This information is intended for use by health professionals

1. Name of the medicinal product

Adrenaline (Epinephrine) Injection 1:10,000

2. Qualitative and quantitative composition

Each ml of solution for injection contains 0.1 mg of adrenaline (as adrenaline acid tartrate)

Each 10 ml pre-filled syringe contains 1 mg adrenaline (as adrenaline acid tartrate)

Excipient with known effect: sodium

Each ml of solution for injection contains 2.695 mg equivalent to 0.117 mmol of sodium.

Each 10 ml pre-filled syringe contains 26.95 mg equivalent to 1.17 mmol of sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

A sterile aqueous clear and colourless solution for slow intravenous injection in pre-filled syringe.

4. Clinical particulars
4.1 Therapeutic indications

Adrenaline (Epinephrine) Injection 1 in 10,000 may be used in the

• Cardiopulmonary Resuscitation in adults and children over 5kg

• Acute anaphylaxis in adults

4.2 Posology and method of administration

This medicinal product is not intended to deliver volumes of less than 2 mL.

Intravenous adrenaline should only be administered by those experienced in the use and titration of vasopressors in their normal clinical practice.

Cardiopulmonary Resuscitation:

10 ml of the 1:10,000 solution (1 mg) by the intravenous or intraosseous route, repeated every 3-5 minutes until return of spontaneous circulation.

Endotracheal use should only be considered as a last resort if no other route of administration is accessible, at a dose of 20 to 25 ml of the 1:10,000 solution (2 to 2.5 mg).

In cardiac arrest following cardiac surgery, Adrenaline should be administered intravenously in doses of 0.5 ml or 1ml of 1:10,000 solution (50 or 100 micrograms) very cautiously and titrated to effect.

Acute Anaphylaxis:

Titrate using intravenous boluses of 0.5 ml 1:10,000 solution (0.05 mg) according to response.

Adrenaline 1mg/10ml (1:10,000) solution for injection in pre-filled syringe is not recommended for intramuscular use in acute anaphylaxis. For intramuscular administration, a 1mg/ml (1:1000) solution should be used

Paediatric Population

This medicinal product is not appropriate to deliver a dose of less than 0.5 ml and should therefore not be used by the intravenous or intraosseous route, in neonates and infants with body weight less than 5 kg.

Cardiac arrest in children:

Intravenous or intraosseous route (above 5 kg only): 0.1 ml/kg of 1:10,000 solution (10 micrograms/kg) to a maximum single dose of 10 ml of 1:10,000 solution (1 mg), repeated every 3-5 minutes until return of spontaneous circulation.

Endotracheal use (any body weight) should only be considered as a last resort if no other route of administration is accessible, at a dose of 1 ml/kg of 1:10,000 solution (100 micrograms/kg) to a maximum of single dose of 25 ml of 1:10,000 solution (2.5 mg).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, where an alternative presentation of adrenaline or alternative vasopressor is available.

4.4 Special warnings and precautions for use

Adrenaline 1 mg/10 ml (1:10,000), solution for injection in pre-filled syringe is indicated for emergency treatment. Medical supervision is necessary after administration.

For intramuscular administration, a 1 mg/ml (1:1000) solution should be used.

In the treatment of anaphylaxis and in other patients with a spontaneous circulation, intravenous adrenaline can cause life-threatening hypertension, tachycardia, arrhythmias and myocardial ischaemia.

Intravenous adrenaline should only be used by those experienced in the use and titration of vasopressors in their normal clinical practice. Patients who are given IV adrenaline require continuous monitoring of ECG, pulse oximetry and frequent blood pressure measurements as a minimum.

The risk of toxicity is increased if the following conditions are pre-existing

• Hyperthyroidism

• Hypertension

• Structural cardiac disease, cardiac arrhythmias, severe obstructive cardiomyopathy,

• Coronary insufficiency

• Phaeochromocytoma,

• Hypokalaemia

• Hypercalcaemia

• Severe renal impairment

• Cerebrovascular disease, organic brain damage or arteriosclerosis

• Patients taking Monoamine oxidase (MAO) inhibitors (see section 4.5)

• Patients taking concomitant medication which results in additive effects, or sensitizes the myocardium to the actions of sympathomimetic agents (see section 4.5)

Prolonged use of adrenaline can result in severe metabolic acidosis because of elevated blood concentrations of lactic acid.

Adrenaline may increase intra-ocular pressure in patients with narrow angle glaucoma.

Adrenaline should be used with caution in patients with prostatic hyperplasia with urinary retention.

Adrenaline may cause or exacerbate hyperglycaemia, blood glucose should be monitored, particularly in diabetic patients.

Adrenaline should be used with caution in elderly patients.

Adrenaline should not be used during the second stage of labour (See Section 4.6).

This medicinal product contains 2.70 mg of sodium per ml of solution for injection: to be taken into consideration by patients on a strict sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Volatile halogen anaesthetics: severe ventricular arrhythmia (increase in cardiac excitability).

Imipramine antidepressants: paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibres).

Serotoninergic-adrenergic antidepressants: paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibres).

Sympathomimetic agents: concomitant administration of other sympathomimetic agents may increase toxicity due to possible additive effects.

Non-selective MAO inhibitors: increased pressor action of adrenaline, usually moderate.

Selective MAO-A inhibitors, Linezolid (by extrapolation from non-selective MAO inhibitors): Risk of aggravation of pressor action.

Alpha-adrenergic blocking agents: Alpha-blockers antagonise the vasoconstriction and hypertension effects of adrenaline, increasing the risk of hypotension and tachycardia.

Beta-adrenergic blocking agents: Severe hypertension and reflex bradycardia may occur with non-cardioselective beta-blocking agents. Beta-blockers, especially non-cardioselective agents, also antagonise the cardiac and bronchodilator effects of adrenaline.

Insulin or oral hypoglycaemic agents: Adrenaline-induced hyperglycaemia may lead to loss of blood-sugar control in diabetic patients treated with insulin or oral hypoglycaemic agents.

4.6 Fertility, pregnancy and lactation

Pregnancy

Teratogenic effect has been demonstrated in animal experiments.

Adrenaline should only be used during pregnancy if the potential benefits outweigh the possible risks to the foetus. If used during pregnancy, adrenaline may cause anoxia to the foetus.

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, adrenaline may cause a prolonged period of uterine atony with haemorrhage. For this reason, parenteral adrenaline should not be used during the second stage of labour.

Breast-feeding

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

Fertility

No information available concerning impact of adrenaline on fertility.

4.7 Effects on ability to drive and use machines

Not applicable in normal conditions of use.

4.8 Undesirable effects

The adverse events of adrenaline mainly relate to the stimulation of both alpha- and beta-adrenergic receptors. The occurrence of undesirable effects depends on the sensitivity of the individual patient and the dose involved.

Frequencies are defined using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to<1/100), rare (>1/10000 to<1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

System organ class

Frequency

Undesirable effects

Metabolism and nutrition disorders

Not known

Hyperglycaemia, Hypokalaemia, Metabolic acidosis.

Psychiatric disorders

Not known

Anxiety, Nervousness, Fear, Hallucinations.

Nervous system disorders

Not known

Headache, Tremors, Dizziness, Syncope.

Eye disorder

Not known

Mydriasis

Cardiac disorders

Not known

Palpitations, Tachycardia.

In high dosage or for patients sensitive to adrenaline: cardiac dysrhythmia (sinus tachycardia, ventricular fibrillation/cardiac arrest), acute angina attacks, and risk of acute myocardial infarction.

Vascular Disorder

Not known

Pallor, Coldness of the extremities. In high dosage or for patient's sensitive to adrenaline: hypertension (with risk of cerebral haemorrhage), vasoconstriction1

Respiratory, thoracic and mediastinal disorders

Not known

Dyspnoea

Gastrointestinal disorders:

Not known

Nausea, Vomiting

General disorders and administration site conditions

Not known

Sweating, Weakness

Repeated local injections may produce necrosis at sites of injection as a result of vascular constriction.

1 For example cutaneous, in the extremities or kidneys.

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 or search for MHRA Yellow card in the Google Play or Apple App Store.

4.9 Overdose

Over dosage or inadvertent intravenous administration of adrenaline may produce severe hypertension. Cerebral, cardiac or vascular accidents which could be potentially fatal may occur as a result (cerebral haemorrhage, dysrhythmias such as transient bradycardia followed by tachycardia that may result in arrhythmia, myocardial necrosis, acute pulmonary oedema, renal insufficiency).

The effects of adrenaline may be counteracted, depending on the condition of the patient, by administration of quick-acting vasodilators, of quick-acting alpha-adrenoreceptor blocking agents (e.g. phentolamine), or beta-adrenoreceptor blocking agents (e.g. propanolol).

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: adrenergic and dopaminergic agents, adrenaline.

ATC code: C01 CA 24

Adrenaline is a direct acting sympathomimetic agent, which exerts effects on both α and β adrenoceptors. It has more pronounced effects on β than on α adrenoceptors, although α effects prevail at high doses.

The effects of adrenaline include increased rate and force of cardiac contraction, cutaneous vasoconstriction and broncho-dilatation. With higher doses, stimulation of peripheral α receptors results in an increase in peripheral resistance and in blood pressure.

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

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.

Distribution

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.

Biotransformation

Adrenaline is rapidly inactivated in the body, mostly in the liver by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Most of a dose of adrenaline is excreted as metabolites in urine.

Elimination

After intravenous administration, the plasma half-life is about 2-3 minutes.

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 Citric Acid monohydrate

Sodium Citrate Dihydrate

Sodium Metabisulphite

Water for Injections

Hydrochloric acid (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this product must not be mixed with other medicinal products.

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

10 ml sterile aqueous solution in glass (Type 1 Borosilicate) prefilled syringes.

6.6 Special precautions for disposal and other handling

The syringe should only be opened immediately prior to administration.

Any unused product or waste material should be disposed of in accordance with local requirements.

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

16/04/2018