SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Hypnomidate™ 2 mg/ml Injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of Hypnomidate contains etomidate 2 mg.

3.    PHARMACEUTICAL FORM

Solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypnomidate is an intravenous induction agent of anaesthesia.

4.2 Posology and method of administration

For intravenous administration.

Hypnomidate should be injected slowly by the intravenous route.

The product must only be used by physicians trained in endotracheal intubation. Equipment for artificial respiration must be available.

Adults and children:

A dose of 0.3 mg/kg bodyweight given intravenously at induction of anaesthesia, gives sleep lasting from 4 to 5 minutes.

Dosage should be adjusted to the individual patient response and to clinical effects.

In children under 15 years the dosage may need to be increased: a supplementary dose of up to 30% of the normal dose for adults is sometimes necessary to obtain the same depth and duration of sleep as obtained in adults.

Elderly:

A dose of 0.15-0.2 mg/kg bodyweight should be given and the dose should be further adjusted according to the individual patient response and to clinical effects (see Section 4.4 Special Warnings and Precautions for Use).

Since Hypnomidate has no analgesic action, appropriate analgesics should be used in procedures involving painful stimuli.

Hypnosis can be prolonged by additional injections of Hypnomidate.

Do not exceed a total dose of 30 ml (3 ampoules).

Hypnomidate may be diluted with sodium chloride infusion BP or dextrose infusion BP but it is not compatible with compound sodium lactate infusion BP (Hartmann’s solution). Combinations with pancuronium bromide may show a very slight opalescence; for this reason the two should not be mixed together.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 (especially after previous administration of droperidol). In debilitated patients in whom hypotension may be hazardous, the following measures should be taken:

1.    Before induction, intravenous access should be obtained for the management of circulatory blood volume.

2.    Other inducing agents should be avoided to the extent possible.

3.    The induction should be carried out with the patient supine.

4.    The drug should be injected slowly (e.g. 10 ml in 1 min).

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

Induction doses of etomidate have been associated with a reduction in plasma cortisol and aldosterone concentrations (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. In such situations stimulation of the adrenal gland with ACTH is not useful.

Hypnomidate should be used with caution in patients with underlying cortico-adrenal insufficiency such as 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 ACTH is not useful. However, when etomidate is used for induction, the postoperative 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 droperidol or 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).

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

Hypnomidate has no primary effect on fertility, nor primary embryotoxic or teratogenic effects. At maternally toxic doses in rats, decreased survival was noted. Safety in human pregnancy has not been established. As with other drugs, the possible risks should be weighed against the potential benefits before the drug is administered during pregnancy. Hypnomidate may cross the placental barrier during obstetric anaesthesia. The Apgar scores of newborns whose mothers have received etomidate are comparable to those of infants 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.

Lactation: It is not known whether etomidate is excreted in human milk. However, caution should be exercised when Hypnomidate is administered to a nursing mother.

4.7 Effects on ability to drive and use machines

Etomidate has a major influence on the ability to drive and use machines. It is not recommended to use potentially dangerous machinery or to drive a car during the first 24 hours after administration. The return of normal alertness may vary according to the duration of the operation, the total dose of etomidate administered and concomitant medication used. Hence, a decision to allow for driving or operating machinery must be a judgment made by the post-anaesthesiology treatment team.

4.8 Undesirable effects

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).

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common (>1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Not Known
Immune System Disorders				Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, anaphylactoid reaction)
Endocrine Disorders				Adrenal insufficiency
Nervous System Disorders	Dyskinesia	Myoclonus	Hypertonia, Muscle contractions involuntary, Nystagmus	Convulsion (including grand mal convulsion)
Cardiac Disorders			Bradycardia, Extrasystoles, Ventricular extrasystoles	Cardiac arrest, Atrioventricular block complete
Vascular Disorders		Vein pain, Hypotension	Phlebitis, Hypertension	Shock, Thrombophlebitis (including superficial thrombophlebitis and deep vein thrombosis)
Respiratory, Thoracic and Mediastinal Disorders		Apnoea, Hyperventilation, Stridor	Hypoventilation, Hiccups, Cough	Respiratory depression, Bronchospasm (including fatal outcome)
Gastrointestinal Disorders		Vomiting, Nausea	Salivary hypersecretion
Skin and Subcutaneous Tissue Disorders		Rash	Erythema	Stevens-Johnson syndrome, Urticaria
Musculoskeletal and Connective Tissue Disorders			Muscle rigidity	Trismus
General Disorders and Administration Site Conditions			Injection site pain
Injury, Poisoning and Procedural Complications			Anaesthetic complication, Delayed recovery from anaesthesia,

Inadequate analgesia, Procedural nausea

4.9 Overdose

Symptoms

Overdosing is likely to result in prolonged anaesthesia with the possibility of respiratory depression and even arrest, in which case adequate respiratory support is mandatory. Hypotension has also been observed. Overdosage may depress cortical secretion. This may be associated with disorientation and delayed awakening.

Treatment

General supportive measures and close observation are recommended. In addition, administration of 50 - 100 mg hydrocortisone (not ACTH) may be required for depression of cortisol secretion.

5 PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

ATC code N01AX07

Etomidate is a short acting intravenous hypnotic which is rapidly inactivated by enzyme metabolism so that it does not give rise to a hangover effect. It does not release histamine, and has no effect on liver function. In vitro studies have shown etomidate to be an inhibitor of microsomal enzymes. Limited in vivo studies have demonstrated only minimal inhibition of hepatic metabolism.

Adrenal Suppression

Etomidate when used for the introduction of anaesthesia, produces a decrease in plasma cortisol and aldosterone, which remains suppressed for 6-8 hours. These levels usually return to baseline within 24 hours. Etomidate appears to be a specific and reversible inhibitor of the 11-beta-hydroxylation of adrenal steroid synthesis.

5.2 Pharmacokinetic properties

Profile in Plasma:

After intravenous administration, the time-course of the etomidate plasma levels can be described by a three-compartment model reflecting distribution, metabolism, and elimination processes. Plasma concentrations decrease rapidly for about 30 minutes and then more slowly; traces are still detectable after about 6 hours. Metabolites, chiefly of hydrolysis, are more slowly excreted.

Distribution

Etomidate is approximately 76.5% bound to plasma proteins. Etomidate is rapidly distributed to the brain and other tissues. Its volume of distribution is about 4.5 L/kg.

Metabolism and Elimination

Etomidate is metabolized in the liver. After 24 hours, 75% of the administered dose of etomidate has been eliminated in the urine primarily as metabolites. Only 2% of etomidate is excreted unchanged via the urine. The terminal halflife of about 3 to 5 hours reflects the slow distribution of etomidate from the deep peripheral compartment.

5.3 Preclinical safety data

No relevant information other than that contained elsewhere in the Summary of Product Characteristics.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Propylene glycol Water for injections 1N sodium hydroxide*

1N hydrochloric acid*

* for occasional pH adjustment only

6.2 Incompatibilities

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

Shelf life

2 years.

Special precautions for storage

Do not store above 25°C.

Nature and contents of container

Colourless glass ampoule, Ph.Eur Type I, containing 10 ml Hypnomidate, in packs of 5 and 10 ampoules.

Not all pack sizes may be marketed

Special precautions for disposal

None stated

MARKETING AUTHORISATION HOLDER

Janssen-Cilag Limited 50-100 Holmers Farm Way High Wycombe Buckinghamshire HP12 4EG UK

MARKETING AUTHORISATION NUMBER

PL 00242/0019

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/07/2009

03/05/2013