SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

EpiPen® Adrenaline (Epinephrine) Auto-Injector 0.3mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Per 1 ml:

Active ingredient    Quantity / Unit    Reference Standards

Adrenaline    1.0 mg    BP/USP

(Epinephrine)

Excipients with known effect: Sodium metabisulfite (E223) 0.5 mg/dose, sodium chloride 1.8 mg/dose.

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Solution for injection in an auto-injector (prefilled, disposable automatic injection device) for intramuscular use.

Clear and colourless solution.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

EpiPen Auto-Injectors are automatic injection devices containing adrenaline for allergic emergencies. The Auto-Injectors should be used only by a person with a history or an acknowledged risk of an anaphylactic reaction. The AutoInjectors are indicated in the emergency treatment of allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis. Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhoea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritis, rashes, urticaria or angioedema.

For these reasons Auto-Injectors should always be carried by such persons in situations of potential risks.

Adrenaline is considered the first line drug of choice for allergic emergencies. Adrenaline effectively reverses the symptoms of rhinitis, urticaria, bronchospasm and hypotension because it is a pharmacological antagonist to the effects of the chemical mediators on smooth muscles, blood vessels and other tissues. Adrenaline is recommended as the initial and primary therapeutic agent in the treatment of anaphylaxis by every recognised authority in allergy, and its appropriate use in these circumstances is widely documented in the medical literature.

4.2 Posology and administration

Posology:

The EpiPen® auto injector is for adult intramuscular administration.

It is designed for easy use by the lay person and has to be considered as first aid. EpiPen® auto injector delivers a single dose 0.3 ml injection equal to 0.3 mg adrenaline when activated. Usual adrenaline adult dose for allergic emergencies is 0.3 mg. For paediatric use, the appropriate dosage may be 0.15 mg or 0.3 mg depending upon the body weight of the patient (0.01 mg/kg body weight). However the prescribing physician has the option of prescribing more or less than these amounts based on careful assessment of each individual patient and recognising the life-threatening nature of reactions for which this is being described.

The physician should consider using other forms of injectable adrenaline if lower doses are felt to be necessary for small children.

An initial dose should be administered as soon as symptoms of anaphylaxis are recognised. In the absence of clinical improvement or if deterioration occurs after the initial treatment, a second injection with an additional EpiPen® auto injector may be administered 5 - 15 minutes after the first injection. It is recommended that patients are prescribed two EpiPen® auto injectors which they should carry at all times.

As EpiPen® auto injector is designed as emergency treatment only, the patient should be advised to always seek medical help immediately.

A physician who prescribes EpiPen® auto injector should take appropriate steps to ensure that the patient understands the indications and use of this device thoroughly. The physician should review with the patient, or any other person who might be in a position to administer EpiPen® auto injector to a patient experiencing anaphylaxis, in detail, the patient instructions and operation of the EpiPen® auto injector.

Method of administration:

Inject the delivered dose of the EpiPen® auto injector (0.3 ml equal to 0.3 mg) into the anterolateral aspect of the thigh, through clothing if necessary. See detailed instructions for use, point 6.6

The patient/carer should be informed that following each use of EpiPen® auto injector:

•    They should call for immediate medical assistance, ask for an

ambulance and state ‘anaphylaxis’ even if symptoms appear to be improving (see section 4.4)

•    Conscious patients should preferably lie flat with feet elevated but sit

up if they have breathing difficulties. Unconscious patients should be placed on their side in the recovery position.

•    The patient should if possible remain with another person until medical

assistance arrives.

4.3 Contraindications

There are no known absolute contraindications to the use of EpiPen AutoInjector during an allergic emergency. Clinical conditions where special precautions are advised and drug interactions are prescribed in sections 4.4 and 4.5.

4.4 Special warnings and precautions for use

All patients who are prescribed EpiPen® should be thoroughly instructed to understand the indications for use and the correct method of administration (see section 6.6). It is strongly advised also to educate the patient’s immediate associates (e.g. parents, caregivers, teachers) for the correct usage of EpiPen® in case support is needed in the emergency situation.

Adrenaline is ordinarily administered with extreme caution to patients who have heart disease. Adrenaline should only be prescribed to those patients, and elderly individuals, if the potential benefit justifies the potential risk.

There is a risk of adverse reactions following adrenaline administration in patients with high intraocular pressure, severe renal impairment, prostatic adenoma leading to residual urine, hypercalcaemia and hypokalaemia. In patients with Parkinson’s disease, adrenaline may be associated with a transient worsening of Parkinson’s symptoms such as rigidity and tremor.

Use of adrenaline with drugs that may sensitise the heart to arrhythmias, e.g., digitalis, mercurial diuretics, or quinidine, ordinarily is not recommended. Anginal pain may be induced by adrenaline in patients with coronary insufficiency.

Hyperthyroid individuals (hyperfunction of the thyroid gland), individuals with cardiovascular disease, hypertension (raised blood pressure), or diabetes, elderly individuals, pregnant women, and children under 25 kg body weight using EpiPen® auto injector may theoretically be at greater risk of developing adverse reactions after adrenaline administration.

Accidental injection into the hands or feet may result in loss of blood flow to the affected area and should be avoided. If there is an accidental injection into these areas, advise the patient to go immediately to the nearest emergency room or hospital casualty department for treatment.

The patient should be instructed to check the contents of the glass cartridge in the auto injector periodically through the viewing window of the unit to make sure the solution is clear and colourless. The auto injector should be discarded if discoloured or contains a precipitate. For emergency treatment, use of an EpiPen® auto injector with discoloured contents may be recommended rather than to postpone the treatment.

The auto injectors should ONLY be injected into the anterolateral aspect of the thigh. Patients should be advised NOT to inject into the buttock. Large doses or accidental intravenous injection of adrenaline may result in cerebral haemorrhage due to sharp rise in blood pressure. Directions for proper use of the auto injectors must be followed in order to avoid intravenous injection. Rapidly acting vasodilators can counteract the marked pressor-effects of adrenaline.

In patients with a thick subcutaneous fat layer, there is a risk of adrenaline not reaching the muscle tissue resulting in a suboptimal effect.

The adrenaline solution contains sodium metabisulfite, a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using adrenaline in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations.

Despite these concerns, adrenaline is essentially for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen® auto injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which this life-saving medication should be used.

The patient/carer should be informed about the possibility of biphasic anaphylaxis which is characterised by initial resolution followed by recurrence of symptoms some hours later.

Patients with concomitant asthma may be at increased risk of severe anaphylactic reaction

Patients should be warned regarding related allergens and should be investigated whenever possible so that their specific allergens can be characterised.

This medicinal product contains less than 1 mmol (23mg) per dose, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Caution is indicated in patients receiving drugs that may sensitise the heart to arrhythmias, including digitalis, mercurial diuretics or quinidine. The effects of adrenaline may be potentiated by tricyclic antidepressants and mono amine oxidase inhibitors (MAO-inhibitors) and catechol-O-methyl transferase inhibitors (COMT inhibitors), thyroid hormones, theophylline, oxytocin, parasympatholytics, certain antihistamines (diphenhydramine, chlorpheniramine), levodopa and alcohol.

Pressor effects of adrenaline may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug, such as levarterenol.

Adrenaline inhibits the secretion of insulin, thus increasing the blood glucose level. It may be necessary for diabetic patients receiving adrenaline to increase their dosage of insulin or oral hypoglycaemic drugs.

The P-stimulating effect can be inhibited by simultaneous treatment with P-blocking drugs.

4.6 Fertility, pregnancy and lactation

Adrenaline has been used for years in the treatment of allergic emergencies and its use is well documented in the literature. No clinical trials were performed in conjunction with this application.

Pregnancy

Adrenaline should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Fertility

As adrenaline is a substance that naturally occurs in the body, it is unlikely that this drug would have any detrimental effects on fertility.

4.7 Effects on ability to drive and use machines

The patient’s 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

Repeated dose toxicity studies were not performed in conjunction with this application. Side effects associated with adrenaline's alpha and beta receptor activity may include palpitations, tachycardia and hypertension as well as undesirable effects on the central nervous system, sweating, nausea and vomiting, respiratory difficulty, pallor, dizziness, weakness, tremor, headache, apprehension, nervousness and anxiety. Cardiac arrhythmias may follow administration of adrenaline.

Evaluation of undesirable effects is based on the following frequency information:

•    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)

•    Not known (Frequency cannot be estimated from the available data).

Organ System	Frequency	Adverse drug reaction
Psychiatric disorders	Frequency not known	Anxiety
Nervous system disorders	Frequency not known	Headache, dizziness, tremor
Cardiac disorders	Rare	Stress cardiomyopathy
	Frequency not known	Tachycardia, cardiac arrhythmia
Vascular disorders	Frequency not known	Hypertension, peripheral ischaemia following accidental injection of the pens in hands or feet
Gastrointestinal disorders	Frequency not known	Nausea, vomiting
Skin and subcutaneous tissue disorders	Frequency not known	Hyperhidrosis
General disorders and administration site condition	Frequency not known	Asthenia

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:

Overdose or inadvertent intravascular or intra-osseus injection of adrenaline may cause cerebral haemorrhage resulting from a sharp rise in blood pressure. Fatalities may also result from pulmonary oedema because of peripheral vascular constriction together with cardiac stimulation.

Management:

Pressor effects of adrenaline may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug, such as levarterenol.

If an adrenaline overdose induces pulmonary oedema that interferes with respiration, treatment consists of a rapidly acting alpha-adrenergic blocking drug such as phentolamine and/or intermittent positive-pressure respiration.

Adrenaline overdose can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Treatment of arrhythmias may consist of administration of beta-adrenergic blocking drugs.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac stimulants excluding cardiac glycosides, adrenergic and dopaminergic agents.

ATC-code: C01CA24

Adrenaline is one of the catecholamines which are a group of sympathomimetic amines containing a catechol moiety. Adrenaline activates an adrenergic receptive mechanism on effector cells and imitates all actions of the sympathetic nervous system except those on the arteries of the face and sweat glands. Adrenaline acts on both alpha and beta receptors and is the most potent alpha receptor activator.

The strong vasoconstrictor action of adrenaline through its effect on alpha adrenergic receptors acts quickly to counter vasodilation and increased vascular permeability which can lead to loss of intravascular fluid volume and hypotension during anaphylactic reactions. Adrenaline through its action on beta receptors on bronchial smooth muscles causes bronchial smooth muscle relaxation which alleviates wheezing and dyspnoea. Adrenaline also alleviates pruritus, urticaria and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis.

5.2 Pharmacokinetic properties

Adrenaline is a naturally occurring substance produced by the adrenal medulla and secreted in response to exertion or stress. It is rapidly inactivated in the body mostly by the enzymes COMT and MAO. The liver is rich in these enzymes and is an important, although not essential, tissue in the degradation process. Much of the dose of adrenaline is accounted for by excretion of metabolites in the urine.

According to Remington’s Pharmaceutical Sciences, the plasma half-life of adrenaline is about 2.5 min. However, by subcutaneous or intramuscular routes, local vasoconstriction retards absorption, so that the effects occur insidiously and last much longer than the half-life would predict. Massage around the injection area is advised.

5.3 Preclinical safety data

Adrenaline has been utilised in the treatment of allergic emergencies for many years. No preclinical studies have been performed in connection with this application.

6.1    List of excipients

Sodium chloride,

Sodium metabisulfite (E223),

Hydrochloric acid (for pH adjustment),

Water for injections

6.2    Incompatibilities

Adrenaline and its salts are rapidly destroyed in solution with oxidising agents. The solution darkens in colour upon exposure to air or light.

6.3 Shelf life

The expiration period for the EpiPen Auto-Injector is 18 months from the date of manufacture. The expiry date is indicated on the label, and EpiPen AutoInjector should not be used after this date. Replace the Auto-Injector by expiration date or earlier if the solution is discoloured or contains a precipitate. Check the solution periodically through the viewing window of the unit to make sure the solution is clear and colourless.

Shelf life after opening: The Auto-Injectors must be discarded immediately after use.

6.4 Special precautions for storage

Adrenaline is sensitive to light. Keep the Auto-Injector in the outer carton. Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature and contents of container

The immediate container/closure system consists of a glass cartridge sealed by a rubber plunger at one end and by a rubber diaphragm, which has been inserted into an aluminium hub with an attached stainless steel needle, at the other end. The glass cartridge contains the product.

The auto injector administration device:

Glass cartridge container:

Type I, borosilicate glass - complies with USP and Ph. Eur.

Diaphragm - Stopper:

PH 701/50/Black (butyl rubber plunger) - complies with USP and Ph. Eur. Needle - Hub - Sheath:

Materials compatible with adrenaline injection.

Needle: Siliconised Type 304 stainless steel. The exposed needle length after activation is approximately 16 mm.

Hub: Anodized 3003 aluminium alloy Sheath: Synthetic polyisoprene

The EpiPen® auto injector contains 2 ml of adrenaline injection 1 mg/ml in a prefilled disposable automatic injection device which is designed to deliver a single dose (0.3 ml) of 0.3 mg adrenaline when activated. After activation of the auto injector, 1.7 ml remains in the auto injector.

Pack sizes: 1 auto injector and 2 auto injectors.

6.6 Special precautions for disposal and other handling

Do not remove blue safety cap until ready for use.

Under no circumstances place the orange end of the EpiPen® auto injector on or near your thumbs, fingers or hands. Accidental injection into hand or finger resulting in peripheral ischaemia has been reported. See section 4.4

The EpiPen® auto injector should be used on the outer thigh. The injection is activated immediately once the orange end of the EpiPen® auto injector comes into contact with any skin or other surface.

The EpiPen® auto injector’s are designed for easy use by the lay person and has to be considered as a first aid. The EpiPen® auto injector should simply be jabbed firmly against the outer portion of the thigh from a distance of approximately 10 cm. There is no need for more precise placement in the outer portion of the thigh. When EpiPen® auto injector is jabbed against the thigh, it releases a spring activated plunger, pushing a concealed needle into the thigh muscle and expelling a dose of adrenaline:

1.    Grasp EpiPen® auto injector in dominant hand, with thumb closest to blue safety cap.

2.    With the other hand, pull off blue safety cap.

3.    Hold the EpiPen® auto injector at a distance of approximately 10 cm away from the outer thigh. The orange tip should point towards the outer thigh.

4.    Jab firmly into the outer thigh, so that the EpiPen® auto injector is at a right-angle (at a 90 degree angle) to the outer thigh.

5.    Hold firmly in place for 10 seconds. The injection is now complete and the window of the auto injector is obscured. The EpiPen® auto injector should be removed (the orange needle cover will extend to cover needle) and safely discarded.

6.    Massage the injection area for 10 seconds.

A small bubble may occur in the EpiPen® auto injector. It has no influence on either the use or the efficacy of the product.

See section 4.2 for instructions to be conveyed to the patient/carer regarding actions to be taken following each use of EpiPen® auto injector.