WARNINGS
SUFENTA 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 use
Intravenous administration or unintentional intravascular injection during epidural administration of SUFENTA may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is dose related. Administration of SUFENTA may produce muscular rigidity with a more rapid onset of action than that seen with fentanyl. SUFENTA 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 SUFENTA 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 SUFENTA at dosages of up to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of consciousness when SUFENTA is used in anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion, or, 3) simultaneous administration of SUFENTA and a full paralyzing dose of a neuromuscular blocking agent when SUFENTA 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 SUFENTA. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.
PRECAUTIONS
General
The initial dose of SUFENTA 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 SUFENTA (see CLINICAL PHARMACOLOGY).
Bradycardia has been reported infrequently with SUFENTA-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 SUFENTA 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 SUFENTA 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 SUFENTA.
Proper placement of the needle or catheter in the epidural space should be verified before SUFENTA is injected to assure that unintentional intravascular or intrathecal administration does not occur. Unintentional intravascular injection of SUFENTA 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. SUFENTA should be administered epidurally by slow injection.
Neuromuscular Blocking Agents
The hemodynamic effects and degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. High doses of pancuronium may produce increases in heart rate during SUFENTA-oxygen anesthesia. Bradycardia and hypotension have been reported with other muscle relaxants during SUFENTA-oxygen anesthesia; this effect may be more pronounced in the presence of calcium channel and/or beta-blockers. Muscle relaxants with no clinically significant effect on heart rate (at recommended doses) would not counteract the vagotonic effect of SUFENTA, therefore a lower heart rate would be expected. Rare reports of bradycardia associated with the concomitant use of succinylcholine and SUFENTA have been reported.
Interaction with Calcium Channel and Beta Blockers
The incidence and degree of bradycardia and hypotension during induction with SUFENTA may be greater in patients on chronic calcium channel and beta blocker therapy. (See Neuromuscular Blocking Agents.)
Interaction with Other Central Nervous System Depressants
Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when SUFENTA is administered to patients receiving barbiturates, tranquilizers, other opioids, general anesthetic or other CNS depressants. In such cases of combined treatment, the dose of SUFENTA and/or these agents should be reduced.
The use of benzodiazepines with SUFENTA during induction may result in a decrease in mean arterial pressure and systemic vascular resistance.
Head Injuries
SUFENTA may obscure the clinical course of patients with head injuries.
Impaired Respiration
SUFENTA should be used with caution in patients with pulmonary disease, decreased respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration.
Impaired Hepatic or Renal Function
In patients with liver or kidney dysfunction, SUFENTA should be administered with caution due to the importance of these organs in the metabolism and excretion of SUFENTA.
Carcinogenesis, Mutagenesis and Impairment of Fertility
No long-term animal studies of SUFENTA have been performed to evaluate carcinogenic potential. The micronucleus test in female rats revealed that single intravenous doses of SUFENTA as high as 80 mcg/kg (approximately 2.5 times the upper human intravenous dose) produced no structural chromosome mutations. The Ames Salmonella typhimurium metabolic activating test also revealed no mutagenic activity. See ANIMAL TOXICOLOGY for reproduction studies in rats and rabbits.
Pregnancy Category C
SUFENTA has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human intravenous dose for a period of 10 days to over 30 days. These effects were most probably due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug.
No evidence of teratogenic effects have been observed after administration of SUFENTA in rats or rabbits.
Labor and Delivery
The use of epidurally administered SUFENTA in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections.) SUFENTA 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).
Nursing Mothers
It is not known whether sufentanil is excreted in human milk. Because fentanyl analogs are excreted in human milk, caution should be exercised when SUFENTA is administered to a nursing woman.
Pediatric Use
The safety and efficacy of intravenous SUFENTA in pediatric patients as young as 1 day old undergoing cardiovascular surgery have been documented in a limited number of cases. The clearance of SUFENTA in healthy neonates is approximately one-half that in adults and children. The clearance rate of SUFENTA 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.
Animal Toxicology
The intravenous LD50 of SUFENTA 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.
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