SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Adrenaline (Epinephrine) Injection 1:10,000.

	%w/v
Adrenaline (Epinephrine) as Acid Tartrate BP	0.01
Sodium Chloride BP	0.6
Citric Acid Monohydrate BP	0.16
Sodium Citrate Dihydrate BP	0.04
Sodium Metabisulphite BP	0.1
Hydrochloric Acid BP	qs
Water for Injections BP	To 100%
Nitrogen PF9	qs

3 PHARMACEUTICAL FORM

A sterile aqueous solution for slow intravenous injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Cardiopulmonary Resuscitation in adults children and newborn

Acute anaphylaxis

4.2 Posology and method of administration

Cardiopulmonary Resuscitation:

1 in 10,000 (1mg in 10ml) is recommended in a dose of 10ml by intravenous injection.

The procedure for Cardiopulmonary Resuscitation as given in the algorithm which reflects the recommendations of the European Resuscitation Council and the Resuscitation Council (UK) should be employed.

Cardiac arrest:

Recommended dose:

Ventricular Fibrillation / Pulseless ventricular tachycardia:

1mg adrenaline IV/IO, repeated every 3-5 minutes until return of spontaneous circulation.

Asystole / Pulseless electrical activity (PEA):

1mg adrenaline IV/IO, repeated every 3-5 minutes until return of spontaneous circulation.

Once a perfusing rhythm is established, if further adrenaline is deemed necessary, the dose should be titrated against response carefully to achieve an appropriate blood pressure. Intravenous doses of 50 microgram are usually sufficient for most hypotensive patients.

Cardiac arrest following cardiac surgery:

Cardiac arrest following major cardiac surgery is relatively common in the immediate post-operative period. The resuscitation council recommends that during the management of such patients, according to guidelines, adrenaline is administered intravenously in doses of up to 100microgram in adults (1ml of 1 in 10000 solution) very cautiously and titrated to effect.

Children under 12 years:

Management of non shockable asystole and pulseless electrical activity:

10 microgram/kg (0.1ml/kg of 1 in 10000 or 0.01ml/kg of 1 in 1000 solution) repeated every 3-5 minutes.

Management of shockable VF/ pulseless VT:

Adrenaline 10microgram/kg and amiodarone 5mg/kg given after the third shock, once CPR has been resumed.

Adrenaline can be repeated every alternative cycle (i.e. every 3-5 minutes during CPR)

In the management of respiratory and circulatory failure in children:

First and subsequent dose: 10microgram /kg by IV or IO route.

Maximum dose is 1mg.

If needed, further doses of adrenaline should be given every 3-5 minutes

Tracheal administration should be used as a last resort only if there is no alternative. If required, consider giving adrenaline 100 microgram/kg (1ml /kg of 1 in 10000 or 0.1ml /kg of 1 in 1000 solution) via the tracheal tube. This is the least satisfactory route.

Newborn:

When adequate ventilation and chest compression have failed to increase the heart rate above 60 beats per minute, adrenaline may be given in a dose of 10-30microgram/kg intravenously as soon as possible (0.1-0.3ml/kg of the 1:10000 solution or 0.01-0.03ml/kg of the 1:1000 solution). This is best given via an umbilical venous catheter.

The tracheal route is not recommended, but if used, the dose is 50-100 microgram/kg (0.5ml/kg of the 1:10000 solution or 0.05ml/kg of the 1:1000 solution).

Acute Anaphylaxis:

Constant vigilance is needed to ensure that the correct strength of Adrenaline solution is used in the treatment of anaphylaxis. Anaphylactic shock kits need to make a very clear distinction between the 1 in 10,000 strength and the 1 in 1000 strength Adrenaline solutions.

(The intramuscular route is the first choice route for administration of Adrenaline (1:1000) in the management of anaphylactic shock. It is also important that, where intramuscular injection might still succeed, time should not be wasted seeking intravenous access.)

Intravenous adrenaline should only be administered by those experienced in the use and titration of vasopressors in their normal clinical practice. In adults, titrate IV adrenaline 1 in 10000 using 50 microgram boluses according to response.

4.3 Contraindications

These should be regarded as relative and not absolute contraindications in life threatening emergency situations

Adrenaline is contraindicated in patients with shock (other than anaphylactic shock), organic heart disease, or cardiac dilatation, as well as most patients with arrhythmias, organic brain damage, or cerebral arteriosclerosis. Adrenaline injection is contraindicated in patients with narrow angle glaucoma. Adrenaline is contraindicated for use during general anaesthesia with chloroform, trichloroethylene, or cyclopropane, and should be used cautiously, it at all, with other halogenated hydrocarbon anaesthetics and adrenaline is contraindicated for use in fingers, toes, ears, nose or genitalia.

Adrenaline should not be used during the second stage of labour (see pregnancy and lactation).

4.4 Special warnings and precautions for use

IM injection of adrenaline into the buttocks should be avoided because of the risk of tissue necrosis. Prolonged use of adrenaline can result in severe metabolic acidosis because of elevated blood concentrations of lactic acid.

Adrenaline Injection 1 in 10000 BP contains sodium metabisulphite that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.

The presence of sodium metabisulphite in parenteral adrenaline and the possibility of allergic-type reactions should not deter use of the drug when indicated for the treatment of serious allergic reactions or for other emergency situations.

4.5 Interaction with other medicinal products and other forms of interaction

Sympathomimetic agents: Adrenaline should not be administered concomitantly with other sympathomimetic agents because of the possibility of additive effects and increased toxicity.

Alpha and beta blocking agents: The cardiac and bronchodilating effects of adrenaline are antagonised by P-adrenergic blocking drugs such as propranolol, and the vasoconstriction and hypertension caused by high doses of adrenaline are antagonised by alpha-adrenergic blocking agents such as phentolamine. Because of their alpha-adrenergic blocking properties, ergot alkaloids can reverse the pressor response to adrenaline.

General anaesthetics

Administration of adrenaline in patients receiving cyclopropane or halogenated hydrocarbon general anaesthetics that increase cardiac irritability and seem to sensitise the myocardium to adrenaline may result in arrhythmias including ventricular premature contractions, tachycardia, or fibrillation.

Prophylactic administration of lignocaine or prophylactic administration of propranolol 0.05 mg/kg may protect against ventricular irritability if adrenaline is used during anaesthesia with a halogenated hydrocarbon anaesthetic.

Dopaminergics: increased risk of toxicity can be seen with the effects of adrenaline enhanced by entacapone.

Other Drugs: Adrenaline should not be used in patients receiving high dosage of other drugs (e.g. cardiac glycosides) that can sensitise the heart to arrhythmias. Tricyclic antidepressants such as imipramine, some antihistamines (e.g. diphenhydramine) and thyroid hormones may potentiate the effects of adrenaline, especially on heart rhythm and rate. Although monoamine oxidase (MAO) is one of the enzymes responsible for adrenaline metabolism, MAO inhibitors do not markedly potentiate the effects of adrenaline.

Adrenaline should not be used to counteract circulatory collapse of hypotension caused by phenothiazines: a reversal of adrenaline’s pressor effects resulting in further lowering of blood pressure may occur.

Because adrenaline may cause hyperglycaemia, diabetic patients receiving adrenaline may require increased dosage of insulin or oral hyperglycaemia agents.

4.6 Pregnancy and lactation

Adrenaline usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labour. In dosage sufficient to reduce uterine contractions, the drug may cause a prolonged period of uterine atony with haemorrhage.    If used during

pregnancy, adrenaline may cause anoxia to the foetus. For this reason parenteral adrenaline should not be used during the second stage of labour. Adrenaline should only be used during pregnancy if the potential benefits justify the possible risks to the foetus.

Adrenaline is distributed into breast milk. Breast-feeding should be avoided in mothers receiving adrenaline injection.

4.7 Effects on ability to drive and use machines

Not applicable in normal conditions of use.

4.8 Undesirable effects

Side effects such as anxiety, dyspnoea, hyperglycaemia, restlessness, palpitations, tachycardia, tremors, weakness, dizziness, headache, and coldness of the extremities may occur even with small doses of adrenaline.

Other side effects include; cerebral haemorrhage, nausea vomiting, sweating and pulmonary oedema (on excessive dosage or extreme sensitivity)

In patients with Parkinsonian Syndrome, adrenaline increases rigidity and tremor.

Adrenaline causes ECG changes including a decrease in T-wave amplitude in all leads in normal persons.

Disturbances of cardiac rhythm and rate may result in palpitation and tachycardia. Adrenaline can cause potentially fatal ventricular arrhythmias including fibrillation, especially in patients with organic heart disease or other receiving other drugs that sensitise the heart to arrhythmias.

Subarachnoid haemorrhage and hemiplegia have resulted from hypertension, even following subcutaneous administration of usual doses of adrenaline.

Repeated injections of adrenaline can cause necrosis as a result of vascular constriction at the injection site. Tissue necrosis may also occur in the extremities, kidneys and liver.

4.9 Overdose

After overdose or inadvertent IV administration of usual subcutaneous doses of adrenaline, systolic and diastolic blood pressure rise sharply; venous pressure also rises. Cerebrovascular or other haemorrhage and hemiplegia may result, especially in elderly patients. Because adrenaline is rapidly inactivated in the body, treatment of acute toxicity is mainly supportive. The pressor effects of adrenaline may be counteracted by an immediate intravenous injection of a quick-acting alpha-adrenoreceptor blocking agents, such as 5 - 10mg of phentolamine mesylate, followed by a beta-adrenoreceptor blocking agent such as 2.5mg to 5mg of propranolol.

Adrenaline overdose causes transient bradycardia followed by tachycardia and may cause other potentially fatal cardiac arrhythmias. Arrhythmias, if they occur, may be counteracted by propranolol injection. Kidney failure, metabolic acidosis and cold, white skin may also occur.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Adrenaline is a direct acting sympathomimetic agent, which exerts effects on both ^ and P adrenoceptors. It exhibits little selectivity towards ^¹ and ^² receptors but is significantly more selective to p² than p¹ . Major effects include increased systolic blood pressure, reduced diastolic pressure, tachycardia, hyperglycaemia and hypoglycaemia.

5.2 Pharmacokinetic properties

Pharmacologically active concentrations of adrenaline are not achieved following oral administration as it is rapidly oxidised and conjugated in the gastrointestinal mucosa and the liver. Absorption from subcutaneous tissue is slow due to local vasoconstriction; effects are produced within 5 minutes. Absorption is more rapid after intramuscular injection than after subcutaneous injection.

Adrenaline is rapidly distributed into the heart, spleen, several glandular tissues and adrenergic nerves. It readily crosses the placenta and is approximately 50% bound to plasma proteins.

Adrenaline is rapidly metabolised in the liver, neuronal tissues and elsewhere. Up to 91% of the intravenous dose is excreted in the urine, but only 1% of the dose can be recovered unchanged.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Chloride BP Citric Acid monohydrate BP Sodium Citrate Dihydrate BP Sodium Metabisulphite BP

Water for Injections BP Nitrogen PF9

6.2    Incompatibilities

Oxidising agents rapidly denature adrenaline and alkalis including sodium bicarbonate, halogens, nitrates, nitrites, and salts of iron, copper and zinc. Adrenaline may be mixed with 0.9% sodium chloride injection but is incompatible with 5% sodium chloride injection. The stability of adrenaline in 5% dextrose injection decreases when the pH is greater than 5.5.

6.3    Shelf life

18 Months

6.4    Special precautions for storage

Store below 25°C.

Protect from light

6.5    Nature and contents of container

Sterile aqueous solution in glass (Type 1 Borosilicate) prefilled syringes.

6.6    Instructions for Use, Handling and Disposal

None

7    MARKETING AUTHORISATION HOLDER

Aurum Pharmaceuticals Ltd Bampton Road,

Harold Hill,

Romford,

Essex RM3 8UG

8    MARKETING AUTHORISATION NUMBER(S)

PL 12064/0006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04 September 1996

10 DATE OF REVISION OF THE TEXT

29/07/2013