Sufentanil

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 sufentanil in such patients. Patients with moderate to severe hepatic or severe renal impairment should be monitored carefully for symptoms of sufentanil overdose.

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 sufentanil is given.

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 (C_max) 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.

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.

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.

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 as a μ-opioid receptor agonist may slow the gastrointestinal motility. Therefore, sufentanil 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, sufentanil should be used with caution in patients with biliary tract disease, including acute pancreatitis.

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.

Sufentanil 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 sufentanil 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.

Fertility

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 sufentanil. Patients should only drive and use machines if sufficient time has elapsed after the last administration of sufentanil.

Summary of the safety profile

The most serious adverse reaction of sufentanil is respiratory depression, potentially leading to apnoea and respiratory arrest. Based on the combined safety data from these clinical studies, nausea and vomiting were the most frequently reported adverse reactions (≥1/10 frequency).

List of adverse reactions

Adverse reactions identified either from clinical studies or from post-marketing experience with other medicinal products containing sufentanil are summarised in the list 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.

Immune system disorders

Uncommon: Hypersensitivity*

Not known: Anaphylactic shock

Psychiatric disorders

Common: Confusional state

Uncommon: Apathy*, Nervousness*

Nervous system disorders

Common: Dizziness, Headache, Sedation

Uncommon: Somnolence, Paraesthesia, Ataxia*, Dystonia*, Hyperreflexia*

Not known: Convulsions, Coma

Eye disorders

Uncommon: Vision disturbances

Not known: Miosis

Cardiac disorders

Common: Heart rate increased

Uncommon: Heart rate decreased*

Vascular disorders

Common: Blood pressure increased, Blood pressure decreased

Respiratory, thoracic and mediastinal disorders

Common: Respiratory depression

Uncommon: Apnoea

Not known: Respiratory arrest

Gastrointestinal disorders

Very common: Nausea, Vomiting

Common: Constipation, Dyspepsia

Uncommon: Dry mouth

Skin and subcutaneous tissue disorders

Common: Pruritus

Uncommon: Hyperhidrosis, Rash, Dry skin*

Not known: Erythema

Musculoskeletal and connective tissue disorders

Common: Involuntary muscle spasms, Muscle twitching*

Renal and urinary disorders

Common: Urinary retention

General disorders and administration site conditions

Very common: Pyrexia

Uncommon: Chills, Asthenia

Not known: Drug Withdrawal Syndrome

* see "Description of selected adverse reactions"

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 sufentanil. 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.