Allerject Product Monograph

SUMMARY PRODUCT INFORMATION

Epinephrine

INDICATIONS AND CLINICAL USE

ALLERJECT 0.3 mg (0.3 mL Epinephrine Injection, USP) and ALLERJECT 0.15 mg (0.15 mL Epinephrine Injection, USP) are indicated for the emergency treatment of anaphylactic reactions in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (see DOSAGE AND ADMINISTRATION section).

ALLERJECT is intended for immediate self-administration for the emergency treatment of severe allergic reactions (Type I), including anaphylaxis associated with:

• foods (e.g., peanuts, tree nuts, shellfish, fish, milk, eggs, and wheat)
• stinging insects (e.g., Order Hymenoptera, including bees, wasps, hornets, yellow jackets, and fire ants) and biting insects (e.g., mosquitoes and black flies)
• medications
• latex
• idiopathic anaphylaxis
• exercise-induced anaphylaxis
• other allergens

Epinephrine is the drug of choice for the emergency treatment of severe allergic reactions. The strong vasoconstrictor action of epinephrine, through its effect on alpha adrenergic receptors, quickly counteracts vasodilation and increased vascular permeability which can lead to loss of intravascular fluid volume and hypotension during anaphylactic reactions.

ALLERJECT is designed as emergency supportive therapy only and not as a replacement or substitute for subsequent medical or hospital care, nor are they intended to supplant insect venom hyposensitization. After injection seek immediate medical attention. All individuals receiving emergency epinephrine must be immediately transported to hospital, ideally by ambulance, for evaluation and observation.

Clinical Signs and Symptoms of Anaphylaxis

Anaphylaxis is a serious, acute, allergic reaction that may cause death. It has a sudden onset and generally lasts less than 24 hours. Because anaphylaxis is a generalized reaction, a wide variety of clinical signs and symptoms may be observed.

One to 2% of the general population are estimated to be at risk for anaphylaxis from food allergies and insect stings, with a lower reported prevalence for drugs and latex. People with asthma are at particular risk.

Symptoms of anaphylaxis may include:

Oral: pruritus of lips, tongue, and palate, edema of lips and tongue; metallic taste in the mouth.

Cutaneous: flushing, pruritus, urticaria, angioedema, morbilliform rash, and pilor erecti.

Gastrointestinal: nausea, abdominal pain, vomiting, and diarrhea.

Respiratory:

Laryngeal: pruritus and “tightness” in the throat, dysphagia, dysphonia, hoarseness, wheezing, and cough.

Nasal: nasal pruritus, congestion, rhinorrhea, sneezing, and sensation of itching in the external auditory canals.

Cardiovascular: feeling of faintness, syncope, chest pain, dysrhythmia, hypotension. Note: Hypotension is a sign of anaphylaxis. Patients should be treated in the early stages of anaphylaxis to prevent hypotension from developing.

Other: periorbital pruritus, erythema and edema, conjunctival erythema, and tearing; lower back pain and uterine contractions in women; aura of “doom”.

The severity of previous anaphylactic reactions does not determine the severity of future reactions, and subsequent reactions could be the same, better, or worse. The severity may depend on the degree of sensitivity, the dose of allergen, and other factors.

Research shows that fatalities from anaphylaxis are often associated with failure to use epinephrine or a delay in the use of epinephrine treatment.

Epinephrine should be administered as early as possible after the onset of symptoms of a severe allergic response. Patients requiring epinephrine will not always have predictable reactions.

Adequate warning signs are not always present before serious reactions occur.

It is recommended that epinephrine be given at the start of any reaction associated with a known or suspected allergen contact. In patients with a history of severe cardiovascular collapse on exposure to an allergen, the physician may advise that epinephrine be administered immediately after exposure to that allergen, and before any reaction has begun.

Epinephrine may prove to be life saving when used as directed immediately following exposure to an allergen.

In most patients, epinephrine is effective after 1 injection. However, symptoms may recur and further injections may be required to control the reaction. Epinephrine can be re-injected every 5 to 15 minutes until there is resolution of the anaphylaxis or signs of adrenaline excess (such as palpitations, tremor, uncomfortable apprehension and anxiety).

All individuals receiving emergency epinephrine must be immediately transported to hospital, ideally by ambulance, for evaluation and observation. Repeat attacks have occurred hours later without additional exposure to the offending allergen. Therefore, it is recommended that a patient suffering from an anaphylactic reaction be observed in an emergency facility for an appropriate period because of the possibility of either a “biphasic” reaction (a second reaction) or a prolonged reaction. At least a four hour period of observation is advised, although this time may vary. The attending physician will take into consideration such factors as the severity of the reaction, the patient’s response and history and the distance from the hospital to the patient’s home.

Anaphylactic reactions typically follow a uniphasic course; however, 20% will be biphasic in nature. The second phase usually occurs after an asymptomatic period of 1 to 8 hours, but may occur up to 38 hours (mean 10 hours) after the initial reaction. About one third of the second phase reactions are more severe, one third are as severe, and one third are less severe. The second-phase reactions can occur even following administration of corticosteroids.

Following treatment of anaphylaxis, the patient must stay within close proximity to a hospital or where he or she can call 911 for the next 48 hours.

Protracted anaphylaxis, which is frequently associated with profound hypotension and sometimes lasts longer than 24 hours, is minimally responsive to aggressive therapy, and has a poor prognosis.

CONTRAINDICATIONS

There are no absolute contraindications to the use of epinephrine in a life-threatening allergic situation.

WARNINGS AND PRECAUTIONS

General

Patients with a history of anaphylaxis are at risk for subsequent episodes and even death. All patients who have had one or more episodes of anaphylaxis should have injectable epinephrine with them or with their parent or caregiver at all times, and should wear some form of medical identification bracelet or necklace.

Epinephrine injection is not intended as a substitute for medical attention or hospital care. In conjunction with the administration of epinephrine, the patient should seek appropriate medical care. More than two sequential doses of epinephrine should only be administered under direct medical supervision (See DOSAGE AND ADMINISTRATION section).

Antihistamines and asthma medications must not be used as first line treatment for an anaphylactic reaction.

Following the resolution of an anaphylactic episode and discharge from hospital, the patient should immediately obtain and fill a new ALLERJECT auto-injector prescription.

Injection-Related Complications

ALLERJECT should ONLY be injected into the anterolateral aspect of the thigh (see DOSAGE AND ADMINISTRATION - Dosing Considerations).

Do not inject intravenously. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration.

Do not inject into the buttock. Injection into the buttock may not provide effective treatment of anaphylaxis; advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. 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.

Do not inject into digits, hands or feet. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. If there is an accidental injection into one of these areas, the patient must go immediately to the nearest emergency room for treatment. Treatment of such inadvertent administration should consist of vasodilation, in addition to further appropriate treatment of anaphylaxis (see ADVERSE REACTIONS section).

Hold leg firmly during injection. To minimize the risk of injection-related injury when administering ALLERJECT to young children, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection.

Serious Infections at the Injection Site

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 epinephrine 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 the presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the potential risk of a rare, but serious Clostridium infection, do not inject ALLERJECT 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 epinephrine injection site.

The presence of a condition listed below is not a contraindication to epinephrine administration in an acute, life-threatening situation. Therefore, patients with these conditions, or any other person who might be in a position to administer epinephrine to a patient with these conditions experiencing anaphylaxis, should be instructed about the circumstances under which epinephrine should be used:

Cardiovascular

Epinephrine use should be avoided in patients with cardiogenic, traumatic, or hemorrhagic shock; cardiac dilation; and/or cerebral arteriosclerosis.

Epinephrine should be used with caution in patients with cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on medications that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

Patients with hypertension or hyperthyroidism are prone to more severe or persistent effects.

Endocrine and Metabolism

Patients with diabetes may develop increased blood glucose levels following epinephrine administration.

Neurologic

Epinephrine use should be avoided in patients with organic brain damage.

Patients with Parkinson’s disease may notice a temporary worsening of symptoms after treatment with epinephrine.

Ophthalmologic

Epinephrine use should be avoided in patients with narrow-angle glaucoma.

Respiratory

There is a significantly increased risk of respiratory symptoms in patients with concomitant asthma, especially if poorly controlled. These patients are at increased risk of death from anaphylaxis.

Fatalities may also occur from pulmonary edema resulting from peripheral constriction and cardiac stimulation.

Sensitivity

This product contains sodium metabisulfite, a substance which may cause allergic-type reactions including anaphylactic symptoms or mild to severe asthmatic episodes in certain susceptible persons.

Nevertheless, epinephrine is the drug of choice for serious allergic reactions and the presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations, even if the patient is sulfite-sensitive.

Reproduction

No studies have been conducted to determine epinephrine’s potential effect on fertility.

Special Populations

Pregnant Women: Although there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Pediatrics (patients 15-30 kg): There are no data to suggest a difference in safety or effectiveness of epinephrine between adults and children in this weight group.

Geriatrics (patients > 65 years of age): Elderly patients with hypertension, coronary artery disease, or cardiac arrythmias are particularly at risk for epinephrine overdose. More careful monitoring and avoidance of epinephrine overdose is recommended for these patients.

See DOSAGE AND ADMINISTRATION section for dosage requirements based on weight.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Adverse reactions of epinephrine include transient, moderate anxiety; feelings of over stimulation; apprehensiveness; restlessness; tremor; weakness; shakiness; dizziness; sweating; tachycardia; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. Ventricular arrhythmias may follow administration of epinephrine. While these symptoms occur in some patients treated with epinephrine, they are likely to be more pronounced in patients with hypertension or hyperthyroidism. These signs and symptoms usually subside rapidly, especially with bed rest.

Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include elderly individuals, pregnant women, and patients with diabetes. Patients with coronary artery disease are prone to more severe or persistent effects, and may experience angina. Cases of takotsubo (stress) cardiomyopathy have been reported in patients treated with epinephrine. Patients with epinephrine-triggered takotsubo cardiomyopathy are predominantly women and are younger than the typical takotsubo cardiomyopathy patient.

These events are characterized by rapid onset of symptoms after epinephrine administration and high complication rates, mostly in the form of cardiogenic shock and acute pulmonary edema. The prognosis is however good with complete recovery in most cases.

Excessive doses cause acute hypertension. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease.

Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs (see DRUG INTERACTIONS section).

Injection of epinephrine into the buttock has resulted in cases of gas gangrene.

Serious Infections at the Injection Site

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 epinephrine injection in the thigh. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site [see WARNINGS AND PRECAUTIONS section].

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

DRUG INTERACTIONS

Overview

There are no known contraindications to the use of epinephrine in a life-threatening allergic reaction.

Drug-Drug Interactions

Epinephrine should be used with caution in patients who are on medications that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias.

Caution is advised in patients receiving cardiac glycosides or diuretics, since these agents may sensitize the myocardium to beta-adrenergic stimulation and make cardiac arrhythmias more likely.

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, sodium levothyroxine, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. Anaphylaxis may be made worse by beta blockers because these drugs decrease the effectiveness of epinephrine.

The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha- adrenergic blocking drugs, such as phentolamine.

Phenothiazines may also reverse the pressor effects of epinephrine.

Deaths have been reported in asthmatic patients treated with epinephrine following the use of isoproterenol, orciprenaline, salbutamol, and long acting beta agonists.

Drug-Lifestyle Interactions

Cocaine sensitizes the heart to catecholamines (as does uncontrolled hyperthyroidism), and epinephrine use in these patients should be cautious.

DOSAGE AND ADMINISTRATION

A health professional should review the patient instructions and operation of ALLERJECT, in detail, with the patient or caregiver (see CONSUMER INFORMATION section).

Epinephrine is essential for the treatment of anaphylaxis. Patients who are at risk of or with a history of severe allergic reactions (anaphylaxis) should be carefully instructed about the circumstances under which epinephrine should be used (See INDICATIONS AND CLINICAL USE Section).

The prescriber should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is indicated. With severe persistent anaphylaxis episode, repeat injections of epinephrine may be necessary.

More than two sequential doses of epinephrine should only be administered under direct medical supervision (see WARNINGS AND PRECAUTIONS section).

Voice-assisted auto-injector

The voice-assisted auto injector is designed to accurately deliver the required dosage of epinephrine for immediate self-administration for the emergency treatment of severe allergic reactions (Type I), including anaphylaxis (See INDICATIONS AND CLINICAL USE section). The injector has been designed to be easy-to-use, portable and ergonomic in order to assist patients with complying with recommendations that epinephrine should be available at all times and administered without delay in an allergic emergency. The device also includes several features to mitigate use-related hazards, such as a retractable needle system, a safety tab mechanism, and an electronic voice and visual prompt system that assist the user through the injection process (See DOSAGE FORMS, COMPOSITION AND PACKAGING section).

Dosing Considerations

Selection of the appropriate dosage strength (ALLERJECT 0.3 mg or ALLERJECT 0.15 mg) is determined according to patient body weight. A physician who prescribes ALLERJECT 0.3 mg or ALLERJECT 0.15 mg auto-injector should take appropriate steps to ensure that the patient thoroughly understands the indications and use of the device. The physician should review with the patient, in detail, the CONSUMER INFORMATION section and operation of the auto- injector.

ALLERJECT 0.3 mg auto-injector contains 0.76 mL of solution but delivers a single dose of

0.3 mL only, with 0.46 mL remaining in the unit, after activation. The remaining volume cannot be used.

ALLERJECT 0.15 mg auto-injector contains 0.76 mL of solution but delivers a single dose of

0.15 mL only, with 0.61 mL remaining in the unit, after activation. The remaining volume cannot be used.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Inject ALLERJECT intramuscularly into the anterolateral aspect of the thigh, through clothing if necessary. Do not inject into the buttock. Instruct caregivers to hold the leg of young children in place and limit movement prior to and during injection (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

Recommended Dose and Dosage Adjustment

ALLERJECT 0.3 mg

• ALLERJECT 0.3 mg delivers 0.3 mg epinephrine injection (0.3 mL) and is intended for patients who weigh 30 kg or more.

ALLERJECT 0.15 mg

• ALLERJECT 0.15 mg delivers 0.15 mg epinephrine injection (0.15 mL) and is intended for patients who weigh 15 to 30 kg.

Each ALLERJECT contains a single dose of epinephrine. Since the doses of epinephrine delivered from ALLERJECT are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary.

Administration

ALLERJECT instructional and safety systems should be thoroughly reviewed with patients and caregivers prior to use (see CONSUMER INFORMATION sections).

Young children maybe uncooperative and kick or move during an injection. Instruct caregivers to hold the leg of young children or infants firmly in place and limit movement prior to and during injection.

The epinephrine solution in the viewing window of ALLERJECT should be inspected visually for particulate matter and discoloration (see DOSAGE AND ADMINISTRATION and STORAGE AND STABILITY sections).

Replace ALLERJECT if the epinephrine solution appears cloudy, discolored, contains particles, if the RED safety guard has previously been removed, or the expiration date has passed.

Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light (see STORAGE AND STORAGE AND STABILITY section).

OVERDOSAGE

Epinephrine is rapidly inactivated in the body, and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects 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.

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage sometimes also results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure.

Suitable corrective measures must be taken in such situations. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug such as propranolol.

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

Premature ventricular contractions may appear within 1 minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm).

Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block.

ACTION AND CLINICAL PHARMACOLOGY

Epinephrine acts on both alpha- and beta-adrenergic receptors. Through its action on alphaadrenergic receptors, epinephrine counters the vasodilation and high vascular permeability that occurs during an anaphylactic reaction that can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis.

Epinephrine also helps to alleviate pruritus, urticaria, and angioedema, and may be effective in relieving gastrointestinal and genitourinary symptoms of anaphylaxis because of its relaxant effects on the smooth muscle of the stomach, intestine, and urinary bladder. Epinephrine contracts the smooth muscle of the uterus.

Epinephrine, when given intramuscularly or subcutaneously, has a rapid onset and short duration of action.

STORAGE AND STABILITY

Always store ALLERJECT auto-injector in the carrier case until use. Store at room temperature between 15°C - 30°C.

Do not refrigerate or freeze.

Protect from light.

Periodically check to make sure the solution in the auto-injector is not brown in color. Replace auto-injector if solution shows haziness, particulate matter, discoloration or leakage.

Replace auto-injector before expiry.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ALLERJECT 0.3 mg or ALLERJECT 0.15 mg auto-injectors are designed to be compact and easy to carry.

Highly sensitive individuals should have epinephrine injectable products readily available at all times.

ALLERJECT 0.3 mg voice-assisted auto-injector

• Each auto-injector contains: 0.76 mL of 1 mg/mL epinephrine injection and is designed to deliver a single dose of epinephrine 0.3 mg in 0.3 mL.
• Approximately 0.46 mL remains in the ALLERJECT 0.3 mg, after activation and cannot be used.
• Nonmedicinal ingredients: Each 0.3 mL contains: sodium metabisulfite, sodium chloride, hydrochloric acid to adjust pH and water for injection. Contains no latex.

ALLERJECT 0.15 mg voice-assisted auto-injector

• Each auto-injector contains: 0.76 mL of 1 mg/mL epinephrine injection and is designed to deliver a single dose of epinephrine 0.15 mg in 0.15 mL.
• Approximately 0.61 mL remains in the ALLERJECT 0.15 mg, after activation and cannot be used.
• Nonmedicinal ingredients: Each 0.15 mL contains: sodium metabisulfite, sodium chloride, hydrochloric acid to adjust pH and water for injection. Contains no latex.

How supplied

ALLERJECT 0.3 mg voice-assisted auto-injector

• Carton containing one ALLERJECT 0.3 mg (Epinephrine Injection, USP, 0.3 mL) with English voice-assisted auto-injector.
• Carton containing one ALLERJECT 0.3 mg (Epinephrine Injection, USP, 0.3 mL) with French voice-assisted auto-injector.

ALLERJECT 0.15 mg voice-assisted auto-injector

• Carton containing one ALLERJECT 0.15 mg (Epinephrine Injection, USP, 0.15 mL) with English voice-assisted auto-injector.
• Carton containing one ALLERJECT 0.15 mg (Epinephrine Injection, USP, 0.15 mL) with French voice-assisted auto-injector.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Epinephrine

Chemical name: 1,2-Benzenediol, 4- [1-hydroxy-2-(methylamino)ethyl]-, (R)-. (-)-3,4- Dihydroxy- α-[(methylamino)methyl]benzyl alcohol

Molecular formula and molecular mass: C₉H₁₃NO₃, 183.20

Structural formula:

Physicochemical properties: Epinephrine is a sympathomimetic catecholamine. Its naturally occurring l-isomer, which is twenty times as active as the d-isomer, is obtained in pure form by separation from the synthetically produced racemate.

TOXICOLOGY REPRODUCTION

Teratogenic Effects

Epinephrine has been shown to have adverse developmental effects in rabbits at a subcutaneous dose of 1.2 mg/kg (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m² basis), in mice at a subcutaneous dose of 1 mg/kg (approximately 7 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m² basis), and in hamsters at a subcutaneous dose of 0.5 mg/kg (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m² basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m² basis).

REFERENCES

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