ADRENALINE (EPINEPHRINE) INJECTION BP 1:1000 FOR ANAPHYLAXIS - summary of medicine characteristics

Summary of medicine characteristics - ADRENALINE (EPINEPHRINE) INJECTION BP 1:1000 FOR ANAPHYLAXIS

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Adrenaline (Epinephrine) (1:1000) Injection for Anaphylaxis

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 1mg Adrenaline (Epinephrine) as the Acid Tartrate

Excipient with known effect:

Sodium metabisulfite : 0.90 – 1.10 mg/ml

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for Injection

Clear and colourless solution, practically free from particles

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

To provide rapid relief for Anaphylaxis or Acute Allergy (Angioedema) both to drugs and other allergens.

4.2 Posology and method of administration

The intramuscular (IM) route is recommended by the UK Resuscitation Council as the most appropriate for most individuals who have to give adrenaline to treat an anaphylactic reaction.

The subcutaneous route for adrenaline is not recommended for treatment of an anaphylactic reaction as it is less effective.

Half doses of adrenaline may be safer for patients who are taking amitriptyline, imipramine or a beta blocker.Dosage:

Adults:

500 micrograms (0.5ml) of 1:1000 adrenaline solution

Elderly:

There are no specific dosage regimes for adrenaline injection in elderly patients. However, Adrenaline should be used with great caution in these patients who may be more susceptible to the cardiovascular side effects of adrenaline.

Paediatric population:

The following doses of adrenaline 1/1,000 are recommended:

Age	Dose
Over 12 years	0.5 mg IM (0.5ml 1:1000 solution)
6 – 12 years	0.3 mg IM (0.3ml 1:1000 solution)
6 months – 6 years	0.15 mg IM (0.15ml 1:1000 solution)
Under 6 months	0.01mg/kg IM (0.01ml/kg 1:1000 solution)

Repeat the IM adrenaline dose if there is no improvement in the patient’s condition. Further doses can be given at about 5-minute intervals according to the patient’s response.

There is a much greater risk of causing harmful side effects by inappropriate dosage or misdiagnosis of anaphylaxis when using IV adrenaline. This is why the IM route is recommended for most healthcare providers.

The UK Resuscitation Council advises the IV adrenaline for anaphylaxis should be administered by those experienced in the use and titration of vasopressors in their normal clinical practice (e.g. anaesthetists, emergency physicians or intensive care doctors).

Intravenous administration of adrenaline for anaphylaxis requires the use of a 1:10000 adrenaline solution.

Do not give the undiluted 1:1000 adrenaline intravenously.

Method of Administration

Adrenaline Injection 1/1000 (1mg/ml) may be administered undiluted by

IM injection. In the shocked patient, the intramuscular route is recommended as absorption from the intramuscular site is more rapid and reliable

A small volume syringe should be used

4.3 Contraindications

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

Adrenaline/epinephrine is contraindicated in patients with shock (other than anaphylactic shock)

Adrenaline/epinephrine injection is contraindicated in patients with narrow angle glaucoma.

Adrenaline/epinephrine 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.

Adrenaline should not be used during labour or, with local anaesthesia of

peripheral structures including digits and ear lobe.

Use in the presence of ventricular fibrillation, cardiac dilatation, coronary insufficiency, organic brain disease or atherosclerosis, except in emergencies where the potential benefit clearly outweighs the risk.

Do not use if solution is discoloured.

4.4 Special warnings and precautions for use

Adrenaline should be used with caution in patients with hyperthyroidism, diabetes mellitus, phaeochromocytoma, narrow angle glaucoma, hypokalaemia, hypercalcaemia, severe renal impairment, prostatic adenoma leading to residual urine, cerebrovascular disease, organic brain damage or arteriosclerosis, in elderly patients, in patients with shock (other than anaphylactic shock) and in 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.

Repeat administration may produce local necrosis at the sites of injection.

Prolonged administration may produce metabolic acidosis, renal necrosis and adrenaline fastness or tachyphylaxis.

Adrenaline should be avoided or used with extreme caution in patients undergoing anaesthesia with halothane or other halogenated anaesthetics, in view of the risk of inducing ventricular fibrillation.

Do not mix with other agents unless compatibility is known.

The patient should be monitored as soon as possible (pulse, blood pressure, ECG, pulse oximetry). This will help monitor 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.

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.

Adrenaline 1:1000 should not be diluted to 1 in 10,000 for use in cardiac resuscitation – when the 1 in 10,000 strength of adrenaline is required for this indication a “ready to use” preparation should be selected.

IM injection of adrenaline/epinephrine into the buttocks should be avoided because of the risk of tissue necrosis.

Adrenaline/Epinephrine Injection 1:1000 contains sodium metabisulfite that 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/epinephrine 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/Oxytocin:

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

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).

Because of their alpha-adrenergic blocking properties, ergot alkaloids can reverse the pressor response to adrenaline.

Beta-adrenergic blocking agents:

Severe hypertension and reflex bradycardia may occur with non-selective betablocking drugs 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/epinephrine in patients receiving cyclopropane or halogenated hydrocarbon general anaesthetics that increase cardiac irritability and seem to sensitise the myocardium to adrenaline/epinephrine may result in arrhythmias including ventricular premature contractions, tachycardia, or fibrillation (See section 4.4)..

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

Other Drugs:

Adrenaline/epinephrine 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/epinephrine, especially on heart rhythm and rate.

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

Although monoamine oxidase (M.A.O.) is one of the enzymes responsible for adrenaline metabolism, M.A.O. inhibitors do not markedly potentiate the effects of adrenaline.

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.

Phenothiazine:

Phenothiazines block alpha-adrenergic receptors.

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

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 incidence of congenital abnormalities,

Injection of adrenaline may cause anoxia, foetal tachycardia, cardiac irregularities, extra systoles, and louder heart sounds.

Adrenaline/epinephrine 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/epinephrine may cause anoxia to the foetus.

For this reason, parenteral adrenaline/epinephrine should not be used during the second stage of labour.

Breast-feeding

Adrenaline/epinephrine is distributed into breast milk. Breast-feeding should therefore be avoided in mothers receiving Adrenaline/Epinephrine Injection.

Adrenaline should not be used in pregnancy unless clearly necessary.

4.7 Effects on ability to drive and use machines

Adrenaline has moderate influence on the ability to drive and use machines. The 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. 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
Immune system disorders	Not known	Anaphylaxis, possibly with severe bronchospasm (see section 4.4)
Metabolism and nutrition disorders	Not known	Hypokalaemia, metabolic acidosis (see section 4.4). Inhibition of insulin secretion and hyperglycaemia even with low doses, gluconeogenesis, glycolysis, lipolysis, and ketogenesis.
Psychiatric disorders	Not known	Psychotic states, anxiety, fear confusion, irritability, and insomnia

Nervous system disorders	Not known	Headache, dizziness, tremors, restlessness 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	Not known	Disturbances of cardiac rhythm and rate may result in palpitation and tachycardia. Chest pain/angina may occur. 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. (See section 4.5) Adrenaline causes E.C.G. changes including a decrease in T-Wave amplitude in all leads in normal subjects.
Vascular Disorder	Not known	Hypertension (with risk of cerebral haemorrhage). Coldness of extremities may occur even with small doses of Adrenaline.
Respiratory, thoracic and mediastinal disorders	Not known	Dyspnoea, Pulmonary oedema may occur after excessive doses or in extreme sensitivity.
Gastrointestinal disorders	Not Known	Dry mouth, Reduced appetite, nausea, vomiting, hypersalivation.
Renal and urinary disorders	Not Known	Difficulty in micturition, urinary retention.
General disorders and administration site conditions	Not known	Sweating, weakness. Repeated injections of Adrenaline can cause local ischaemic 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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Symptoms:

After overdose or inadvertent IV administration of usual intramuscular subcutaneous doses of adrenaline/epinephrine, 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 be caused by overdosage or extreme sensitivity to adrenaline.

Adrenaline/epinephrine 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 /epinephrine is rapidly inactivated in the body, treatment of acute toxicity is mainly supportive.

The pressor effects of adrenaline/epinephrine may be counteracted by an immediate intravenous injection of a quick-acting alpha-adrenoceptor blocking agent, such as 5 –10mg of phentolamine mesylate, followed by a beta-adrenoceptor blocking agent such as 2.5mg to 5mg of propranolol.

Arrhythmias, if they occur, may be counteracted by propranolol injection

5 PHARMACOLOGICAL PROPERTIES

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.

The overall effect of adrenaline depends on the dose used, and may be complicated by the homeostatic reflex responses. In resuscitation procedures, it is used to increase the efficacy of basic life support. It is a positive cardiac inotrope.

5.2 Pharmacokinetic properties

Absorption

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. 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.

Biotransformation

Adrenaline is rapidly inactivated in the body, mostly in the liver by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

Elimination

Much of a dose of adrenaline is excreted as metabolites in urine.

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.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride

Sodium Metabisulfite Water for Injections Dilute Hydrochloric Acid

6.2 Incompatibilities

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

6.3

Shelf life

15 Months

6.4

Special precautions for storage

Keep container in the outer carton

Do not store above 25°C

Do not freeze

6.5 Nature and contents of container

Type 1 Glass prefilled Syringe with needle in situ with rubber needle shield, rubber plunger (Type PH 701/50C)

6.6 Special precautions for disposal

Do not use if the contents of the syringe are discoloured. Do not use if the tamper evident seal is broken or the packaging is damaged. Use once and discard any remaining solution at the end of the session.

MARKETING AUTHORISATION HOLDER

Aurum Pharmaceuticals Ltd

Bampton Road

Harold Hill

Romford

Essex

RM3 8UG

8 MARKETING AUTHORISATION NUMBER(S)

PL 12064/0058

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 29/07/1999

Date of renewal: 25/05/2005