Allergenic Extract Non Pollens Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 3. Serious Warnings and Precautions Box ............................................................................ 4
4. 4.

   Dosage and Administration ............................................................................................. 5

   4.1. Dosing Considerations .............................................................................................. 5

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 5

   4.3. Dilution ..................................................................................................................... 7

   4.4. Administration .......................................................................................................... 7

5. 5. Overdose ......................................................................................................................... 7
6. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 7
7. 7.

   Warnings and Precautions ............................................................................................. 11

   General ............................................................................................................................... 11

   Carcinogenesis and Genotoxicity ........................................................................................ 12

   Monitoring and Laboratory Tests ....................................................................................... 12

   7.1. Special Populations ................................................................................................ 13

   7.1.1. Pregnancy ...................................................................................................... 13

   7.1.2. Breastfeeding ................................................................................................ 13

   7.1.3. Pediatrics ....................................................................................................... 13

8. 8.

   Adverse Reactions ......................................................................................................... 13

   8.1. Adverse Reaction Overview .................................................................................... 13

9. 9.

   Drug Interactions ........................................................................................................... 14

   9.2. Drug Interactions Overview .................................................................................... 14

   9.3. Drug-Behaviour Interactions .................................................................................. 14

   9.4. Drug-Drug Interactions ........................................................................................... 14

   9.5. Drug-Food Interactions........................................................................................... 14

   9.6. Drug-Herb Interactions ........................................................................................... 15

   9.7. Drug-Laboratory Test Interactions ......................................................................... 15

10. 10.

    Clinical Pharmacology ................................................................................................... 15

    10.1. Mechanism of Action .............................................................................................. 15

    10.2. Pharmacodynamics .................................................... Error! Bookmark not defined.

11. 11. Storage, Stability, and Disposal ...................................................................................... 15

Part 2: Scientific Information ................................................................................................ 16

1. 13. Pharmaceutical Information .......................................................................................... 16

Patient Medication Information ........................................................................................... 17

Part 1: Healthcare Professional Information

1. Indications

ALLERGENIC EXTRACTS (Non-standardized Allergenic Extracts) is indicated as an allergy immunotherapy for treatment of patients experiencing allergic reactions to related seasonal pollens, molds, animal danders or various other inhalants in situations where the offending allergen cannot be avoided.

Prior to initiation of therapy, the clinical sensitivity should be established by careful evaluation of the patient’s history confirmed by diagnostic skin testing.

1.1. Pediatrics

Children can receive the same dose as adults, however, to minimize the discomfort associated with dose volume it may be advisable to reduce the volume of the dose by one-half and administer the injection at two different sites.

1.2. Geriatrics

Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2. Contraindications

• A patient should not be treated with an allergen extract to which the patient has not demonstrated symptoms, IgE antibodies, positive skin tests, or properly controlled challenge testing. In most cases, allergy immunotherapy is not indicated for those allergens that can be eliminated or minimized by environmental control.
• Patients previously have had a severe systemic allergic reaction to the related allergenic extract immunotherapy.
• Patients on beta-blockers are not candidates for allergy immunotherapy, as they can be non-responsive to beta-agonists that may be required to reverse a systemic reaction (also, see 3 Serious Warnings and Precautions Box and 8 Adverse Reactions).
• Also, there is some evidence, although inconclusive, that routine immunizations may exacerbate autoimmune diseases. Hyposensitization should be given cautiously to patients with this predisposition. Patients with severe cardiorespiratory symptoms are at an additional risk during a systemic reaction. The physician must weigh risk to benefit in these cases.
• .Patients with unstable, severe, uncontrolled chronic or seasonal asthma (FEV1 <70% of predicted value after adequate pharmacologic treatment) or steroid dependent asthmatics.
• Patients with severe cardiovascular disease. See also 7 Warnings and Precautions and 8 Adverse Reactions.

3. Serious Warnings and Precautions Box

• This product is intended for use by physicians who are experienced in the administration of allergenic extracts and the emergency care of anaphylaxis or for use under the guidance of an allergy specialist.

• As with all allergenic extracts, severe systemic reactions may occur. In certain individuals, these

  • life-threatening reactions may result in death. Patients should be observed for 20 to 30 minutes following each treatment. Emergency measures and adequately trained personnel should be immediately available in the event of a life-threatening reaction.
• Patients with unstable asthma or steroid dependent asthmatics and patients with underlying cardiovascular disease are at greater risk to a fatal outcome from a systemic allergic reaction.
• Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death.
• Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators. Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require theophylline, oxygen, intubation and the use of life support systems. Parenteral fluid and/or plasma expanders may be utilized for the treatment of shock. Adrenocorticosteroids may be administered parenterally or intravenously. Refer to 7 Warnings and Precautions, and 8 Adverse Reactions.
• This product should not be injected intravenously.

4. Dosage and Administration

4.1. Dosing Considerations

• If the protective action of allergenic extract injections is considered essential for the patient’s welfare, appropriate symptomatic therapy with antihistaminic, adrenergic or other drugs might be needed either prior to or in conjunction with the allergenic extract injections.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

4.2. Recommended Dose and Dosage Adjustment

• Starting dose for immunotherapy is related directly to a patient’s sensitivity as determined by carefully executed skin testing. Degree of sensitivity can be established by determination of D₅₀. A general rule is to begin at 1/10 of the dose that produces sum of erythema of 50 mm (approximately a 2+ positive skin test reaction).
• For example, if a patient exhibits a 2+ intradermal reaction to 1 AU/mL, the first dose should be no higher than 0.05 mL of 0.1 AU/mL. Dosage may be increased by 0.05 mL each time until 0.5 mL is reached, at which time the next 10-fold more concentrated dilution can be used, beginning with 0.05 mL, if no untoward reaction is observed.
• Interval between doses in the early stages of immunotherapy is no more than once to twice a week, and may gradually be increased to once every two weeks. Generally, maintenance injections may be given as infrequently as once every two weeks to once a month.

Pre-Seasonal Method of Treatment

• Treatment of hay fever by the pre-seasonal method should be started 6-10 weeks prior to the usual onset of symptoms. Therapy should be started early enough to permit a graduated series of doses at 2-7 day intervals. It is recommended that the larger doses be spaced 5-7 days apart.

• Some physicians continue therapy into or through the season by repeating a reduced or MAINTENANCE dose at weekly or biweekly intervals. If during the season, hay fever symptoms develop, relief may be provided by giving supplemental treatment. If the last dose was well-

  • tolerated and not more than 2 weeks has elapsed since it was given, this dose may be given again and repeated every 4 to 7 days.

Perennial Treatment

• The patient’s tolerance to the offending pollen or pollens is first established by the injection of a series of graduated doses as outlined in the PRE-SEASONAL METHOD, not necessarily given pre-seasonally, since perennial therapy may be begun at any time. After completion of the ascending series of injections, from 1/4 to 1/2 of the highest well-tolerated dose is continued at 2 to 3 week intervals throughout the year. Shortly before the usual onset of symptoms (4 to 5 weeks prior to the season) the interval between injections is shortened and the dosage is gradually increased, according to the Pre-Seasonal schedule, until maximum well-tolerated dose is again attained. This top dose should be reached just before the usual onset of symptoms at which time the treatment is discontinued. If patient’s symptoms persist, therapy may be continued at a reduced dosage level, usually 1/4 to 1/2 of the top dose.

Dosage Adjustments

For Products Containing Short Ragweed.

• In transferring patients from non-standardized to standardized product, the physician should establish the potency relationships, perhaps by comparative skin testing, prior to injecting the first standardized dose.
• AgE is important in adjusting dosage of Short Ragweed extracts to accurately transfer a patient from older extracts to fresher material. In such cases, the dosage of AgE should be considered in addition to the W/V dilution or protein nitrogen units. Antigen E concentration continuously declines in Short Ragweed Pollen extracts at a rate that varies with the formulation of the product. Aqueous extracts retain Antigen E potency less effectively than glycerin 50% (v/v) extracts. These differences are reflected in the expiration date declared on the vial. The continuous decline should be considered. Also, where ragweed is a component of an allergen mixture, clinical response to the other components must be considered in adjustment of dosage based on AgE content alone. The usual course of immunotherapy is three to five years.
• Caution: A small percent of individuals allergic to Short Ragweed are more sensitive to minor antigens such as Ra3 Ra5 than AgE. There is no correlation between the amount of these antigens and either AgE or PNU content.

• NOTE: For extracts of Short Ragweed or equal part mixture of Short and Tall Ragweed refer to AgE dosage schedule. The AgE content for those products is indicated on the vial label. The physician may use the formula below to determine the AgE dosage for each injection.

  AgE dosage can be monitored by using the following formula:

  W/V compounded products:

  Labeled AgE X Dose (mL) = dose in AgE

  PNU compounded products:

  Labeled AgE/mL X dose in PNU = dose in AgE

  Labeled PNU/mL

4.3. Dilution

Bulk concentrated extracts must be diluted for therapy.

• When diluting bulk extracts, use of Sterile Diluent for Allergenic Extracts or Sterile Diluent for Allergenic Extracts Normal Saline with HSA (albumin saline) is recommended. Dilutions should be made with sterile disposable syringes using aseptic technique. Commonly, 10 fold dilutions are used to achieve a desired concentration for initiation and continuation of immunotherapy. For example, transferring 0.5 mL of a 10,000 PNU/mL extract into 4.5 mL of diluent will yield 5 mL of extract at 1,000 PNU/mL. For weight volume products, a 1:100 w/v dilution may be prepared from a 1:10 w/v by transferring 0.5 mL of the 1:10 w/v to 4.5 mL of diluent. Prepare as many additional serial dilutions as necessary to reach the appropriate concentration.
• Formal stability studies for diluted and undiluted forms of non-standardized extracts have not been performed; therefore, it is recommended that minimal amounts of the concentrate be diluted so that the diluted product is used up within a relatively short period of time; i.e., preferably not more than four weeks.

4.4. Administration

Injections are given subcutaneously, preferably in the arm. After inserting the needle, but before injecting the dose, pull plunger of the syringe slightly. If blood returns in the syringe, discard the syringe and contents and repeat injection at another site.

It is advantageous to give injections in alternate arms and routinely in the same area. In some patients, a local tolerance to the allergen may develop thus preventing a possible severe local reaction.

5. Overdose

Systemic reactions are uncommon after injection, but if the patient receives more extract than can be tolerated at that particular time and begins to experience immediate hypersensitivity anaphylaxis, the procedures listed under 8 Adverse Reactions should be instituted.

Overdosage may occur because of an error in the volume of extract injected, or an incorrect dilution injected, or because the patient may be exposed to airborne or environmental antigens simultaneously with injection of the same antigens. In the event of a systemic reaction occurring, the dosage schedule should be carefully adjusted as outlined under 7 Warnings and Precautions.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

1. 1.

   Concentrate in multiple dose vials:

   10 mL and 50 mL, single antigens or specified mixtures, potency expressed in PNU/mL (up to and including 40,000 PNU/mL) or W/V (up to and including 1:10 W/V) aqueous or in 50% glycerin (up to and including 1:10 W/V), to be diluted prior to use. 1:10 W/V Short Ragweed extracts contain ≥ 300 units/mL of AgE.

2. 2. Sterile Diluent for Allergenic Extracts (Normal Saline with Phenol, Glycerinated Phenol Saline and Albumin Saline with Phenol) is supplied in vials of 5 mL, 10 mL, 50 mL and 100 mL.

See Tables below for specific therapeutic concentrations available.

Table 2 – Therapeutic Pollen Extracts

Table 3 – Therapeutic Non-Pollen Extracts

7. Warnings and Precautions

General

In the presence of active symptoms such as rhinitis, wheezing, dyspnea, etc., the indication of immunotherapy must be weighed carefully against the risk of temporarily aggravating the symptoms by the injection itself. Objective assessment of pulmonary function such as Peak Expiratory Flow Rate (PEFR) before allergen administration may be useful in unstable asthmatics to reduce the chances of exacerbation of the patient’s asthma. Patients should be instructed to describe any active allergic symptoms such as rhinitis, wheezing, dyspnea, etc. prior to injection including any late reactions from previous administration. Also, see 3 Serious

Warnings and Precautions Box and 8 Adverse Reactions.

Severe Allergic Reactions:

Patients should always be observed for at least 20-30 minutes after any injection. In the event of a marked systemic reaction such as urticaria, angioedema, wheezing, dyspnea, respiratory obstruction, hypotension, coma and death (see 8 Adverse Reactions), application of a tourniquet above the injection site and administration of 0.2 mL to 1 mL (0.01 mg/kg) of Epinephrine Injection (1:1,000) is recommended. Maximal recommended dose for children between 2 and 12 years is 0.5 mL. The tourniquet is then gradually released at 15-minute intervals. Patients under treatment with beta-blockers may be refractory to the usual dose of epinephrine.

Volume expanders and vasopressor agents may be required to reverse hypotension. Inhalation bronchodilators and parenteral aminophylline may be required to reverse bronchospasm. In cases of respiratory obstruction, oxygen and intubation may be necessary. Life-threatening reaction unresponsive to the above may require cardiopulmonary resuscitation.

Withhold allergenic extracts temporarily or reduce the dose in patients with any one of the following conditions:

• Severe rhinitis or asthma symptoms;
• Infection or flu accompanied by fever;
• Exposure to excessive amounts of clinically relevant allergen prior to therapy.

Switch between products with different formulations of an allergic extract in the same patient: From pyridine extracted alum-complexed allergenic extracts to aqueous extracted and glycerinated allergenic extracts : In order to avoid untoward reaction, it is recommended that therapy be initiated as though patients were previously untreated. The first dose should be related to the patient’s sensitivity, determined by history and confirmed by skin testing.

From non-standardized aqueous extracts to standardized aqueous extracted and glycerinated allergenic extracts: The physician should establish the potency relationship, perhaps by comparative skin testing at equal concentration, prior to injecting the first standardized dose.

From aqueous alum precipitated or modified extracts to aqueous extracted and glycerinated allergenic extracts: Since this subject has not been studied, it is recommended that therapy be initiated as if the patient were not previously treated.

Carcinogenesis and Genotoxicity

Studies in animals have not been performed.

Monitoring and Laboratory Tests

Patients should always be observed for at least 20-30 minutes after any injection.

7.1. Special Populations

7.1.1. Pregnancy

Animal reproduction studies have not been conducted with allergenic extracts. It is also not known whether allergenic extracts can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Controlled studies of hyposensitization with moderate to high doses of allergenic extracts during conception and all trimesters of pregnancy have failed to demonstrate any risk to the fetus or to the mother. However, on the basis of histamine’s known ability to contract uterine muscle, the release of significant amounts of histamine from allergen exposure or hyposensitization overdose should be avoided on theoretical grounds. Therefore, allergenic extracts should be used cautiously in a pregnant woman and only if clearly needed.

7.1.2. Breastfeeding

It is not known if allergens administered subcutaneously appear in human milk. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

7.1.3. Pediatrics

Children can receive the same dose as adults, however, to minimize the discomfort associated with dose volume it may be advisable to reduce the volume of the dose by one-half and administer the injection at two different sites.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Anaphylaxis and deaths following the injection of =allergenic extracts have been reported.

With careful attention to dosage and administration, such reactions occur infrequently, but it must be remembered that allergenic extracts are highly potent to sensitive individuals and OVERDOSE could result in anaphylactic symptoms. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Local: Reactions at the site of injection may be immediate or delayed. Immediate wheal and erythema reactions are ordinarily of little consequence; but if very large, may be the first manifestation of a systemic reaction. If large local reactions occur, the patient should be observed for systemic symptoms for which treatment is outlined below.

Delayed reactions start several hours after injection with local edema, erythema, itching or pain. They are usually at their peak at 24 hours and usually require no treatment. Antihistamine drugs may be administered orally.

The next therapeutic dose should be reduced to the dose which did not elicit a reaction, and subsequent doses should be increased more slowly, i.e., use of intermediate dilutions.

Systemic: Systemic reactions are characterized by one or more of the following symptoms: Sneezing, mild to severe generalized urticaria, itching other than at the injection site, extensive or generalized edema, wheezing, asthma, dyspnea, cyanosis, tachycardia, lacrimation, marked perspiration, cough, hypotension, syncope and upper airway obstruction. Symptoms may progress to shock and death. Patients should always be observed for at least 20 to 30 minutes after any injection.

Volume expanders and vasopressor agents may be required to reverse hypotension. Inhalational bronchodilators and parenteral aminophylline may be required to reverse bronchospasm. Severe airway obstruction, unresponsive to bronchodilator, may require tracheal intubation and use of oxygen. In the event of a marked systemic reaction, application of a tourniquet above the injection site and the administration of 0.2 mL to 1 mL of Epinephrine Injection (1:1,000) are recommended. Maximal recommended dose for children under 2 years of age is 0.3 mL. Maximal recommended dose for children between 2 and 12 years of age is 0.5 mL. The tourniquet should not be left in place without loosening for 90 seconds every 15 minutes.

The next therapeutic injection of extract should be reduced to the dose which did not elicit a reaction, and subsequent doses increased more slowly; i.e., use of intermediate dilutions.

9. Drug Interactions

9.2. Drug Interactions Overview

Drugs can interfere with the performance of skin tests.

9.3. Drug-Behaviour Interactions

The interaction of ALLERGENIC EXTRACTS with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

Antihistamines: Response to mediator (histamine) released by allergens is suppressed by antihistamines. The length of suppression varies and is dependent on individual patient, type of antihistamine and length of time the patient has been on antihistamines. The duration of this suppression may be as little as 24 hours (chlorpheniramine) and can be as long as 40 days (astemizole).

Tricyclic Antidepressants: These exert a potent and sustained decrease of skin reactivity to histamine which may last for a few weeks.

Beta₂ Agonists: Oral terbutaline and parenteral ephedrine, in general, have been shown to decrease allergen induced wheal.

Dopamine: Intravenous infusion of dopamine may inhibit skin test responses.

Beta Blocking Agents: Propranolol can significantly increase skin test reactivity.

Other Drugs: Short acting steroids, inhaled beta2 agonists, theophylline and cromolyn do not seem to affect skin test response.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

The treatment consists of the subcutaneous injection of gradually increasing doses of the allergens to which the patient is allergic. It has been demonstrated that this method of treatment induces an increased tolerance to the allergens responsible for the symptoms on subsequent exposure. The exact relationships between allergen, skin-sensitizing antibody (IgE) and the blocking antibody (IgG) have not been precisely established. Clinically confirmed immunological studies have adduced evidence of the efficacy of hyposensitization therapy.

1. 11. Storage, Stability, and Disposal

To maintain stability of allergenic extracts, proper storage conditions are essential. Bulk concentrates and diluted extracts are to be stored at 2° to 8° C even during use. Bulk or diluted extracts are not to be frozen. Do not use after the expiration date shown on the vial label.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper name: Allergenic Extract Pollens

Allergenic Extract Non Pollens

Product Characteristics:

Sterile therapeutic allergenic extracts are supplied in either phenol-saline diluent or in diluent containing glycerin 50% (v/v) for subcutaneous injection. Inactive ingredients may include: sodium chloride for isotonicity, glycerin, and sodium bicarbonate as a buffer.

Pollens are individually extracted from pure pollen extracted in a phenol-preserved sodium bicarbonate solution. Short Ragweed and Mixed (Tall and Short) Ragweed extracts are standardized by Antigen E content and so labeled. The Antigen E content of extracts containing Short Ragweed at a concentration more dilute than a weight/volume ratio of 1:10 are obtained by calculating the Antigen E content based on the assay value of more concentrated extract. Pollen extracts are filtered aseptically and, after final packaging, they are tested for sterility. Molds are individually extracted from pure powdered inactivated mold source material extracted in phenol preserved saline. Mold extracts are filtered aseptically and after final packaging are tested for sterility. Molds (fungi) are present in all inhabited places at all seasons of the year; they are so ubiquitous that they are prevalent at times when common allergic pollens and other inhalants are not. In the home and surroundings, molds are found in upholstered furniture, mattresses, drapes, woolens, leather goods, fruits, meats, cheeses, garden soil and on plants. Spores, mycelial fragments and mold residues are thus inhaled, contacted and ingested continuously.

Miscellaneous inhalants and epidermals are individually extracted in phenol preserved saline, filtered aseptically and after final packaging are tested for sterility.