SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Adrenaline (Epinephrine) Injection BP 1 in 1000.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for injection contains 1 mg of adrenaline (epinephrine) as the acid tartrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Sterile Injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adrenaline Injection BP 1 in 1000 may be used in the treatment of acute allergy and anaphylactic shock.

4.2    Posology and method of administration

The intramuscular route is the preferred choice for most individuals who have to be given adrenaline for the management of an anaphylactic reaction. The generally accepted dosage of adrenaline in this indication is 0.01mg/kg body weight. An additional dosage table according to age is presented below.

Dose of intramuscular injection of Adrenaline (Epinephrine) Injection BP 1 in 1000 for a severe anaphylactic reaction
Age	Dose	Volume of adrenaline 1 in 1000 (1mg/ml)
Under 6 months	0.01 mg/kg IM	0.01 ml/kg
6 months - 6 years	0.15 mg IM	0.15 ml
Child 6 - 12 years	0.3 mg IM	0.3 ml
Child > 12 years	0.5 mg IM	0.5 ml
Adult	0.5 mg IM	0.5 ml

4.3 Contraindications

Hypersensitivity to adrenaline, sodium metabisulfite or any of the other ingredients.

Adrenaline 1 in 1000 should not be used in fingers, toes, ears, nose or genitalia owing to the risk of ischaemic tissue necrosis.

4.4 Special warnings and precautions for use

Adrenaline should be used with caution in patients with:

•    hyperthyroidism, psychoneurosis, phaeochromocytoma, narrow angle glaucoma, diabetes mellitus, hypokalaemia or hypercalcaemia.

•    severe renal impairment, prostatic hypertrophy or urination difficulty

•    cerebrovascular disease, organic brain damage or arteriosclerosis

•    autonomic dysreflexia (hyperreflexia), particularly in spinal cord injury (e.g., tetraplegics)

•    shock (other than anaphylactic shock)

•    organic heart disease or cardiac dilatation (severe angina pectoris, obstructive cardiomyopathy, hypertension) as well as most patients with arrhythmias. Anginal pain may be induced when coronary insufficiency is present.

Adrenaline should be used with caution in older patients

Adrenaline should be used with extreme caution in patients with long-standing bronchial asthma and emphysema who have developed degenerative heart disease.

Adrenaline should be used cautiously, if at all, during general anaesthesia with halogenated hydrocarbon anaesthetics (See section 4.5).

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

Accidental intravascular injection may result in cerebral haemorrhage due to the sudden rise in blood pressure.

The IM route is generally preferred in the initial treatment of anaphylaxis, the IV route is generally more appropriate in the Intensive Care Unit (ICU) or Emergency Department (ED) setting. Adrenaline (epinephrine) injection 1:1000 (1mg/ml) is not suitable for IV use. If the epinephrine 1:10000 (0.1mg/ml) injection is not available, epinephrine injection 1:1000 must be diluted to 1:10000 before IV use. The IV route for injection of epinephrine must be used with extreme caution and is best reserved for specialists familiar with IV use of epinephrine (adrenaline).

Monitor the patient as soon as possible (pulse, blood pressure, ECG, pulse oximetry) in order to assess the response to adrenaline.

The best site for IM injection is the anterolateral aspect of the middle third of the thigh. The needle used for injection needs to be sufficiently long to ensure that the adrenaline is injected into muscle. Intramuscular injections 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), renal necrosis and tachyphylaxis.

Adrenaline Injection contains sodium metabisulfite, which can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.

The presence of sodium metabisulfite 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-adrenergic agents:

The vasoconstrictor and pressor effects of adrenaline, mediated by its alpha-adrenergic action, may be enhanced by concomitant administration of drugs with similar effects, such as ergot alkaloids or oxytocin.

Alpha-adrenergic blocking agents:

Alpha-blockers such as phentolamine antagonise the vasoconstriction and hypertension effects of adrenaline. This effect may be beneficial in adrenaline overdose (See section 4.9). Adrenaline specifically reverses the antihypertensive effects of adrenergic neurone blockers such as guanethidine with the risk of severe hypertension.

Beta-adrenergic blocking agents:

Severe hypertension and reflex bradycardia may occur with non-cardioselective betablocking agents such as propranolol, due to alpha-mediated vasoconstriction.

Beta-blockers, especially non-cardioselective agents, also antagonise the cardiac and bronchodilator effects of adrenaline. Patients with severe anaphylaxis who are taking non-cardioselective beta-blockers may not respond to adrenaline treatment.

General Anaesthetics:

Administration of Adrenaline in patients receiving 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 (See section 4.4).

Antihypertensive agents:

Adrenaline specifically reverses the antihypertensive effects of adrenergic neurone blockers such as guanethidine, with the risk of severe hypertension. Adrenaline increases blood pressure and may antagonise the effects of antihypertensive drugs.

Antidepressant agents:

Tricyclic antidepressants such as imipramine inhibit reuptake of directly acting sympathomimetic agents, and may potentiate the effect of adrenaline, increasing the risk of development of hypertension and cardiac arrhythmias.

Concurrent use or use within 2 weeks of a monoamine oxidase inhibitor increases the risk of adverse events.

Phenothiazines:

Phenothiazines block alpha-adrenergic receptors (see above).

Adrenaline should not be used to counteract circulatory collapse or hypotension caused by phenothiazines; a reversal of the pressor effects of Adrenaline may result in further lowering of blood pressure.

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. Some antihistamines (e.g. diphenhydramine) and thyroid hormones may potentiate the effects of Adrenaline, especially on heart rhythm and rate. Adrenaline increases the risk of cardiac adverse effects of levodopa. Use of Entacapone may potentiate the chronotropic and arrhythmogenic effects of adrenaline.

Hypokalaemia:

The hypokalaemic effect of adrenaline may be potentiated by other drugs that cause potassium loss, including corticosteroids, potassium-depleting diuretics, aminophylline and theophylline.

Hyperglycaemia:

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

Adrenaline crosses the placenta. There is some evidence of a slightly increased evidence of congenital abnormalities. Injection of adrenaline may cause anoxia to the foetus, foetal tachycardia, cardiac irregularities, extrasystoles and louder heart sounds.

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. 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.

Lactation

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

Patients' ability to drive and use machines may be affected by the anaphylactic reaction, as well as by possible adverse reactions to adrenaline.

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.

Immune system disorders:

Anaphylaxis, possibly with severe bronchospasm (See section 4.4).

Metabolism and nutrition disorders:

Hypokalaemia, metabolic acidosis (see section 4.4).

Inhibition of insulin secretion and hyperglycaemia even with low doses, gluconeogenesis, glycolysis, lipolysis and ketogenesis.

Psychiatric disorders:

Psychotic states, anxiety, fear, confusion, irritability, insomnia, restlessness Nervous system disorders:

Headache, dizziness, tremors

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

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

Cardiac disorders:

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 those receiving other drugs that sensitise the heart to arrhythmias. Myocardial ischaemia and myocardial infarction have been reported.

Adrenaline causes E.C.G. changes including a decrease in T-Wave amplitude in all leads in normal subjects.

In rare cases stress cardiomyopathy has been seen in patients treated with adrenaline.

Vascular disorders:

Hypertension (with risk of cerebral haemorrhage).

Coldness of extremities may occur even with small doses of Adrenaline.

Bowel necrosis

Respiratory disorders:

Dyspnoea. Pulmonary oedema may occur after excessive doses or in extreme sensitivity.

Gastrointestinal disorders:

Dry mouth, reduced appetite, nausea, vomiting, hypersalivation.

Renal and urinary disorders:

Difficulty in micturition, urinary retention.

General disorders and administrative site conditions:

Sweating, weakness, pallor.

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.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

After overdosage or inadvertent intravenous administration of usual intramuscular/subcutaneous doses of Adrenaline, systolic and diastolic blood pressure rise sharply; venous pressure also rises. Cerebrovascular or other haemorrhages and hemiplegia may result, especially in elderly patients. Pulmonary oedema may occur.

Adrenaline overdosage causes transient bradycardia followed by tachycardia and may cause other potentially fatal cardiac arrhythmias. Kidney failure, metabolic acidosis and cold white skin may also occur.

Treatment

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 agent, such as 5-10 mg of phentolamine mesylate, followed by a beta-adrenoreceptor blocking agent, such as 2.5 - 5 mg of propranolol. Arrhythmias, if they occur, may be counteracted by propranolol injection.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: adrenergic and dopaminergic agents, adrenaline.

ATC code: C01 CA 24

Adrenaline is a naturally occurring catecholamine secreted by the adrenal medulla in response to exertion or stress. It is a sympathomimetic amine which is a potent stimulant of both alpha- and beta-adrenergic receptors and its effects on target organs are therefore complex. It is used to provide rapid relief of hypersensitivity reactions to allergies or to idiopathic or exercise-induced anaphylaxis.

Adrenaline has a strong vasoconstrictor action through alpha- adrenergic stimulation. This activity counteracts the vasodilatation and increased vascular permeability leading to loss of intravascular fluid and subsequent hypotension, which are the major pharmacological features in anaphylactic shock.

Adrenaline stimulates bronchial beta-adrenergic receptors and has a powerful bronchodilator action. Adrenaline also alleviates pruritus, urticaria and angioedema associated with anaphylaxis.

5.2    Pharmacokinetic properties

Adrenaline has a rapid onset of action after intramuscular administration and in the shocked patient its absorption from the intramuscular site is faster and more reliable than from the subcutaneous site.

Adrenaline is rapidly inactivated in the body, mostly in the liver by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Much of a dose of adrenaline is excreted as metabolites in urine. The plasma half-life is about 23 minutes. However, when given by subcutaneous or intramuscular injection, local vasoconstriction may delay absorption so that the effects may last longer than the half-life suggests.

5.3    Preclinical safety data

No further information other than that which is included in the Summary of Product Characteristics.

6.    Pharmaceutical Particulars

6.1    List of excipients

Sodium Metabisulfite Ph. Eur. Sodium Chloride Ph. Eur. Sodium Hydroxide Ph. Eur.

Water for Injections Ph. Eur. Hydrochloric Acid Ph. Eur.

6.2 Incompatibilities

Adrenaline is rapidly denatured by oxidising agents 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

24 months.

6.4 Special precautions for storage

Store at less than 25 °C and protect from light.

6.5 Nature and contents of container

Clear glass ampoules of 1ml.

Packed in cardboard cartons to contain 10 ampoules x 1ml.

6.6 Special precautions for disposal

Use as directed by the Physician.

7 MARKETING AUTHORISATION HOLDER

hameln pharmaceuticals ltd

Gloucester

UK

MARKETING AUTHORISATION NUMBER(S)

PL 01502/0024

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14^th December 1978 / 23^rd August 2001

DATE OF REVISION OF THE TEXT

16/11/2015