Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: FGK Representative Service GmbH, Heimeranstrasse 35, 80339 Munich, Germany Tel. +49 89 89 3119 22
Sufentanil may cause respiratory depression, for which the degree/severity is dose related. The respiratory effects of sufentanil should be assessed by clinical monitoring, e. g. respiratory rate, sedation level and oxygen saturation. Patients at higher risk are those with respiratory impairment or reduced respiratory reserve. Respiratory depression caused by sufentanil can be reversed by opioid antagonists. Repeat antagonist administration may be required as the duration of respiratory depression may last longer than the duration of the effect of the antagonist (see section 4.9).
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Sufentanil should be used with caution in patients who may be particularly susceptible to the cerebral effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Sufentanil may obscure the clinical course of patients with head injury. Sufentanil should be used with caution in patients with brain tumours.
Sufentanil may produce bradycardia. Therefore, it should be used with caution in patients with previous or pre-existing bradyarrhythmias. Sufentanil may cause hypotension, especially in hypovolemic patients. Appropriate measures should be taken to maintain stable arterial pressure.
Sufentanil is primarily metabolised in the liver and excreted in the urine and faeces. The duration of activity may be prolonged in patients with severe hepatic and renal impairment. Only limited data are available for the use of Zalviso in such patients. Patients with moderate to severe hepatic or severe renal impairment should be monitored carefully for symptoms of sufentanil overdose (see section 4.9).
Sufentanil has potential for abuse. This should be considered when prescribing or administering sufentanil where there is concern about an increased risk of misuse, abuse or diversion.
Patients on chronic opioid therapy or opioid addicts may require higher analgesic doses than the Zalviso administration device can deliver.
Sufentanil as a μ-opioid receptor agonist may slow the gastrointestinal motility. Therefore, Zalviso should be used with caution in patients at risk of ileus. Sufentanil as a μ-opioid receptor agonist may cause spasm of the sphincter of Oddi. Therefore, Zalviso should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Concomitant use of Zalviso and sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Zalviso concomitantly with sedating medicinal products the duration of the concomitant 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).
Before use, the health-care professional should ensure that the patients have been appropriately instructed on how to operate the Zalviso administration device to self-administer tablets as needed to manage their pain post-operatively. Only patients who are able to understand and follow the instructions to operate the administration device should use Zalviso. The health-care professional should take into consideration the ability (e.g. visual or cognitive) of the patient to use the device appropriately.
Zalviso sublingual tablets contain the azo colouring agent sunset yellow FCF Aluminium Lake (E110), which may cause allergic reactions. Zalviso sublingual tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium free’.
Sufentanil is primarily metabolised by the human cytochrome P450-3A4 enzyme. Ketoconazole, a potent CYP3A4 inhibitor, can significantly increase the systemic exposure to sublingual sufentanil (maximal plasma levels (Cmax) increase of 19%, overall exposure to the active substance (AUC) increase of 77%) and prolong the time to reach maximum concentration by 41%. Similar effects with other potent CYP3A4 inhibitors (e.g. itraconazol, ritonavir) cannot be excluded. Any change in efficacy/tolerability associated with the increased exposure would be compensated in practice by an alteration in dosing frequency (see section 4.2).
The concomitant use of CNS depressants including barbiturates, neuroleptics or other opioids, halogen gases or other non-selective CNS depressants (e.g. alcohol) may enhance respiratory depression.
The concomitant use of opioids with sedating medicinal products such as benzodiazepines or related substances increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The duration of the concomitant use should be limited (see section 4.4). Serotonergic agents Co-administration of sufentanil with a serotonergic agent, such as Selective
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 Zalviso is given.
Interaction with other sublingually administered products or products intended to dilute/establish an effect in the oral cavity were not evaluated and simultaneous administration should be avoided.
There is insufficient data on the use of sufentanil during human pregnancy to evaluate its potential harmful effects. There are no indications to date that the use of sufentanil during pregnancy increases the risk of congenital abnormalities.
Sufentanil crosses the placenta.
Reproductive toxicity has been shown in animal studies (see section 5.3). Zalviso is not recommended during pregnancy and in women of childbearing potential not using contraception.
Sufentanil is excreted in human milk when applied intravenously; therefore caution is advised when Zalviso is administered to breast-feeding women. Breastfeeding is not recommended when sufentanil is administered, due to the risk of opioid effects or toxicity in the breastfed newborns/infants (see section 4.9).
There are no data on the effects of sufentanil on fertility in women or men.
Sufentanil has major influence on the ability to drive and use machines. Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance while taking or after the treatment with Zalviso. Patients should only drive and use machines if sufficient time has elapsed after the last administration of Zalviso.
The most serious adverse reaction of sufentanil is respiratory depression, potentially leading to apnoea and respiratory arrest (see section 4.4). Based on the combined safety data from these clinical studies, nausea and vomiting were the most frequently reported adverse reactions (≥1/10 frequency).
Adverse reactions identified either from clinical studies or from post-marketing experience with other medicinal products containing sufentanil are summarised in the table below. The frequencies are defined as: Very common ≥1/10, Common ≥1/100 and <1/10, Uncommon ≥1/1,000 and <1/100, Rare ≥1/10,000 and <1/1,000, Very rare <1/10,000, Not known Cannot be estimated from the available data.
Uncommon: Hypersensitivity*
Not known: Anaphylactic shock
Common: Confusional state
Uncommon: Apathy*, Nervousness*
Common: Dizziness, Headache, Sedation
Uncommon: Somnolence, Paraesthesia, Ataxia*, Dystonia*, Hyperreflexia*
Not known: Convulsions, Coma
Uncommon: Vision disturbances
Not known: Miosis
Common: Heart rate increased
Uncommon: Heart rate decreased*
Common: Blood pressure increased, Blood pressure decreased
Common: Respiratory depression
Uncommon: Apnoea
Not known: Respiratory arrest
Very common: Nausea, Vomiting
Common: Constipation, Dyspepsia
Uncommon: Dry mouth
Common: Pruritus
Uncommon: Hyperhidrosis, Rash, Dry skin*
Not known: Erythema
Common: Involuntary muscle spasms, Muscle twitching*
Common: Urinary retention
Very common: Pyrexia
Uncommon: Chills, Asthenia
Not known: Drug Withdrawal Syndrome
* see "Description of selected adverse reactions"
After prolonged use of other substances with µ-opioid receptor activity, symptoms of withdrawal were observed after abrupt interruption of the treatment. Some adverse reactions were not observed in the clinical trials with Zalviso. Their frequencies were established based on data from intravenous administration of sufentanil: common – muscle twitching; uncommon – hypersensitivity, apathy, nervousness, ataxia, dystonia, hyperreflexia, heart rate decreased and dry skin.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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