SOFENTIL Solution for injection / infusion Ref.[50941] Active ingredients: Sufentanil

Intravenous administration of sufentanil should only be performed by experienced anaesthesiologists in hospitals or other institutions with facilities for endotracheal intubation and mechanical ventilation. The patient’s vital functions must be routinely monitored. This also includes the postoperative phase.

As with all potent opioids

Respiratory depression is dose related and can be reversed by specific opioid antagonists. As respiratory depression may last longer than the effect of the opioid antagonist, the patient should be observed and further doses of the specific opioid antagonist may be necessary.

Deep anesthesia is accompanied by marked respiratory depression and loss of consciousness that may last or return in the postoperative phase.

Hyperventilation during anaesthesia may alter the patient’s responses to CO2, resulting in decreased oxygenation in the postanesthesia period.

The risk of delayed respiratory depression should always be taken into consideration and the patient must be under adequate supervision. Resuscitation equipment and opioid antagonists must be readily available.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of sufentanil and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe sufentanil concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

It is generally recommended to discontinue MAO inhibitors two weeks prior to anesthesia or surgical procedures.

Muscular rigidity may occur and may lead to respiratory depression. This can be avoided by slow i.v. injection (usually low doses are sufficient), premedication with benzodiazepines and the use of muscle relaxants.

Myasthenia Gravis

Sufentanil may cause muscle rigidity after i.v. administration, which may require the use of muscle relaxants. Therefore, sufentanil should not be used in patients with myasthenia gravis as the use of muscle relaxants is inappropriate for these patients.

Non-epileptic (myo)clonic movements may occur.

Bradycardia and possibly cardiac arrest may occur if the patient has received a low dose of anticholinergic, or if Sofentil is combined with nonvagolytic muscle relaxants. Bradycardia can be treated with atropine.

Opioids can induce hypotension, especially in hypovolemic patients and in patients with heart failure. Induction doses must be adjusted and administered slowly to avoid cardiovascular depression. Appropriate measures must be taken to maintain stable arterial pressure.

Caution is required in patients with cranial cerebral trauma and elevated intracranial pressure. Rapid bolus injections of opioids should be avoided in patients with compromised cerebral circulation or intracranial compliance, as the short-term decrease in arterial pressure may be accompanied by a briefly reduced cerebral perfusion pressure.

Patients who receive chronic opioid therapy or with a history of opioid abuse may need higher doses.

It is recommended to reduce the dose in elderly or debilitated patients. Although no longer half-lives have been measured in the elderly, a higher frequency of circulatory disorders has been observed in these patients.

Opioids should be titrated with caution in patients with the following disorders: uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism, hepatic or renal impairment. These patients require prolonged post-operative monitoring.

For epidural administration, caution should be exercised in patients with respiratory depression or compromised respiratory function and in fetal exposure. The patient should be carefully monitored for at least 1 hour after each dose, as both early and protracted respiratory depression may occur.

The fetal heart rate may change during epidural administration, therefore it is necessary to monitor the frequency and treatment may be needed.

Pediatric population

Due to the high variability of of pharmacokinetic parameters in newborns, there is a risk of overdosing or underdosing of intravenous sufentanil during the neonatal period. See also section 4.2 and 5.2.

The safety and efficacy of Sofentil administered epidural in children under 1 year have not yet been established (see also sections 4.2 and 5.1).

Newborns and children may be expected to be particularly sensitive to sufentanil’s respiratory depression, as this is the case with other opioids. Therefore, benefit / risk ratio should be carefully evaluated before sufentanil is used in newborns and children.

This medicinal product contains 9 mg sodium per ml solution for injection, equivalent to 0.45% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Central nervous system depressants (CNS depressants)

Barbiturates, benzodiazepines, antipsychotics, general anesthetics and other non-selective CNS depressants (e.g. alcohol) may potentiate the respiratory depressant effect of opioids. Once the patient has received such CNS depressants, a lower dose of Sofentil will be required. Concomitant use of Sofentil in patients with spontaneous respiration may increase the risk of respiratory depression, deep sedation, coma and death.

Effect of Sofentil on other drugs

Following Sofentil administration, the dose of CNS depressants should be lowered. This is particularly important after surgery, as deep analgesia is accompanied by marked respiratory depression that may last or return during the postoperative period. Administration of a CNS depressant, e.g. benzodiazepine, during this period may increase the risk of respiratory depression disproportionately.

At high doses of sufentanil, concomitant administration of nitrous oxide or even small doses of benzodiazepines (e.g. diazepam or midazolam) may lead to a reduction in cardiac function (blood pressure drop and decrease in cardiac volume and heart rate).

Administration of sufentanil with suxamethonium may induce bradycardia, especially if the pulse is already low (e.g. in patients receiving calcium antagonists or beta-blockers). Therefore, it is advisable to make an appropriate dose reduction of one or both drugs.

Monoamine oxidase inhibitors (MAOIs)

In case of treatment with MAOIs up to 14 days prior to opioid therapy with pethidine, life-threatening interactions have been observed on CNS (agitation, muscle rigidity, high fever, convulsions), as well as in respiratory and circulatory functions (circulatory depression, hypotension, hemodynamic instability, coma). These interactions cannot be excluded with sufentanil, and therefore it is recommended to discontinue MAOIs (at least) 2 weeks prior to surgery or anesthesia.

Serotonergic drugs

Co-administration of sufentanil with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), or Monoamine Oxidase Inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life threatening condition. Monoamine Oxidase Inhibitors must not be taken in the 2 weeks before or at the same time as Sofentil is given.

CYP3A4 inhibitors (cytochrome P450 3A4)

Sufentanil is metabolised mainly via cytochrome P450 3A4, but no in vivo inhibition of erythromycin (a known cytochrome P450 3A4 enzyme inhibitor) has been observed. Although clinical data is missing, in vitro data indicates that other potent CYP 3A4 inhibitors such as ketoconazole, itraconazole and ritonavir may inhibit the metabolism of sufentanil to such extent as to increase the risk of prolonged or delayed respiratory depression. If a simultaneous application is required, it requires the patient to be monitored very carefully. Dosage reduction of Sofentil may be necessary.

Pregnancy

There is little experience of intravenous use of sufentanil in pregnant women. Animal studies have not shown any teratogenic effect. As with other drugs, the risk must be weighed against the potential benefits for the patient.

Intravenous use in labour or before clamping of the cord during caesarean section is contraindicated due to the possibility of respiratory depression in the newborn infant.

Sufentanil passes rapidly into the placenta and the concentration rises linearly at an increased maternal concentration. The ratio of the concentration in the umbilical vein to the maternal venous concentration is 0.81.

Sufentanil can be administered epidural. Controlled clinical studies during labour have shown that sufentanil added to epidural bupivacaine in total doses up to 30 micrograms has no detrimental effect on the mother or the newborn. Sufentanil crosses the placenta. Following epidural administration of a total dose not exceeding 30 micrograms, mean plasma concentrations of 0.016 nanograms/mL were detected in umbilical vein.

An antidote for the child should always be available.

Breastfeeding

Sufentanil is excreted in breast milk. Caution should be exercised when sufentanil is administered to a nursing woman.

Sufentanil significantly affects the ability to drive or use machines.

Patients should only drive motor vehicles and operate machines if sufficient time has elapsed after administration of Sofentil.

Patients should not be sent home without supervision and should be advised to avoid drinking alcohol.

The safety of sufentanil was evaluated in 650 sufentanil-treated subjects who participated in 6 clinical trials. Of these, 78 subjects participated in 2 trials of sufentanil administered intravenously as an anaesthetic agent for induction and maintenance of anaesthesia in subjects undergoing major surgical procedures (coronary artery bypass or open-heart surgical procedures). The remaining 572 subjects participated in 4 trials of epidural sufentanil administered as a postoperative analgesic, or as an supplementary analgesic agent to epidural bupivacaine during labour and vaginal deliveries. These subjects received at least 1 dose of sufentanil and provided safety data.

Based on overall safety data from these clinical trials, the most commonly reported ADRs (≥5% incidence) were: sedation (19.5%), pruritus (15.2%), nausea (9.8%) and vomiting (5.7%).

Pediatric population

The frequency, nature and severity of adverse events in children are expected to be the same as in adults.

The following table shows the adverse reactions related to sufentanil, reported from clinical trials, including those mentioned above, or from postmarketing use.

The following frequency convention applies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the authorisation of the medicinal product is important. This allows continued monitoring of the benefit/risk balance of the medicinal product. Doctors and other healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.