HYPNOMIDATE Solution for injection Ref.[9262] Active ingredients: Etomidate

Warnings: In patients with liver cirrhosis, or in those who have already received neuroleptic, opiate or sedative agents, the dose of etomidate should be reduced.

Induction with Hypnomidate may be accompanied by a slight and transient drop in blood pressure due to a reduction of the peripheral vascular resistance. In debilitated patients in whom hypotension may be harmful, the following measures should be taken:

1. Keep the patient supine during induction.
2. Ensure good intravenous access to manage circulatory blood volume.
3. Give Hypnomidate by slow intravenous injection (e.g. 10 ml in 1 min.).
4. Avoid giving other induction agents if possible.

When Hypnomidate is used, resuscitation equipment should be readily available to manage respiratory depression and the possibility of apnoea.

Single induction doses of etomidate can lead to transient adrenal insufficiency and decreased serum cortisol levels (See section 5.1 Pharmacodynamic Properties). Where concern exists for the patients undergoing severe stress, particularly those with adrenocortical dysfunction, supplementation with exogenous cortisol should be considered.

Etomidate should be used with caution in critically ill patients, including patients with sepsis.

Prolonged suppression of endogenous cortisol and aldosterone may occur as a direct consequence of etomidate when given by continuous infusion or in repeated doses. Use of Hypnomidate for maintenance of anaesthesia should therefore be avoided. In such situations stimulation of the adrenal gland with adrenocorticotropic hormone (ACTH) is not useful. However, when etomidate is used for induction, the post-operative rise in serum cortisol which has been observed after thiopentone induction is delayed for approximately 3-6 hours.

Spontaneous movements may occur in one or more groups of muscles, particularly when no premedication has been administered. These movements have been ascribed to subcortical disinhibition. They can be largely prevented by the intravenous administration of small doses of fentanyl, with diazepam 1-2 min. before induction with Hypnomidate.

Myoclonus and pain on injection, including venous pain, is observed during the administration of Hypnomidate especially when it is injected into a small vein. This can largely be avoided by intravenous application of a small dose of suitable opioids, e.g. fentanyl, 1 to 2 minutes before induction.

Hypnomidate should be used with caution in elderly patients, since the potential exists for decreases in cardiac output, which have been reported with doses greater than recommended (see Section 4.2 Posology and Method of Administration for recommended dose in the elderly).

Convulsions may occur in unpremedicated patients.

Precautions: Hypnomidate by injection should be given slowly (e.g. 10 ml over 30-60 seconds).

The hypnotic effect of etomidate may be enhanced by neuroleptic drugs, opioids, sedatives and alcohol.

Induction with etomidate may be accompanied by a slight and transient reduction in peripheral resistance which may enhance the effect of other drugs reducing blood pressure.

Hypnomidate is pharmacologically compatible with the muscle relaxants, premedicant drugs and inhalation anaesthetics in current clinical use.

Effect of Other Drugs on Etomidate

Co-administration of etomidate with alfentanil has been reported to decrease the terminal half-life of etomidate to approximately 29 minutes. Caution should be used when both drugs are administered together as the concentrations of etomidate may drop below the hypnotic threshold.

The total plasma clearance and volume of distribution of etomidate is decreased by a factor of 2 to 3 without a change in half-life when administered with fentanyl IV. When etomidate is co-administered with fentanyl IV, the dose may need to be reduced.

Effect of Etomidate on Other Drugs

Co-administration of etomidate and ketamine appears to have no significant effect on the plasma concentrations or pharmacokinetic parameters of ketamine or its principal metabolite, norketamine.

Pregnancy

In animals, no primary embryotoxic or teratogenic effects were observed with etomidate. Safety in human pregnancy has not been established. Hypnomidate should be used during pregnancy only if the potential benefit justifies the risks to the fetus.

During obstetric anaesthesia etomidate crosses the placenta. The Apgar scores of neonates whose mothers have received Hypnomidate are comparable to those of neonates born after the use of other hypnotic agents. A transient fall in cortisol levels lasting about 6 hours was observed in the neonate after the mother was given Hypnomidate. The decreased values remained within the normal range.

Breast-feeding

Etomidate has been identified in breast milk. The effect of etomidate on neonates is unknown. Breast-feeding should be discontinued during treatment and for a period of approximately 24 hours after treatment with Hypnomidate.

Fertility

In a reproduction study in animals, results showed that Hypnomidate has no effect on fertility at recommended doses.

Etomidate has a major influence on the ability to drive and use machines. Even though a patient may regain normal alertness 30 to 60 minutes after awakening, it is recommended that patients do not drive or use machines for at least 24 hours after administration of Hypnomidate. Hence, a decision to allow for driving or operating machinery must be a judgment made by the post-anaesthesiology treatment team.

The safety of Hypnomidate was evaluated in 812 subjects who participated in 4 open-label clinical trials of Hypnomidate used for the induction of general anaesthesia. These subjects took at least one dose of Hypnomidate and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (≥5% incidence) adverse drug reactions (ADRs) were (with % incidence) dyskinesia (10.3) and vein pain (7.6).

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of Hypnomidate from either clinical trial or postmarketing experiences.

The displayed frequency categories use the following convention: 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); and not known (cannot be estimated from the available clinical trial data).

Immune System Disorders

Not Known: Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, anaphylactoid reaction)

Endocrine Disorders

Very Common: Cortisol decreased

Not Known: Adrenal insufficiency

Nervous System Disorders

Very Common: Dyskinesia

Common: Myoclonus

Uncommon: Hypertonia, Muscle contractions involuntary, Nystagmus

Not Known: Convulsion (including grand mal convulsion)

Cardiac Disorders

Uncommon: Bradycardia, Extrasystoles, Ventricular extrasystoles

Not Known: Cardiac arrest, Atrioventricular block complete

Vascular Disorders

Common: Vein pain, Hypotension

Uncommon: Phlebitis, Hypertension

Not Known: Shock, Thrombophlebitis (including superficial thrombophlebitis and deep vein thrombosis)

Respiratory, Thoracic and Mediastinal Disorders

Common: Apnoea, Hyperventilation, Stridor

Uncommon: Hypoventilation, Hiccups, Cough

Not Known: Respiratory depression, Bronchospasm (including fatal outcome)

Gastrointestinal Disorders

Common: Vomiting, Nausea

Uncommon: Salivary hypersecretion

Skin and Subcutaneous Tissue Disorders

Common: Rash

Uncommon: Erythema

Not Known: Stevens-Johnson syndrome, Urticaria

Musculoskeletal and Connective Tissue Disorders

Uncommon: Muscle rigidity

Not Known: Trismus

General Disorders and Administration Site Conditions

Uncommon: Injection site pain

Injury, Poisoning and Procedural Complications

Uncommon: Anaesthetic complication, Delayed recovery from anaesthesia, Inadequate analgesia, Procedural nausea

Reporting of suspected adverse reactions

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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

Combinations with pancuronium bromide may show a very slight opalescence; for this reason the two should not be mixed together.