For the emergency treatment of anaphylaxis (acute severe allergic reactions) due to insect stings, or bites, foods, drugs or other allergens.

Dosage:

Selection of the appropriate dosage strength is determined according to patient body weight and this decision should be based on careful assessment of the individual patient and recognition of the life-threatening nature of reactions for which EpiPen is prescribed.

Adults (≥ 30 kg): Intramuscular injection of EpiPen Auto-Injector containing 0.3 mg adrenaline injection (0.3 mg/0.3 mL)

Children (15 to 30 kg): Intramuscular injection of EpiPen Jr. Auto-Injector containing 0.15 mg adrenaline

injection (0.15 mg/0.3 mL)

The doctor or pharmacist may choose to recommend more or less than this amount*. With severe persistent anaphylaxis, repeat injections with an additional EpiPen Auto-Injector may be necessary.

To manage severe anaphylaxis, repeat EpiPen injections may be necessary. Each EpiPen Auto-Injector is used once only. The EpiPen dose may be repeated every 5 to 15 minutes if symptoms recur or have not subsided (see Section 4.9 OVERDOSE).

Use of Adrenaline:

1. Before using, check to make sure the solution in the Auto-Injector is not brown in color. If it is

discolored or contains a precipitate, do not use, since these changes indicate that the effectiveness of the

drug product may be decreased.

2. The delivered dose of the EpiPen Auto-Injector should be injected intramuscularly into the anterolateral aspect of the thigh, through clothing if necessary. The EpiPen Auto-Injector should be pushed firmly into the outer mid-thigh until a “click” is heard or felt and it should then be held firmly against the thigh for approximately 3 seconds to ensure the dose is delivered. Instruct caregivers of young children who are prescribed an EpiPen and who may be uncooperative and kick or move during an injection to hold the leg firmly in place and limit movement prior to and during an injection.

3. DO NOT INJECT INTRAVENOUSLY. Every effort should be made to avoid inadvertent intravascular administration (see Section 4.9 OVERDOSE).

4. Appropriate steps should be taken to ensure that the patient thoroughly understands the

indications and use of this device. The EpiPen Auto-Injector should not be used for

demonstration purposes. An EpiPen Training Device is available to assist with patient education

and practice. The healthcare professional, educator or caregiver should regularly review in detail

with the patient, the package leaflet provided inside the EpiPen Auto-Injector carton, which

includes usage instructions for the EpiPen Auto-Injector.

5. Patients should be instructed to dispose of the device safely after use by placing the used Auto-Injector

in a sharp’s disposal unit.

The EpiPen Auto-Injector is intended for immediate self-administration. It is designed as emergency supportive therapy only and is not a replacement or substitute for subsequent medical or hospitalcare.

A severe anaphylactic reaction is a life-threatening emergency and administration of EpiPen is not intended as a substitute for immediate medical care. In conjunction with the administration of adrenaline, the patient should seek immediate medical or hospital care. More than two sequential doses of adrenaline should only be administered under direct medical supervision.

The presence of anaphylactic shock should be confirmed before administering EpiPen, as EpiPen is only

indicated for the treatment of anaphylaxis. Anaphylaxis 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, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnoea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema.

For these reasons, auto-injectors should always be carried by such persons in situations of potential risk.

EpiPen Adrenaline Auto-Injector contains sodium metabisulfite, a sulfite, which may itself cause allergic-type reactions 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 for serious allergic reactions even if the patient is sulfite sensitive.

DO NOT INJECT INTRAVENOUSLY as cerebral haemorrhage may occur due to a sharp rise in blood

pressure. Rapidly acting vasodilators can counteract the marked pressor effects of adrenaline if there is such inadvertent administration.

Use with caution in patients with ventricular fibrillation, cerebral arteriosclerosis, prefibrillatory rhythm,

tachycardia, myocardial infarction, phenothiazine-induced circulatory collapse and prostatic hypertrophy.

Adrenaline should not be used in the presence of cardiac dilation.

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

Caution should be taken when administering in the presence of cardiac dilation.

Adrenaline should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease or hypertension.

Adrenaline can cause potentially fatal ventricular arrhythmias including fibrillation, especially in patients with organic heart disease or those receiving other drugs that sensitive the heart to arrhythmias (see Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).

Anginal pain may be induced by adrenaline in patients with coronary insufficiency.

Use with caution in patients with pre-existing conditions whereby the use of vasopressor drugs is

contraindicated (e.g. thyrotoxicosis).

Administer with caution to the elderly, and to individuals with diabetes, cardiovascular disease, hypertension, organic brain damage, narrow angle glaucoma, hyperthyroidism and psychoneurosis. In patients with Parkinsonism the drug increases rigidity and tremor.

Syncope has occurred following administration to asthmatic children.

EpiPen should not be injected into the hands, feet, ears, nose, buttocks or the genitalia as it may result in loss of blood flow to the affected area and may not provide effective treatment of anaphylaxis. Treatment should be directed at vasodilatation in addition to further treatment of anaphylaxis. If an accidental injection into one of these areas occurs, specialist medical advice must be sought immediately. Ensure the product is kept well clear of the face.

Additionally, injection into the buttock has been associated with Clostridial infections (gas gangrene).

Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk.

Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following adrenaline injection for anaphylaxis. Clostridium spores can be present on the skin and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject EpiPen into the buttock. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the adrenaline injection site.

Hold leg firmly during injection. Lacerations, bent needles, and embedded needles have been reported when EpiPen has been injected into the thigh of young children who are uncooperative and kick or move during an injection. To minimize the risk of injection related injury when administering EpiPen to young children, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection. Despite these concerns, adrenaline is essential 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 adrenaline should be used.

Use in the Elderly

No data available.

Pediatric Use

No data available.

Effects on Laboratory Tests

No data available.

Central nervous system and other medicines

The effects of adrenaline may be potentiated by tricyclic antidepressants, levothyroxine sodium, thyroid

hormones, monoamine oxidase inhibitors and some antihistamines (e.g. diphenhydramine,

dexchlorpheniramine, chlorpheniramine and tripelennamine).

Other sympathomimetic agents

Adrenaline should not be administered with other sympathomimetic agents because of the danger of additive effects and increased toxicity.

Alpha-adrenergic blocking agents

Alpha-adrenergic blocking agents such as ergot alkaloids and phentolamine can reverse the pressor response to adrenaline.

Beta-adrenergic blocking agents

Patients taking non-selective beta-blocking drugs when administered adrenaline for the treatment of an

anaphylactic reaction may experience severe hypertension and bradycardia. Propranolol inhibits the

bronchodilator effect of adrenaline. The risk of cardiac arrhythmias is higher when adrenaline is given to

patients receiving digoxin or quinidine.

General anesthetics

Halothane and other anesthetics such as cyclopropane and trichlorethylene increase the risk of adrenaline-induced ventricular arrhythmias and acute pulmonary oedema if hypoxia is present.

Hypoglycemics agents

Adrenaline-induced hyperglycemia may lead to loss of blood sugar control in diabetic patients treated with hypoglycemic agents.

Effects on Fertility

Studies of adrenaline after repeated exposure in animals to evaluate the effect on fertility have not been

conducted. This should not prevent the use of adrenaline under the conditions noted under Section 4.1

THERAPEUTIC INDICATIONS.

Use in Pregnancy

Pregnancy Category: A

Adrenaline has been given to a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.

Adrenaline may delay the second stage of labour by inhibiting contractions of the uterus.

Use with caution in pregnant women whose maternal blood pressure is in excess of 130/80.

Use in Lactation

Adrenaline is excreted in breast milk.

The patients’ ability to drive and use machinery may be affected by the anaphylactic reaction, as well as by possible adverse effects to adrenaline.

Common symptomatic adverse events include anxiety, apprehensiveness, restlessness, tachycardia, respiratory difficulty, tremor, weakness, dizziness, headache, dyspnoea, cold extremities, sweating, pallor, nausea, vomiting, sleeplessness, hallucinations, palpitations, respiratory difficulties, fear and flushing or redness of face and skin. Psychomotor agitation, disorientation, impaired memory and psychosis may occur.

Potentially fatal ventricular arrhythmias, including ventricular fibrillation may occur and severe hypertension may lead to cerebral haemorrhage and pulmonary oedema.

Angina may occur in patients with coronary arterydisease.

Rare cases of stress cardiomyopathy have been reported in patients treated with adrenaline.

The potential for adrenaline to produce these types of adverse effects does not contraindicate its use in an acute life-threatening allergic reaction.

Accidental injection into the hands, fingers or feet may result in loss of blood flow to the affected area (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Adverse events experienced as a result may include increased heart rate, local reactions including injection site pallor, coldness or hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discolouration, erythema or skeletal injury.

Lacerations, bent needles, and embedded needles have been reported when EpiPen has been injected into the thigh of young children who are uncooperative and kick or move during the injection (see Section 4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Injection into the buttock has resulted in cases of gas gangrene (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

Reporting Suspected Adverse Effects

Reporting suspected adverse reactions after registration 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 at

To report side effect(s):

The National Pharmacovigilance and Drug Safety Centre (NPC)

Fax: +966-11-205-7662,

Call NPC at +966-11-2038222, Ext 2317-2356-2340

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

Effects

Overdosage or inadvertent intravascular 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.

Cardiac arrhythmias may lead to ventricular fibrillation and death.

Repeated administration of adrenaline can result in severe metabolic acidosis because of elevated blood

concentration of lactic acid.

Treatment

Adrenaline is rapidly inactivated in the body and treatment of acute toxicity is mainly supportive. If necessary, the combined alpha and beta mediated effects of adrenaline may be counteracted by labetalol. Individually, alpha mediated effects may be counteracted by phentolamine whilst beta mediated effects may be counteracted by beta blocking agents.

Mechanism of Action

Adrenaline is a sympathomimetic drug, acting on both alpha and beta receptors. Through its action on alpha adrenergic receptors, adrenaline lessens the vasodilatation and increased vascular permeability that occurs during anaphylaxis, which can lead to a loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, adrenaline causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing and dyspnoea that may occur during anaphylaxis. Other major effects are increased systolic blood pressure, reduced diastolic pressure, tachycardia, hyperglycemia and hypokalemia. It is a powerful cardiac stimulant. It has vasopressor properties, an antihistaminic action and is a bronchodilator.

Adrenaline also alleviates pruritus, urticaria, and angioedema and may be effective in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxant effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

Clinical Trials

No data available.

Absorption

The onset of action is rapid and of short duration. After intravenous infusion the half-life is approximately 5 to 10 minutes.

Distribution

Adrenaline is rapidly distributed to the heart, spleen, several glandular tissues and adrenergic nerves. It is

approximately 50% bound to plasma proteins.

Metabolism

Adrenaline is rapidly metabolized in the liver and tissues.

Excretion

Up to 90% of the intravenous dose is excreted as metabolites in the urine. It crosses the placenta and is

excreted in breast milk.

Genotoxicity

Adrenaline and other catecholamines have been shown to have mutagenic potential in vitro and to be an

oxidative mutagen in a WP2 bacterial reverse mutation assay. Adrenaline had a moderate degree of

mutagenicity and was positive in the DNA Repair test with B. Subtilis (REC) assay but was not mutagenic in the Salmonella bacterial reverse mutation assay.

Studies of adrenaline after repeated exposure in animals to evaluate the mutagenic potential have not been

conducted. This should not prevent the use of adrenaline under the conditions noted under Section 4.1 THERAPEUTIC INDICATIONS.

Carcinogenicity

Studies of adrenaline after repeated exposure in animals to evaluate the carcinogenic potential have not been conducted. This should not prevent the use of adrenaline under the conditions noted under Section 4.1 THERAPEUTIC INDICATIONS.

Refer to Section 2 – Qualitative and quantitative composition.

Adrenaline is physically incompatible with alkalis, metals, oxidizing agents, sodium warfarin, hyaluronidase and many other drugs; it forms polymers with sodium bicarbonate.

Adrenaline is light sensitive and should be stored in the carrier tube provided.

STORE BELOW 25ºC. TEMPERATURE EXCURSIONS BETWEEN 15ºC TO 25ºC PERMITTED.

DO NOT REFRIGERATE. PROTECT FROM LIGHT.

Before using, check to make sure the solution in the auto-injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate.

The EpiPen Auto-Injector contains 2 mL Adrenaline Injection USP 0.3 mg/0.3 mL and delivers a single 300 μg adrenaline dose.

EpiPen Auto-Injector is available in a single pack or in a pack of 2.

Not all pack sizes may be marketed.

For single use only. The Auto-Injectors must be discarded immediately after use.

During instruction of the patient in correct use of the EpiPen the prescribing doctor may use a “EpiPen®

TRAINER” (contains no solution for injection and no needle).

The EpiPen Auto-Injector contains 2 ml of adrenaline injection 1 mg/ml which is designed to deliver a single dose (0.3 ml) of 300 micrograms adrenaline when activated. After activation of the Auto-Injector 1.7 ml remains in the Auto-Injector.

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 ischemia 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-Injectors are designed for easy use by the lay person and has to be considered as a first aid. The 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 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 safetycap.

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

3. Hold the EpiPen Auto-Injector in 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 to (at a 90-degree

angle) 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.