Sufenta (Sufentanil Citrate)

SUFENTA®

Janssen-Ortho

Sufentanil Citrate

Opioid Analgesic-Adjunct to Anesthesia

Action and Clinical Pharmacology:

Sufentanil is an opioid analgesic. The analgesic potency of sufentanil is approximately 5 to 7 times that of fentanyl. Dosage requirements for equianalgesic effect will be 1/5 to  1/7 those of fentanyl on a g/kg basis.

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

I.V. Use: At i.v. doses of up to 8 g/kg, sufentanil provides profound analgesia; at doses 8 g/kg, sufentanil produces a deep level of anesthesia. Sufentanil produces a dose-related attenuation of catecholamine release, particularly norepinephrine.

I.V. sufentanil has an immediate onset of action, with a distribution of 0.72 minutes, redistribution of 13.7 minutes and an elimination half-life of 148 minutes. It is rapidly and extensively metabolized into a large number of inactive metabolites that are excreted with the urine and feces. The liver and small intestine are the major sites of biotransformation; oxidative 0- and N-dealkylation are the primary metabolic pathways. 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 is approximately 92.5%. The pharmacokinetics of i.v. sufentanil can be described as a 3-compartment model, with relatively limited accumulation and rapid elimination from tissue storage sites, allowing for relatively more rapid recovery than with fentanyl.

At i.v. dosages of 8 g/kg, sufentanil produces hypnosis and anesthesia without the use of additional anesthetic induction agents. A deep level of anesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 g/kg attenuate the sympathetic response to surgical stress and maintain cardiovascular stability. The sympathetic response is blocked at doses of sufentanil of 25 to 30 g/kg, with dependable cardiovascular stability, infrequent bradycardia and preservation of myocardial oxygen balance.

Pancuronium may produce a dose-dependent elevation in heart rate and blood pressure during sufentanil-oxygen anesthesia that is not suppressed by the minimal effects of high doses of sufentanil on cardiac function, heart rate or blood pressure. The vagolytic effect of pancuronium may be reduced in patients administered nitrous oxide together with sufentanil. The use of moderate doses of pancuronium or of a less vagolytic neuromuscular blocking agent should maintain stable lower heart rate and blood pressure.

In patients administered high doses of sufentanil, dosage requirements for neuromuscular blocking agents are generally lower as compared to patients given fentanyl or halothane, and comparable to patients given enflurane or isoflurane.

Bradycardia is seen infrequently 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.

In one study of patients undergoing craniotomy, sufentanil at 20 g/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. During carotid endarterectomy, sufentanil produced EEG patterns and reductions in cerebral blood flow and oxygen utilization comparable to those of fentanyl.

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

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

Epidural Use: Epidural sufentanil produces spinal analgesia of rapid onset (within 5 to 10 minutes) and moderate duration (generally 4 to 6 hours). The onset and duration of analgesia appear to be dose-related.

Peak plasma concentrations following single epidural doses of sufentanil are reached within 10 minutes and are 4 to 6 times lower than those after i.v. administration. Systemic absorption within the first 3 hours after epidural administration is approximately 1/3 to 1/2 that of an i.v. bolus. Vascular uptake of sufentanil after high thoracic (T3-4) administration is 3 to 4 times lower than after mid-thoracic to lumbar epidural injection. Coadministration of epinephrine reduces systemic availability of sufentanil, especially in the first hours after injection. Time to peak plasma concentrations and maximum plasma concentrations increase with repeated epidural doses of sufentanil.

Mean sufentanil concentrations in CSF exceeded 2 ng/mL within a few minutes after an epidural injection of 75 g; peak concentrations in the CSF occurred within 5 to 90 minutes. Thereafter, the decay of sufentanil concentrations in the CSF was biphasic with an average sufentanil terminal half-life of 165 minutes compared to 355 minutes in plasma.

During labor and vaginal delivery, the addition of 10 to 30 g sufentanil to bupivacaine (0.125% to 0.25%) provided analgesia of better quality and longer duration versus bupivacaine (0.25%) alone. Apgar scores and neurobehavioral scores of neonates were not affected by the epidural administration of sufentanil to women in labor.

Placental transfer of sufentanil was investigated in women undergoing caesarean section. Within 30 to 55 minutes of epidural doses of 22  to 38 g sufentanil, maternal plasma concentrations varied from £ 0.02 to 0.16 ng/mL; neonatal concentrations were generally below 0.02 ng/mL with measurable levels up to 0.9 ng/mL found in only a few neonates. Fetal plasma concentrations rapidly equilibrate with maternal concentrations. Individual umbilical vein:maternal plasma concentration ratios averaged 0.4. Plasma protein binding of sufentanil, related to the a 1 acid glycoprotein level, was 90.7% in mothers and 79.3% in neonates.

Indications And Clinical Uses :

I.V. Administration: As a primary anesthetic agent for the induction and maintenance of anesthesia with 100% oxygen in patients undergoing major surgical procedures, such as cardiovascular surgery or neurosurgical procedures in the sitting position, for whom myocardial or cerebral oxygen imbalance would be particularly detrimental or for whom extended postoperative ventilation is anticipated.

As an analgesic adjunct at doses up to 8 g/kg in the maintenance of balanced general anesthesia for major surgical procedures.

Epidural Administration: For the postoperative management of pain following general surgery, thoracic or orthopedic procedures and caesarean section. As an analgesic adjunct to epidural bupivacaine during labor and vaginal delivery.

Contra-Indications:

In patients with known hypersensitivity to fentanyl or to other morphinomimetics.:

I.V. use in labor, or before clamping of the cord during caesarian section is not recommended due to the possibility of respiratory depression in the newborn infant. This, in contrast to the epidural use in labor, during which sufentanil in doses up to 30 g does not influence the condition of the mother or the newborn.

As with other opiates administered epidurally, sufentanil should not be given to patients exhibiting the following: severe hemorrhage or shock; septicemia; local infection at the site of proposed puncture; disturbances in blood morphology and/or anticoagulant therapy or other concomitant drug therapy or medical conditions which could contraindicate the technique of epidural administration.

Warnings in Clinical States:

Sufentanil should be administered only by persons specifically trained in the use of i.v. anesthetics and management of the respiratory effects of potent opioids and, when administered epidurally, persons specifically trained in the techniques and patient management associated with epidural administration.

Complete resuscitation equipment and an opioid antagonist should be readily available whenever sufentanil is used.

I.V. administration or inadvertent intravascular injection during epidural administration of sufentanil may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence of muscular rigidity associated with i.v. sufentanil can be reduced by: administration of up to 1/4 of the full paralyzing dose of a nondepolarizing neuromuscular blocking agent just prior to administration of sufentanil at dosages of up to 8 g/kg; incremental administration in divided doses of a full paralyzing dose of a neuromuscular blocking agent following loss of the eyelash reflex during induction with thiopental when sufentanil has been used in doses up to 8 g/kg in major surgical procedures; simultaneous administration of sufentanil and a full paralyzing dose of a neuromuscular blocking agent when sufentanil is used in anesthetic doses (above 8 g/kg).

The neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Dosages above 1 g/kg sufentanil/hour of surgery frequently produce respiratory depression. In a clinical study involving 616 patients, 69 of the 86 patients (80%) who required naloxone in the immediate postoperative period had received a sufentanil dosage in excess of 1 g/kg/hour.

Nonepileptic myoclonic movements can occur.

Precautions:

General: The initial dose should be appropriately reduced in elderly or 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).

High doses of pancuronium may produce increases in heart rate during sufentanil-oxygen anesthesia. Bradycardia and possibly asystole can occur if the patient has received an insufficient amount of anticholinergic or when sufentanil is combined with nonvagolytic muscle relaxants. Bradycardia can be treated with atropine.

Head Injuries: Sufentanil may obscure the clinical course of patients with head injuries. In patients with compromised intracerebral compliance, the use of rapid bolus injections should be avoided; in such patients the transient decrease in mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure.

Impaired Respiration: Sufentanil 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, impaired respiration can be managed by assisted or controlled respiration. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO 2 stimulation which may persist into or recur in the postoperative period. Appropriate postoperative monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained prior to patient discharge from the recovery area.

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.

Patients should be closely monitored for at least 2 hours following each administration of an epidural injection of sufentanil as early respiratory depression may occur.

Opioids may induce hypotension, especially in hypovolemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.

Patients on chronic opioid therapy or with a history of opioid abuse, may require increased amounts of sufentanil.

Careful titration of dosage may be required in patients with conditions such as uncontrolled hypothyroidism or alcoholism (see Drug Interactions; alcohol can potentiate the respiratory depression of opioids). In such cases, prolonged postoperative monitoring is required.

Drug Interactions:

Cytochrome P450 3A4 Enzyme Inhibitors: Sufentanil is metabolized mainly via the human cytochrome P450 3A4 enzyme. However, no in vivo inhibition by erythromycin (a known cytochrome P450 3A4 enzyme inhibitor) has been observed. Although clinical data are lacking, in vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may inhibit the metabolism of sufentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such drugs requires special patient care and observation; in particular, it may be necessary to lower the dose of sufentanil.

Interactions with other CNS Depressants: An additive effect with sufentanil may be exhibited in patients receiving barbiturates, tranquilizers, opioids, general anesthetics or other CNS depressants (e.g., alcohol). In such cases of combined treatment, the dose of sufentanil and/or these agents should be reduced.

MAO Inhibitors: It is usually recommended to discontinue MAO inhibitors 2 weeks prior to any surgical or anesthetic procedure.

Interactions with Beta-Blockers: As with all opioids, a decrease in heart rate and/or blood pressure may be seen when sufentanil is administered to patients on beta-blocker medication.

Hepatic or Renal Impairment: In patients with liver or kidney dysfunction, sufentanil should be administered with caution due to the importance of these organs in its metabolism and excretion of sufentanil.

Pregnancy: Sufentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects were 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 its administration of sufentanil in rats or rabbits. Since the safety of sufentanil in pregnant women has not been established, this drug should be used in pregnancy only if the expected benefits are considered to outweigh any potential risks.

Labor and Delivery: Although the use of epidurally administered sufentanil is indicated for labor and delivery (see Indications and Dosage), caution should be exercised in the presence of fetal distress. The use of i.v. sufentanil in labor and delivery is not recommended (see Contraindications).

Lactation: It is not known whether this drug is excreted in human milk. Because fentanyl analogues are excreted in human milk, caution should be exercised when sufentanil is administered to a nursing woman.

Children: The safety and efficacy of sufentanil in children, particularly under 2 years of age, has been documented only in a limited number of cases. Likewise, documented use of epidural sufentanil in pediatric cases is limited.

Drug Abuse and Dependence: Sufentanil can produce drug dependence of the morphine type and, therefore, has the potential for being abused.

Occupational Hazards: Patients should be advised to allow sufficient time to elapse before operating a car or heavy machinery.

Adverse Reactions:

I.V. Use: The most frequent adverse reactions in 320 patients administered sufentanil i.v. were: hypotension (7%), hypertension (3%), chest wall rigidity (3%), bradycardia (3%).

Other adverse reactions that may occur (reported incidence of less than 1%) are:

Cardiovascular: tachycardia, arrhythmia.

Gastrointestinal: nausea, vomiting.

Respiratory: apnea, postoperative respiratory depression, bronchospasm.

Dermatological: itching.

CNS: chills.

Miscellaneous: intraoperative muscle movement.

Postmarketing adverse reports include: laryngospasm, dizziness, myoclonic movements, and respiratory depression.

Allergic reactions and asystole have been reported; but since several drugs were co-administered during anesthesia, it is uncertain whether there is a causal relationship to the drug.

Epidural Use: The frequency of adverse experiences associated with the use of epidural sufentanil was evaluated in 1 478 postoperative patients and 14 467 parturients. The most frequently reported adverse experiences were somnolence or sedation, pruritus, nausea, vomiting and urinary retention.

During clinical trials, slow respiratory rate (<10 breaths/min) and apneic periods were noted in 3.5% and 2.5% of postoperative patients, respectively. These episodes developed early after drug administration and were resolved within 1 hour. Concomitant use of epinephrine may reduce the incidence and severity of respiratory depression. No respiratory depressive episodes were observed in patients receiving epidural sufentanil during labor and delivery.

Other observed adverse experiences include:

Cardiovascular: hypotension (2%).

CNS: motor block (18%, labor patients only), dizziness (2%), euphoria (2%).

Urinary system disorders: urinary incontinence (1%).

Miscellaneous: fever (1%), shivering (2%), pain at injection site (1%), miosis (1%).

Adverse experiences that occurred in less than 1% of patients are: bradycardia, hypopnea, rash, headache, confusion.

Symptoms And Treatment Of Overdose :

Symptoms: Overdosage would be manifested by an extension of the pharmacological actions (see ) as with other potent opioid analgesics. Depending on the individual sensitivity, the clinical picture is determined primarily by the degree of respiratory depression, which varies from bradypnea to apnea. The i.v. LD 50 of sufentanil in male rats is 12.5 mg/kg.

Treatment: I.V. 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. Additional doses of the latter may therefore be required.

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. I.V. fluids and vasopressors for the treatment of hypotension and other supportive measures may be employed.

Dosage And Administration:

The dosage 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 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.

I.V. Use: See Table I for use by i.v. injection: 1) in doses of up to 8 g/kg as an analgesic adjunct to general anesthesia. 2) in doses 8 g/kg as a primary anesthetic agent for induction and maintenance of anesthesia with 100% oxygen.

Administration with Nitrous Oxide/OxygenIndication Approximate Duration of Anesthesia Initial Dosage Maintenance Increments (included in total dosage) Total Dosage (A cumulative dosage in the range of 0.5-1.0g/kg/hour is recommended)

As an adjunct to major surgery at least 1 hour A minimum of 0.5 g/kg is necessary to control or abolish cardiovascular responses to laryngoscopy and intubation. The initial dosage should represent at least 75% of the total dosage administered during the case. 10-25 g as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia. Supplemental doses should be individualized and adjusted to the remaining operative time anticipated. 0.5-2 g/kg administered as an analgesic adjunct with nitrous oxide/oxygen in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required.

As an adjunct to more complicated major surgery at least 2 hours 25-50 g as determined by changes in vital signs that indicate stress or lightening of analgesia. Supplemental dosages should be individualized and adjusted to the remaining operative time anticipated. 2-8 g/kg administered as an analgesic adjunct with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures. At dosages in this range, sufentanil has been shown to attenuate sympathetic reflex activity in response to surgical stimuli, maintain cardiovascular stability and provide relatively rapid recovery.

Administration with 100% Oxygen

Indication Initial Dosage

Maintenance Increments (included in total dosage) Total Dosage

As a primary anesthetic agent The initial dosage should be individualized with due consideration given to patient status, concomitant medications, and anticipated level of surgical stimulation. See total dosage guidelines.

25-50 g as determined by changes in vital signs that indicate stress and lightening of anesthesia. 8-30 g/kg (anesthetic dosages) administered with 100% oxygen and a muscle relaxant. Sufentanil has been found to produce sleep at dosages 8 g/kg and to maintain a deep level of anesthesia without the use of additional anesthetic agents. At dosages in this range of up to 25 g/kg, catecholamine release is attenuated. High dosages are indicated in patients undergoing surgical procedures such as cardiovascular surgery and neurosurgery in the sitting position, in whom myocardial or cerebral oxygen imbalance would be detrimental. Postoperative mechanical ventilation and observation are essential at these dosages due to extended postoperative respiratory depression.

Note: The suggested i.v. administration rate is 250 to 300 g/min.

Children: For induction and maintenance of anesthesia in children less than 12 years undergoing cardiovascular surgery, an anesthetic dose of 10 to 25 g/kg administered with 100% oxygen is generally recommended. Supplemental dosages of 25 to 50 g are recommended for maintenance based on response to initial dose and as determined by changes in vital signs indicating surgical stress or lightening of anesthesia. Since experience with the use of sufentanil, particularly in the young age group, is limited, anesthetists should be guided by progressive experience with the use of the drug in children.

Premedication: The selection of preanesthetic medications should be based upon the needs of the individual patient.

Neuromuscular Blocking Agents: The neuromuscular blocking agent selected should be compatible with the patient’s condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required (see, Warnings and Precautions).

In patients administered high (anesthetic) doses of sufentanil, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression (see Warnings and Precautions).

Epidural Use: Proper placement of the needle or catheter in the epidural space should be verified prior to sufentanil injection to preclude inadvertent intravascular or intrathecal administration. If analgesia is inadequate, the placement and integrity of the catheter should be verified prior to the administration of any additional epidural medication.

Postoperative Management of Pain: An initial dose of 30 to 60 g sufentanil in 10 mL normal saline may be expected to provide adequate pain relief for up to 4 to 6 hours. Additional boluses of up to 25 g sufentanil may be administered at not less than 1-hour intervals if there is evidence of lightening of analgesia.

Analgesic Adjunct during Labor and Delivery: The recommended initial dose for sufentanil, administered with 0.125% to 0.25% bupivacaine, is 10 g in 10 mL normal saline. If required, 2 subsequent injections of the combination may be given; supplemental doses should be separated by intervals of at least 1 hour. It is recommended that the total sufentanil dose administered not exceed 30 g.

Availability And Storage:

Each mL of sterile, preservative-free aqueous solution contains: sufentanil citrate equivalent to 50 g of sufentanil base and water for i.v. and epidural injection. pH range of 3.5 to 6.0. Ampuls of 1 mL and 5 mL. Packages of 10. Store at controlled room temperature (15 to 25°C). Protect from light.

SUFENTA® Janssen-Ortho Sufentanil Citrate Opioid Analgesic–Adjunct to Anesthesia

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