1 Name of Medicine
Adrenaline (epinephrine).
2 Qualitative and Quantitative Composition
Anapen Junior 150 micrograms: Each 0.3 mL contains 150 micrograms of adrenaline (epinephrine).
Anapen 300 micrograms: Each 0.3 mL contains 300 micrograms of adrenaline (epinephrine).
Anapen 500 micrograms: Each 0.3 mL contains 500 micrograms of adrenaline (epinephrine).
Excipients with known effect.
Sulfites.
For full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Solution for injection in a pre-filled syringe (auto-injector). Clear, colourless solution practically free from visible particles.
4.1 Therapeutic Indications
For the emergency treatment of anaphylaxis (acute severe allergic reactions) due to insect stings, drugs or other allergens.
4.2 Dose and Method of Administration
Product is for single use in one patient only. Discard any residue.
The patient should always carry 2 units of auto injectors in case the first administration fails or if one dose is not sufficient.
The effective dose is typically in the range 5-10 micrograms per kilogram of bodyweight but higher doses may be necessary in some cases.
Use in adults.
The usual dose is 300 micrograms. The recommended dose is 300 micrograms for individuals under 60 kg bodyweight. The recommended dose is 300 to 500 micrograms for individuals over 60 kg bodyweight, depending on clinical judgement.
Larger adults may require more than one injection to reverse the effect of an allergic reaction.
In the absence of clinical improvement or if deterioration occurs, a second injection with an additional Anapen may be administered 5-15 minutes after the first injection. It is recommended that patients are prescribed two Anapen which they should carry at all times.
In case of a second injection needed it is recommended to inject in the opposite thigh.
Patients must be shown how to use the Anapen device at the time a prescription is written.
Use in children.
Anapen 500 micrograms is not recommended for use in children. The appropriate dose may be 150 micrograms (Anapen Junior) or 300 micrograms (Anapen) of adrenaline (epinephrine), depending on the body weight of the child and the discretion of the doctor.
Children and adolescents over 30 kg in weight should be prescribed Anapen 300 micrograms. Larger children may require more than one injection to reverse the effect of an allergic reaction. In the absence of clinical improvement or if deterioration occurs, a second injection with an additional Anapen Junior may be administered 5-15 minutes after the first injection. It is recommended that patients are prescribed two Anapen Junior which they should carry at all times.
The auto-injector of Anapen Junior is designed to deliver a single dose of 150 micrograms adrenaline (epinephrine), a dosage below 150 micrograms cannot be administered in sufficient accuracy in children weighing less than 15 kg and use is therefore not recommended unless in a life-threatening situation and under medical advice.
In the absence of clinical improvement or if deterioration occurs, a second injection with an additional Anapen may be administered 5-15 minutes after the first injection. It is recommended that patients are prescribed two Anapen which they should carry at all times.
In case of a second injection needed it is recommended to inject in the opposite thigh.
Method of administration.
For intramuscular route only.
Anapen consists of a pre-filled syringe of adrenaline (epinephrine) contained in an auto-injection device. The whole is referred to as an auto-injector.
One Anapen injection should be administered intramuscularly immediately on the appearance of the signs and symptoms of anaphylactic shock. These may occur within minutes of exposure to the allergen and are most commonly manifested by urticaria, flushing or angioedema; more severe reactions involve the circulatory and respiratory systems. Inject Anapen only into the anterolateral aspect of the thigh, not the buttock. The auto-injector is designed to inject through clothing or directly through the skin.
Anapen auto-injector is intended for immediate self-administration by a person with a history of anaphylaxis and is designed to deliver a single dose of 150/300/500 micrograms adrenaline (epinephrine). For stability reasons 0.75 mL is left in the syringe after use but the unit cannot be used again and should be safely discarded.
The patient/carer should be informed that following each use of Anapen:
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 Special Warnings and Precautions for Use).
Conscious patients should preferably lie flat with legs 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.
Mechanism of action.
A. Parts of the Anapen Auto-Injector. Before using the Anapen Auto-Injector, the patient needs to know about the parts of the autoinjector. These are shown in Figure 1.
Rotating cover over solution window.
The patient rotates the cover over the solution window to line up the lenses with the solution window on the auto-injector body.
Solution window.
The patient looks through the lens into this window before the injection to check that the solution is clear and ready to use.
Injection indicator.
Before the injection, the patient can see a white plastic plunger through the window. This means that the Anapen Auto-Injector has not been fired by mistake or tampered with. After the injection, the injection indicator turns red. This indicates that the Anapen Auto-Injector has been fired correctly.
Black needle shield (reversible).
This protects the needle when the patient is not using the Anapen Auto-Injector. The patient pulls the needle shield off before the injection. After the injection, the patient turns the black needle shield around and puts it back onto the same end of Anapen Auto-Injector, to cover the needle.
Grey safety cap.
This covers the red firing button. It stops the button from being pushed by mistake.
The patient must not remove the black needle shield or the grey safety cap until they need to use the Anapen Auto-Injector.
B. Checking the Anapen Auto-Injector. Before using the Anapen Auto-Injector, the patient must check it as follows:
1. Rotate the cover over the solution window fully anti-clockwise as shown by the arrow to line up the lenses with the solution window on the auto-injector body.
2. Look through the lens into the solution window. Check that the solution is clear and colourless.
If it is cloudy, coloured or contains particles, discard the Anapen Auto-Injector.
3. Make sure that the injection indicator is not red. If it is red, this means that the Anapen Auto-Injector has already been fired and you must discard it.
4. Rotate the cover over the solution window fully back clockwise as shown by the arrow, to ensure that the solution window is covered. Put the Anapen Auto-Injector back in the carton until you need to use it.
C. Using the Anapen Auto-Injector. If the black needle shield has been removed, the patient must not put their thumb, fingers or hand over the open end (needle end) of the Anapen Auto-Injector.
To use the Anapen Auto-Injector, the patient must follow the steps below:
1. Remove the black needle shield by pulling hard in the direction of the arrow.
This also removes a grey protective needle shield.
2. Remove the grey safety cap from the red firing button by pulling as indicated by the arrow.
3. Hold the open end (needle end) of Anapen against the outer part of the thigh. If necessary, Anapen can be used through light clothing, such as denim, cotton or polyester.
4. Press the red firing button so that it clicks. Keep holding the Anapen Auto-Injector against the outer thigh for 3 seconds. Slowly remove Anapen from the thigh.
5. The injection indicator will have turned red. This shows that the injection is complete. If the injection indicator is not red, injection must be repeated with a new Anapen.
6. After the injection, the needle sticks out. To cover it, click the wide end of the black needle shield back on the open end (needle end) of Anapen Auto-Injector (as indicated by the arrow).
Immediately after using Anapen the patient should call the emergency services, ask for an ambulance and say "anaphylaxis". The patient should explain to the paramedic that he/she has received an injection of adrenaline into his/her thigh muscle and show them the box and these instructions.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements (see Section 6.6 Special Precautions for Disposal).4.3 Contraindications
Hypersensitivity to adrenaline (epinephrine) or to any of the excipients listed in Section 6.1 List of Excipients (see Section 4.4 Special Warnings and Precautions for Use for further information on sodium metabisulfite). There are no absolute contraindications for use in allergic emergency situations.
4.4 Special Warnings and Precautions for Use
All patients who are prescribed Anapen should be thoroughly instructed to understand the indications for the use and the correct method of administration (see Section 4.2 Dose and Method of Administration). It is strongly advised also to educate the patient's immediate associates (e.g. family members, caregivers, teachers, co-workers) for the correct usage of Anapen in case support is needed in the emergency situation.
Anapen is indicated as emergency supportive therapy only and patients should be advised to seek immediate medical attention following administration, in order to have close monitoring of the anaphylactic episode and further treatment as required.
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 a severe anaphylactic reaction.
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.
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 dilatation.
In patients with parkinsonism the drug increases rigidity and tremor.
Use with caution in patients with heart disease e.g coronary heart and cardiac muscle diseases (angina may be induced), cor pulmonale, cardiac arrhythmias or tachycardia. There is a risk of adverse reactions following adrenaline (epinephrine) administration in patients with hyperthyroidism, cardiovascular disease (severe angina pectoris, obstructive cardiomyopathy and ventricular arrhythmia and hypertension), phaeochromocytoma, high intraocular pressure, severe renal impairment, prostatic adenoma leading to residual urine, hypercalcemia, hypokalaemia, diabetes, or in elderly or pregnant patients.
Repeated local injection can result in necrosis at sites of injection from vascular constriction.
Accidental intravascular injection may result in cerebral haemorrhage due to a sudden rise in blood pressure.
Accidental injection into hands or feet may cause loss of blood flow to adjacent areas due to vasoconstriction.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium free.
Patients should be warned regarding related allergens and should be investigated whenever possible so that their specific allergens can be characterised.
Anapen contains sodium metabisulfite which can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma. Patients with these conditions must be carefully instructed in regard to the circumstances under which Anapen should be used.
Use in the elderly.
Use in elderly: use with caution in elderly patients (see Section 4.4 Special Warnings and Precautions for Use).
Paediatric use.
Use in children: Anapen 500 micrograms is not recommended for use in children (see Section 4.2 Dose and Method of Administration).
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Central nervous system and other medicines.
The effects of adrenaline (epinephrine) may be potentiated by tricyclic antidepressants mixed noradrenargic-serotoninergic antidepressants like venlafaxine, sibutramine or milnacipran and monoamine oxidase inhibitors (sudden blood pressure increase and possible cardiac arrhythmia), COMT blocking agent, thyroid hormones, theophylline, oxytocin, parasympatholytics, certain antihistamines (diphenhydramine, chlorpheniramine), levodopa and alcohol.
Beta-adrenergic blocking agents.
Severe hypertension and bradycardia may occur when adrenaline (epinephrine) is administered with non-selective beta-blocking medicinal products. Anti-anaphylactic effects can be antagonised by beta-blocking agents, especially non-selective beta blockers.
Other sympathomimetic agents.
Concurrent therapy with sympathomimetics may potentiate the effects of adrenaline (epinephrine).
General anaesthetics.
Use Anapen with caution in patients receiving medicinal products which may sensitise the heart to arrhythmias, e.g. digitalis, quinidine, halogenated anaesthetics.
Alpha-adrenergic blocking agents.
The pressor effects of adrenaline (epinephrine) may be counteracted by administration of rapidly acting vasodilators or alpha-adrenergic blocking medicinal products.
Hypoglycaemic agents.
Adrenaline (epinephrine) inhibits insulin secretion and diabetic patients may require upward adjustment of their insulin or other hypoglycaemic therapy.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Studies of adrenaline (epinephrine) after repeated exposure in animals to evaluate the effect of fertility have not been conducted. This should not prevent the use of adrenaline (epinephrine) under the conditions noted under the Therapeutic Indications (see Section 4.1).
(Category A)
Adrenaline has been given to a large number of pregnant woman 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.
Adrenaline is excreted in breast milk.4.7 Effects on Ability to Drive and Use Machines
It is not recommended that patients should drive or use machines following administration of adrenaline (epinephrine), since patients will be affected by symptoms of the anaphylactic shock.
4.8 Adverse Effects (Undesirable Effects)
The occurrence of undesirable effects depends on the sensitivity of the individual patient and the dose applied.
The following table (see Table 1) is based upon experience with the use of adrenaline.
The adverse events are classified as MedDRA preferred term by system organ class and frequency; frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Anapen contains sodium metabisulfite which may cause allergic-type reactions including anaphylactic reactions, life-threatening or less severe asthmatic episodes in certain susceptible patients.
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 www.tga.gov.au/reporting-problems.4.9 Overdose
Overdose or accidental intravascular injection of adrenaline (epinephrine) may cause cerebral haemorrhage from a sudden rise of blood pressure. Death may result from acute pulmonary oedema arising from peripheral vascular constriction and cardiac stimulation.
The pressor effects of adrenaline (epinephrine) may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking medicinal products. Should prolonged hypotension follow such measures, it may be necessary to administer another pressor medicinal product, such as noradrenaline.
Acute pulmonary oedema with respiratory embarrassment following adrenaline (epinephrine) overdose should be managed by administration of a rapidly acting alpha adrenergic blocking medicinal product such as phentolamine and/or with intermittent positive pressure respiration.
Adrenaline (epinephrine) overdose may also result in transient bradycardia followed by tachycardia; these can be followed by potentially fatal cardiac arrhythmias which may be treated by beta adrenergic blocking medicinal products. These must be preceded or accompanied by an alpha-adrenergic blocker to control the alpha-mediated effects on the peripheral circulation.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: cardiac stimulants excl. cardiac glycosides, adrenergic and dopaminergic agents, adrenaline (epinephrine).
Mechanism of action.
Adrenaline (epinephrine) 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, hyperglycaemia and hypokalaemia. 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.
5.2 Pharmacokinetic Properties
Adrenaline (epinephrine) is rapidly inactivated in the body, mostly in the liver by the enzymes COMT and MAO. Much of a dose of adrenaline (epinephrine) is excreted as metabolites in urine. The plasma half-life is about 2-3 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.
Study P14-04.
This randomized, open-label, cross-over study compared the impact of adrenaline administration at two sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, it was also studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline was evaluated by UPLC-mass spectrometry, and heart rates (HR) were measured using a Holter monitor.
Adrenaline levels showed a double peak, with parallel changes in HR. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 min post-injection, with Cmax and AUC significantly higher with Anapen than with pre-filled syringes; the magnitude of the second peak did not differ among the various conditions. In overweight women treated with Anapen administered at inferior anterior third of the thigh, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous and the overall bioavailability was enhanced.
The results (mean values) of the main pharmacokinetic parameters are presented in Table 2.
The adrenaline pharmacokinetics and cardiovascular responses in both sets of data were well correlated both in the time-course and relative amplitude. In particular, the changes in adrenaline plasma levels and heart rate (HR) clearly showed two successive peaks (see Figure 2). The first peak occurred a few minutes after the injection (Cmax1 and Emax at approximately 10 min post-administration), lasted less than 20 min, and was followed by a larger peak, generally of similar height, which lasted up to 2 h.
5.3 Preclinical Safety Data
Adrenaline (epinephrine) has been widely used in the clinical management of allergic emergencies for many years. There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the PI.
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 carcinogenic potential have not been conducted. This should not prevent the use of adrenaline under the conditions noted, see Section 4.1 Therapeutic Indications.
Carcinogenicity.
Carcinogenicity studies have not been conducted with Anapen.6 Pharmaceutical Particulars
6.1 List of Excipients
Sodium chloride, sodium metabisulfite, hydrochloric acid (for adjustment of pH), water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
Anapen Junior 150 micrograms.
21 months.
Anapen 300 micrograms, Anapen 500 micrograms.
2 years.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
Keep the auto-injector in the outer carton in order to protect from light. Do not refrigerate or freeze.
Anapen should be stored lying down.
See Section 4.2 Dose and Method of Administration for instructions to be conveyed to the patient/ carer regarding actions to be taken following each use of Anapen.
It is very important that the patient receives detailed information on how to use Anapen.
For single use only.
The expiry date is indicated on the label and Anapen should not be used after this date.
Discard and replace the auto-injector after expiry date.
The solution should be examined regularly through the inspection window. Discard and replace Anapen if the solution is cloudy, coloured or contains particles.
The integral medicinal product, as shown (see Section 4.2 Dose and Method of Administration), should be regularly checked to ensure that it is ready to use in an emergency situation.
6.5 Nature and Contents of Container
Anapen consists of a pre-filled syringe contained in a single use auto-injection device.
The syringe contains adrenaline (epinephrine) solution. The auto-injection device delivers this solution.
The immediate container is a glass syringe sealed by a rubber plunger at one end, and at the other end by a rubber needle shield.
Syringe.
BD (Becton Dickinson) borosilicate glass type 1, 27G 1/2".
Exposed needle length: 10 mm ± 1.5 mm.
Plunger.
BD (Becton Dickinson) black chlorobutyl rubber PH 701/50.
In pack sizes of 1 or 2 with a thermoformed tray protection inside a cardboard box. Not all pack sizes may be marketed.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Clear colourless solution practically free from particles.
Anapen Junior 150 micrograms.
Each 0.3 mL dose contains 150 micrograms of adrenaline (epinephrine).
Anapen 300 micrograms.
Each 0.3 mL dose contains 300 micrograms of adrenaline (epinephrine).
Anapen 500 micrograms.
Each 0.3 mL dose contains 500 micrograms of adrenaline (epinephrine).
Chemical structure.
CAS number.
51-43-4.7 Medicine Schedule (Poisons Standard)
S3 (Pharmacist Only Medicine).
Summary Table of Changes
