SUFENTA Solution for injection / infusion Ref.[50458] Active ingredients: Sufentanil

Respiratory depression is dose related and can be reversed by specific opioid antagonists, e.g. naloxone, but a repeated dose of the antagonist may be necessary because the duration of respiratory depression may last longer than the duration of action of the opioid antagonist. Marked respiratory depression accompanies profound analgesia.

The respiratory depression can persist in the post-operative period, and if SUFENTA has been given intravenously this can recur. Therefore, patients should remain under appropriate surveillance. Resuscitation equipment and opioid antagonists should be readily available.

Hyperventilation during anaesthesia may alter the patient’s response to CO₂ thus affecting respiration post-operatively.

The incidence and severity of early respiratory depression with epidural administration may be less if epinephrine (adrenaline) is added.

Vital signs should be monitored routinely.

Concomitant use of SUFENTA and CNS depressants, especially benzodiazepines or related medicines, in spontaneous breathing patients, may increase the risk of profound sedation, respiratory depression, coma and death. If a decision is made to administer SUFENTA concomitantly with a CNS depressant, especially a benzodiazepine or a related medicine, the lowest effective dose of both medicines should be administered, for the shortest period of concomitant use. Patients should be carefully monitored for signs and symptoms of respiratory depression and profound sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Respiratory depression may follow intravenous or epidural use of SUFENTA.

Vital signs should be monitored continuously routinely.

Acute truncal muscular rigidity that may make manual ventilation difficult, may follow intravenous administration of SUFENTA.

Induction of muscle rigidity, which may also involve the thoracic respiratory muscles, can occur but the risk may be reduced if intravenous injections are administered slowly. A neuromuscular blocking agent compatible with the patient’s condition may be administered prophylactically to prevent muscle rigidity or to induce muscle relaxation after rigidity occurs. Non-epileptic (myo)clonic movements can occur.

Because of its weak cholinergic activity, SUFENTA should be used with caution in patients with cardiac dysrhythmias.

Bradycardia and possibly cardiac arrest can occur when SUFENTA is combined with non-vagolytic muscle relaxants. Bradycardia associated with the concomitant use of succinylcholine and sufentanil has been reported. Bradycardia can be treated with atropine.

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

The use of rapid bolus injections of SUFENTA should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has been accompanied by a reduction of the cerebral perfusion pressure.

It is recommended to reduce the dosage in elderly and debilitated patients. SUFENTA should be titrated with caution in patients with any of the following conditions:

• uncontrolled hypothyroidism
• pulmonary disease
• decreased respiratory reserve
• alcoholism
• impaired hepatic or renal function
• increased intracranial pressure.

Such patients also require prolonged post-operative monitoring.

With epidural administration, caution should be exercised in the presence of respiratory depression or compromised respiratory function and in the presence of foetal distress. The patient should be closely monitored for at least 2 hours after each dose, as late respiratory depression may occur.

Paediatric population

Due to the large variability of pharmacokinetic parameters in neonates, there is a risk of over- or underdosing of SUFENTA in the neonatal period (see sections 4.2 and 5.2). Safety and efficacy of intravenous or epidural SUFENTA in children younger than 1 year have not been established (see sections 4.2 and 5.2).

Effect of other medicines on SUFENTA

Central nervous system (CNS) depressants

Barbiturates, benzodiazepines or related medicines, neuroleptics, general anaesthetics and other non-selective CNS depressants (e.g. alcohol), may potentiate the respiratory depressive effects of SUFENTA. When patients have also received central nervous system depressants, the dose of SUFENTA required will be less than usual. Likewise, following the administration of SUFENTA, the dose of other central nervous system depressants should be reduced. Concomitant use with SUFENTA in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see section 4.4).

Effect of SUFENTA on other medicines

Following the administration of SUFENTA, the dose of other CNS depressant medicines should be reduced. This is particularly important after surgery, because profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the post-operative period. Administration of a CNS depressant, such as a benzodiazepine or related medicines, during this period may disproportionally increase the risk for respiratory depression (see section 4.4).

Cytochrome P450 3A4 (CYP3A4) inhibitors

Sufentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. However, no in vivo inhibition by erythromycin (a known CYP3A4 enzyme inhibitor) has been observed. Although clinical data are lacking, in vitro data suggest that other potent CYP3A4 enzyme inhibitors (e.g. fluconazole, ketoconazole, itraconazole, ritonavir, diltiazem and cimetidine) may inhibit the metabolism of sufentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such medicines requires special patient care and observation; in particular, it may be necessary to lower the dose of SUFENTA.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MOAIs) must be discontinued 2 weeks prior to the administration of SUFENTA.

Serotonergic medicines

Co-administration of sufentanil with a serotonergic medicine, 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.

Pregnancy

Safety in pregnancy and lactation has not been established, although studies in animals have not demonstrated any teratogenic effects. SUFENTA added to epidural bupivacaine in total doses up to 30 µg has no detrimental effect on the mother or the newborn, but intravenous use is contraindicated in labour. SUFENTA crosses the placenta. After epidural administration of a total dose not exceeding 30 µg, average plasma concentrations of 0,016 ng/mL were detected in the umbilical vein. An antidote for the newborn should always be at hand.

Breastfeeding

SUFENTA is excreted in human breast milk. Caution should be exercised when SUFENTA is administered to a breastfeeding woman. Infants exposed to sufentanil citrate injection, as in SUFENTA, through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. A woman should not breastfeed her infant for 12–24 hours after receiving SUFENTA.

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Patients should not drive, operate a machine or make legally binding decisions at least until 24 hours after administration of SUFENTA, nor should alcohol be consumed during that time period.

Clinical trial data

The safety of SUFENTA 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). The remaining 572 subjects participated in 4 trials of epidural sufentanil administered as a postoperative analgesic or as an analgesic adjunct to epidural bupivacaine during labour and vaginal deliveries. These subjects took at least 1 dose of sufentanil and provided safety data. Adverse drug reactions (ADRs) that were reported for ≥1% of sufentanil-treated subjects in these trials are shown in Table 1.

Table 1. Adverse drug reactions reported by ≥1% of sufentanil-treated subjects in 6 clinical trials of sufentanil:

Additional ADRs that occurred in <1% of sufentanil-treated subjects in the 6 clinical trials are listed in Table 2.

Table 2. Adverse drug reactions reported by <1% of sufentanil-treated subjects in 6 clinical trials of sufentanil:

^* ADRs reported from only the trials of sufentanil administered intravenously as an anaesthetic agent.

Post-marketing data

Adverse drug reactions first identified during post-marketing experience with sufentanil citrate are included in Table 3 and Table 4.

In Table 3, adverse reactions are presented by frequency category based on spontaneous reporting rates, while in Table 4 the same adverse reactions are presented by frequency category based on incidence in clinical trials or epidemiological studies, when known. The frequency category “not known” is used for adverse reactions for which no valid estimate of the incidence rate can be derived from clinical trials.

Table 3. Adverse drug reactions identified during post-marketing experience with SUFENTA:

Table 4. Adverse reactions identified during post-marketing experience with SUFENTA by frequency category estimated from clinical trials or epidemiologic studies:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: http://www.sahpra.org.za/Publications/Index/8.

SUFENTA solution must not be mixed with other products.

If desired, SUFENTA may be mixed with sodium chloride or glucose intravenous infusions. Such dilutions are compatible with plastic infusion sets. They should be used within 24 hours of preparation.