggest that in patients administered high doses of SUFENTA, 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 SUFENTA-oxygen anesthesia. The use of nitrous oxide with high doses of SUFENTA may decrease mean arterial pressure, heart rate and cardiac output.
SUFENTA 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, SUFENTA-nitrous oxide/oxygen produced reductions in cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen. During cardiovascular surgery, SUFENTA-oxygen produced EEG patterns similar to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate general anesthesia.
The intraoperative use of SUFENTA 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 SUFENTA as compared to patients given inhalation agents.
Skeletal muscle rigidity is related to the dose and speed of administration of SUFENTA. This muscular rigidity may occur unless preventative measures are taken (see WARNINGS).
Decreased respiratory drive and increased airway resistance occur with SUFENTA. The duration and degree of respiratory depression are dose related when SUFENTA 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 SUFENTA and bupivacaine. Duration of analgesia following a single epidural injection of 10 to 15 mcg SUFENTA and bupivacaine 0.125% averaged 1.7 hours.
During labor and vaginal delivery, the addition of 10 to 15 mcg SUFENTA to 10 mL 0.125% bupivacaine provides an increase in the duration of analgesia compared to bupivacaine without an opioid. Analgesia from 15 mcg SUFENTA 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 SUFENTA can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and elimination half-life of 164 minutes in adults. The elimination half-life of SUFENTA 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. 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 alpha 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 to 40 mcg SUFENTA 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.
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