Sufentanil Citrate Injection (sufentanil) is indicated for intravenous administration:
As a primary anaesthetic agent for the induction and maintenance of balanced general anaesthesia 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 mcg/kg in the maintenance of balanced general anaesthesia for major surgical procedures.
Sufentanil Citrate Injection is indicated for epidural administration: For the postoperative management of pain following general surgery, thoracic or orthopaedic procedures and caesarean section. As an analgesic adjunct to epidural bupivacaine during labour and vaginal delivery.
Geriatrics (>65 years of age):
Dose reduction should be considered, as the elderly are more susceptible to the effects of anaesthetic agents.
Paediatrics (< 18 years of age):
The safety and efficacy in children, particularly in children younger than 2 years of age, has been documented only in a limited number of cases. For use in children younger than 12 years of age undergoing cardiovascular surgery, see specific instructions in Dosage and Administration, Intravenous use, Use in Children.
Patients who are hypersensitive to sufentanil or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging section of the product monograph.
Patients with known hypersensitivity to fentanyl or to other morphinomimetics.
Intravenous use in labour or before clamping of the cord during caesarean section is not recommended due to the possibility of respiratory depression in the new-born infant. This is in contrast to the epidural use in labour, during which sufentanil in doses up to 30 mcg does not influence the condition of the mother or the new-born.
As with other opiates administered epidurally, sufentanil should not be given to patients exhibiting the following:
severe haemorrhage or shock;
septicaemia;
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.
General
Skeletal muscle rigidity
Intravenous 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 intravenous sufentanil citrate can be reduced by:
Administration of up to 1/4 of the full paralysing dose of a nondepolarising neuromuscular blocking agent just prior to administration of sufentanil at dosages of up to 8 mcg/kg.
Incremental administration in divided doses of a full paralysing 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 mcg/kg in major surgical procedures;
Simultaneous administration of sufentanil and a full paralysing dose of a neuromuscular blocking agent when sufentanil is used in anaesthetic doses (above 8 mcg/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 anaesthetic doses of sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Dosages above 1 mcg/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 mcg/kg/hour. Nonepileptic myoclonic movements can occur. Elderly and debilitated patients The initial dose of sufentanil should be appropriately reduced in elderly and debilitated patients. Thee of the initial dose should be considered in determine supplemental doses.
Cardiovascular
The cardiovascular effects of opioids may result in drug interactions with other drugs frequently used during anaesthesia. The neuromuscular blocking agent used should be compatible with the patient's cardiovascular status. 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. Opioid analgesics may induce hypotension, especially in hypovolemic patients. Nitrous oxide may produce cardiovascular depression when given with high doses of sufentanil citrate (see Action and Clinical Pharmacology). Appropriate measures to maintain a stable arterial pressure should be taken. [Not to sponsor: Moved from below.]
Endocrine and Metabolism
Hypothyroidism and Alcoholism
Careful titration of dosage may be required in patients with conditions such as uncontrolled hypothyroidism or alcoholism (see Drug Interactions). In such cases, prolonged postoperative monitoring is required.
Gastrointestinal
Smooth muscle spasm
Opioid analgesics stimulate the tonic contraction of the smooth muscle in the gastrointestinal system. The following conditions are associated with use of opioid analgesics, including constipation, delay of gastric emptying, postoperative ilius, and increase in intrabiliary pressure.
Nausea and vomiting
Opioid analgesics activate the chemoreceptor trigger zone. This effect is increased by head movement. Nausea and vomiting may occur in a portion of patients.
Hepatic/Renal
In patients with liver or kidney dysfunction, sufentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of sufentanil.
Neurologic and Neurosurgic
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.
Pupil Constriction
Opioid analgesics cause constriction of the pupils. There is little tolerance to this central effect. This effect is present even at high doses and repeated use.
Driving and Operating Machinery
Patients should be advised to allow sufficient time to elapse before operating a car or heavy machinery.
Respiratory
Respiratory depression
Opioid analgesics depress respiration. In particular, 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 anaesthesia, 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 CO2 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.
Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anaesthetic doses of sufentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Dosages above 1 mcg/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 mcg/kg/hour.
Tolerance and Dependence
Repeated use of opioid analgesics result in tolerance or even dependence and, therefore, has the potential for being abused. Patients on chronic opioid therapy or with a history of narcotic abuse may require increased amounts of sufentanil.
Urinary
Urinary retention
Opioid analgesics can also cause tonic contraction of the urinary smooth muscle, leading to urinary retention. This effect is more likely to occur after epidural analgesia.
Special Populations
Sufentanil has been shown to have an embryocidal effect in rats and rabbits when given at 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 has been observed after 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.
Although the use of epidurally administered sufentanil is indicated for labour and delivery (see
and
), caution should be exercised in the presence of foetal distress. The use of intravenous sufentanil in labour and delivery is not recommended (see
).
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.
The safety and efficacy of intravenous 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 paediatric cases is limited.
For use in children younger than 12 years of age undergoing cardiovascular surgery, see specific instructions in Dosage and Administration, Intravenous use, Use in Children.
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.
Adverse Drug Reaction Overview
Intravenous use
The most frequent adverse reactions in 320 patients administered sufentanil intravenously 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: apnoea, postoperative respiratory depression, bronchospasm; dermatological: itching; central nervous system: chills; miscellaneous: intraoperative muscle movement. Allergic reactions and asystole have been reported; but since several drugs were co-administered during anaesthesia, 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 apnoeic 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 labour and delivery. Other observed adverse experiences include: cardiovascular: hypotension (2%); central nervous system: motor block (18%, labour 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, hypopnoea, rash, headache, and confusion.
Post-Market Adverse Drug Reactions
Postmarketing adverse reports include: laryngospasm, dizziness, myoclonic movements, and respiratory depression.
Overview
As sufentanil is used for intravenous anaesthesia and epidural analgesia during child-birth, drug interactions with medications used in general anaesthesia and obstetrics are likely.
Drug-Drug Interactions
Cytochrome P450 3A4 (CYP 3A4) Enzyme Inhibitors: Sufentanil is metabolised mainly via the human cytochrome CYP 3A4 enzyme. However, no in vivo inhibition by erythromycin (a known cytochrome CYP 3A4 enzyme inhibitor) has been observed. Although clinical data are lacking, other drugs such as ketoconazole, itraconazole, and ritonavir, are also known to be clinically important inhibitors of cytochrome CYP 3A4. As such they 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.
An additive effect with sufentanil may be exhibited in patients receiving barbiturates, tranquilizers, other opioids, general anaesthetics or other CNS depressants (e.g., alcohol). In such cases of combined treatment, the dose of sufentanil and/or these agents should be reduced.
It is usually recommended to discontinue monoamine oxidase (MAO) inhibitors 2 weeks prior to any surgical or anaesthetic procedure.
As with all opioids, a decrease in heart rate and/or blood pressure may be seen when sufentanil is administered to patients who are on beta-blocker medication.
Drug-Food Interactions
Graph fruit juice is known to produce clinically relevant inhibition of CYP 3A4. It may inhibit the metabolism of sufentanil.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Sufentanil can only be administered by qualified professionals working in adequate facilities. Complete equipment for artificial respiration, resuscitation, and opioid antagonism must be readily available whenever sufentanil is used (see Warnings and Precautions). Vital signs should be monitored routinely in all patients receiving sufentanil.
Dosing Considerations
The dosage of sufentanil should be individualised in each case according to body weight, physical status, underlying pathological condition, use of other drugs, and type of surgical procedure and anaesthesia. 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 Warnings and Precautions).
The selection of preanaesthetic medications should be based upon the needs of the individual patient.
The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of particular muscle relaxants and the degree of skeletal muscle relaxation required (see Action and Clinical Pharmacology, Warnings and Precautions).
Recommended Dose and Dosage Adjustment
Intravenous Use
See dosage range chart for the use of sufentanil citrate by intravenous injection:
in doses of up to 8 mcg/kg as an analgesic adjunct to general anaesthesia;
in doses >=8 mcg/kg as a primary anaesthetic agent for induction and maintenance of anaesthesia with 100% oxygen.
Usage in Children
For induction and maintenance of anaesthesia in children less than 12 years of age undergoing cardiovascular surgery, an anaesthetic dose of 10-25 mcg/kg administered with 100% oxygen is generally recommended. Supplemental dosages of 25-50 mcg are recommended for maintenance based on response to initial dose and as determined by changes in vital signs indicating surgical stress or depth of anaesthesia. Since experience with the use of sufentanil, particularly in the young age group, is limited, anaesthetists should be guided by progressive experience with the use of the drug in children.
Proper placement of the needle or catheter in the epidural space should be verified prior to sufentanil citrate 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 30-60 mcg sufentanil in 10 mL normal saline may be expected to provide adequate pain relief for up to 4-6 hours. Additional boluses of up to 25 mcg sufentanil may be administered at not less than one-hour intervals if there is evidence of lightening of analgesia.
Analgesic Adjunct during Labour and Delivery
The recommended initial dose for sufentanil, administered with 0.125%-0.25% bupivacaine, is 10 mcg in 10 mL normal saline. If required, two subsequent injections of the combination may be given; supplemental doses should be separated by intervals of at least one hour. It is recommended that the total sufentanil dose administered not exceed 30 mcg.
ADULT DOSAGE RANGE CHART - INTRAVENOUS USE
| ADMINISTRATION WITH NITROUS OXIDE/OXYGEN | ||||
| INDICATION | APPROXIMATE DURATION OF ANAESTHESIA | INITIAL DOSE | MAINTENANCE INCREMENTS (included in total dosage) | TOTAL DOSAGE (A cumulative dosage in the range of 0.5-1 mcg/kg is recommended) |
| As an adjunct to major surgery | At least one hour | A minimum of 0.5 mcg/kg is necessary to control or abolish cardiovascular response to laryngoscopy and intubation. The initial dosage should represent at least 75% of the total dosage administered during the procedure. | 10-25 mcg 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 mcg/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 two hours | 25-50 mcg 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 mcg/kg administered as an analgesia adjunct with nitrous oxide/oxygen in patients undergoing more complicated major surgical procedures. At dosages in this range, sufentanil citrate 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 DOSE | MAINTENANCE INCREMENTS (included in total dosage) | TOTAL DOSAGE | |
| As primary anaesthetic agent | The initial dose should be individualized with due consideration given to patient status, concomitant medications and anticipated level of surgical stimulation. See total dosage guidelines. | 25-50 mcg as determined by changes in vital signs that indicate stress or lightening of anaesthesia. | 8-30 mcg/kg (anaesthetic doses) administered with 100% oxygen and a muscle relaxant. Sufentanil citrate has been found to produce sleep at dosages >= 8 mcg/kg and to maintain a deep level of anaesthesia without the use of additional anaesthetic agents. At dosages in this range of up to 25 mcg/kg, catecholamine release is attenuated. High doses 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 intravenous administration rate for sufentanil citrate is 250-300 mcg/minutes.
Overdosage would be manifested by an extension of the pharmacological actions of sufentanil (see Actions and Clinical Pharmacology) 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 bradypnoea to apnoea.
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; 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 apnoea. 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.
Pharmacodynamics
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 mcg/kg basis.
At intravenous doses of up to 8 mcg/kg, sufentanil provides profound analgesia; at doses >= 8 mcg/kg, sufentanil produces a deep level of anaesthesia. Sufentanil produces a dose related attenuation of catecholamine release, particularly norepinephrine. At intravenous dosages of >= 8 mcg/kg, sufentanil citrate produces hypnosis and anaesthesia without the use of additional anaesthetic induction agents. A deep level of anaesthesia is maintained at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/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 mcg/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 anaesthesia 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 citrate-oxygen anaesthesia. 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 mcg/kg has been shown to provide more adequate reduction in intracranial volume than equivalent doses of fentanyl, based upon requirements for furosemide and anaesthesia supplementation. During carotid endarterectomy, sufentanil produced EEG patterns and reductions in cerebral blood flow and oxygen utilisation comparable to those of fentanyl. The intraoperative use of sufentanil at anaesthetic 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 apnoea may be produced.
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. During labour and vaginal delivery, the addition of 10 to 30 mcg 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 labour.
Pharmacokinetics
Assays of histamine in patients administered sufentanil citrate have shown no elevation in plasma histamine levels and no indication of histamine release.
Intravenous sufentanil citrate has an immediate onset of action, with a distribution of 0.72 minute, redistribution of 13.7 minutes and an elimination half-life of 148 minutes. It is rapidly and extensively metabolised 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
O- 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 intravenous sufentanil can be described as a three-compartment model, with relatively limited accumulation and rapid elimination from tissue storage sites, allowing for relatively more rapid recovery than with fentanyl.
Peak plasma concentrations following single epidural doses of sufentanil are reached within 10 minutes and are 4 to 6 times lower than those after intravenous administration. Systemic absorption within the first 3 hours after epidural administration is approximately 1/3 to 1/2 that of an intravenous bolus. Vascular uptake of sufentanil after high thoracic (T3-T4) administration is 3 to 4 times lower than after mid-thoracic to lumbar epidural injection. Co-administration 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 mcg; 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. Placental transfer of sufentanil was investigated in women undergoing caesarean section. Within 30 to 55 minutes of epidural doses of 22 to 38 mcg 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. Foetal plasma concentrations rapidly equilibrate with maternal concentrations. Individual umbilical vein to maternal plasma concentration ratios averaged 0.4. Plasma protein binding of sufentanil, related to the a1 acid glycoprotein level, was 90.7% in mothers and 79.3% in neonates.
Store between 15 and 30oC. Protect from light. Discard unused portion.
Sufentanil Citrate Injection 10 - 60 mcg may be diluted in 10 mL of 0.9% Sodium Chloride Injection, stored at room temperature and used within 24 hours. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration whenever solution and container permit. Solution showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion.
Sufentanil Citrate Injection is available in 1 mL ampoules, boxes of 10, and in 5 mL single-use vials, boxes of 5. For single use. Sufentanil Citrate Injection is a preservative-free, sterile aqueous solution. Each mL contains sufentanil citrate equivalent to 50 mcg of sufentanil base, sodium chloride for isotonicity, citric acid and/or sodium hydroxide to adjust pH and water for injection.