Pharmalgen Wasp Venom Protein Product Monograph

Mannitol, Human Serum Albumin, Phenol

For a complete listing see Dosage Forms, Composition and Packaging section.

PHARMALGEN: Honey Bee (Apis mellifera), Yellow Jacket (Vespula spp.), Yellow Hornet (Dolichovespula arenaria), White Faced Hornet (Dolichovespula maculate), Wasp (Polistes spp.), Mixed Vespid (Yellow Jacket, White Faced Hornet & Yellow Hornet) is indicated for:

• Diagnosis and treatment of Hymenoptera sting allergy

1. 1. Approximately two-thirds of adult patients with a history of sting anaphylaxis and a positive venom skin test but who do not receive immunotherapy will experience a systemic reaction if stung by the implicated insect again. These patients should receive therapy⁴. Children whose reactions have been limited to the skin have approximately a 10% risk of future reactions if stung and not immunized. The nature and severity of these reactions is in general similar to the original reaction and therefore children with this kind of history may not need venom therapy⁵.

1. 2. The risk of anaphylaxis following a future sting is unknown in patients who have been stung without experiencing a systemic reaction but who are currently venom skin test positive. At this time, no recommendation can be made that such patients receive venom immunotherapy, but they should be counselled on their condition and may benefit from instruction in the self-administration of intramuscularly injected epinephrine. There is an approximately 10% risk of future systemic reactions if prior

• reactions have consisted of large delayed local reactions⁶. This risk must be considered in deciding whether or not to recommend venom therapy.

1. 3. Patients with a history of serious systemic reaction to a sting but who are skin test negative to all five venoms are not candidates for therapy. It is not known whether such patients may be resensitized by future stings, and such patients should be retested after any subsequent sting.

1. 4. A small percentage of patients who have reached the maintenance dose suggested below, may still experience some degree of allergic response upon being stung by the implicated insect.

The single-venom extracts are intended for both diagnosis and immunotherapy; the mixed vespid product is intended for immunotherapy only.

Multiple venom preparations are indicated in patients with multiple skin test sensitivities.

Geriatrics (> 65 years of age):

Allergenic extracts have not been studied systematically in various age groups (see WARNINGS AND PRECAUTIONS, Special Populations).

Pediatrics (> 5 years of age):

Allergenic extracts have been used in children greater than 5 years of age (see WARNINGS AND PRECAUTIONS, Special Populations).

Hymenoptera venom is contraindicated in patients who have or are:

• Immune pathologic conditions such as immune complex and immunodeficiency diseases.
• Malignancy
• Unstable or severe chronic or severe seasonal asthma (FEV1 consistently under 70% of predicted value after adequate pharmacologic treatment)
• Diseases or conditions preventing the treatment of possible anaphylactic reactions, e.g. chronic heart and lung diseases, severe arterial hypertension and treatment with -blockers
• Treated with tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs)
• Treated with ACE inhibitors

Also see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Serious Warnings and Precautions

• Treatment should only be carried out by or under supervision of physicians experienced in specific immunotherapy and where full facilities for cardio-respiratory resuscitation are immediately available.
• Patients with asthma may be more susceptible to severe adverse reactions. (See Contraindications).
• The patient must be under observation for at least 30 minutes (longer in high risk patients) after having received an injection with PHARMALGEN.
• All patients receiving venom immunotherapy should be instructed in the procedure for emergency self-injection of epinephrine (See WARNINGS AND PRECAUTIONS).
• Severe fatal life-threatening systemic reactions including anaphylactic shock can occur with the use of PHARMALGEN (Ref. ADVERSE REACTIONS).
• Sterile technique should be ensured throughout. In order to avoid possible contamination it is advised that solutions, once made up, should be discarded after four hours.
• Avoid intra-vascular injection

Treatment with hymenoptera venom should be administered under the supervision of a physician experienced in specific immunotherapy.

Due to the risk of potentially fatal anaphylactic reactions, treatment with hymenoptera venom must be carried out in hospitals or clinics where full resuscitation equipment and drugs, including epinephrine for injection, are immediately available for use by adequately trained personnel.

Should a serious systemic reaction occur:

• Inject 0.3 – 0.5 mL of 1:1000 epinephrine into the opposite arm; this may be repeated every 5 to 10 minutes, as a succession of smaller doses is more effective and less dangerous than a single large dose. Use a smaller dose for infants and children, in the range of 0.01 mL/kg of body weight.
• Apply a tourniquet proximal to the injection site; loosen it at least every 10 minutes.
• Inject no more than 0.1 mL of 1:1000 epinephrine at the injection site, to delay the absorption of the remaining extract.

• When the patient has and unexpectedly severe local or any systemic reaction to the previous dose.
• If the patient is experiencing allergic symptoms such as rhinitis or asthma, or is ill with flu or infection accompanied by fever.
• If an unusually long time has passed since the previous injection.

General

It is not unusual for patients to be treated with multiple venom preparations simultaneously. Although the majority of patients receiving multiple venoms tolerate treatments as well as patients receiving a single venom extract. The theoretically greater risk of systemic reactions in patients receiving multiple venom extracts should be kept in mind.

Patients are most at risk of serious systemic reactions:

• During skin testing and the build-up to maintenance dose, before tolerance of the extract is established. Do not begin immunotherapy without establishing the appropriate initial dose by skin testing (see DOSAGE AND ADMINISTRATION), and do not inject the undiluted extract concentrate at any time unless tolerance has been demonstrated.

• When changing to a freshly-reconstituted extract; all extracts lose potency over time, and a fresh extract could have an effective potency that is substantially greater than that of the old extract. Reduce the dose by at least 50% when switching a patient to a freshly-reconstituted extract; this is particularly important when the previous extract was near its expiration date.

• When changing to an extract from a different manufacturer. Processing and source materials may differ markedly among manufacturers, and extracts from different manufacturers should not be considered interchangeable. Such changes should not be made without establishing the proper dosage by skin testing.

• If an error in dosage occurs. Take care to properly prepare, label, store, and control all dilutions.

Carcinogenesis and Mutagenesis

No long term studies with this or any allergenic extract have been carried out to determine their effect on carcinogenesis, mutagenesis, or impairment of fertility.

Immune

In patients with increased baseline serum tryptase levels and/or mastocytosis, the risk of systemic allergic reactions and the severity of these may be increased.

Patients suffering from mastocytosis may expect less efficacy compared with the general insect venom allergic population.

Special Populations

Pregnant Women:

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. Allergenic extracts should be given to a pregnant woman only if clearly needed.

Nursing Women:

It is not know whether this drug is excreted in human milk. Because many drugs

Pediatrics (> 5 years of age):

The Hymenoptera venom extracts are indicated for immunotherapy in children (> 5 years of age) who have a history of a systemic reaction not confined to the skin, and a positive skin test to one or more of the venom extracts. The maintenance dose of 100 µg is recommended for both children and adults. If the injection volume is too large for a small child to tolerate comfortably, then the injection volume may be split into multiple injections (SEE DOSAGE AND ADMINISTRATION).

Geriatrics (> 65 years of age):

Clinical studies of venom extracts did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Monitoring and Laboratory Tests

Patients receiving allergenic extracts should be kept under observation a minimum of 30 minutes so that any adverse reaction can be observed and properly handled. Airway obstruction in high risk patients can be monitored by peak flow measurements before and after administration of allergens.

Adverse Drug Reaction Overview

Severe anaphylactic reactions to this extract can occur in extremely allergic patients and at any dosage level (see WARNINGS AND PRECAUTIONS).

Post-Market Adverse Drug Reactions

Adverse reactions are divided into groups according to the MedDRA-convention frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to ≤1/100), rare (≥1/10,000 to ≤1/1,000), very rare (≤1/10,000). Frequencies are based on clinical trials with immunotherapy products in general, and includes allergens from pollen, hymenoptera venom and animal hair and dander.

Concomitant treatment of beta-blocking drugs, tricyclic antidepressants and monoamine oxidase inhibitors (MAO-inhibitors) may interfere with treatment of an anaphylactic reaction. The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors (MAO-inhibitors). The beta-stimulating effect of epinephrine can be inhibited by concomitant beta-blocking drugs.

Concomitant treatment with ACE inhibitors may aggravate an anaphylactic reaction.

Therefore, concomitant use of bee venom with these drugs is contraindicated.

Dosing Considerations

Skin testing:

Patients with relevant sting histories should be skin tested with appropriate concentrations of each of the five single Hymenoptera venom preparations (honey bee, yellow jacket, yellow hornet, white faced hornet, wasp).

1. 1. Reconstitute each of the five vials of a diagnostic kit using HSA diluent, and prepare serial dilutions such as those in Table 1.

1. 2. Perform a preliminary skin prick test with each preparation at the 1.0 µg/mL concentration, with the diluent as a negative control, and with histamine base at 1 mg/mL as a positive control. For most patients, all tests but the positive control should be negative. Patients reacting to the prick test at 1.0 µg/mL of venom should be considered highly sensitive to the venom, and suitable precautions should be taken. If the positive control is negative, the possibility of skin non-reactivity must be considered.

1. 3. Begin intradermal testing with all venoms, starting at the 0.001 µg/mL dilution for all patients who did not react to the skin prick test, and the 0.0001 µg/mL for highly sensitive patients.

1. 4. Read the test response after 15 minutes, and determine the degree of response to the injection, in comparison to the negative control. A suggested grading system appears in Table 1.

Table 1

Skin Test Grading System

0

+

1+

2+

3+

4+

< 0.5

0.5 – 1.0

0.5 – 1.0

0.5 – 1.0

1.0 – 1.5, pseudopodia

> 1.5, many pseudopodia

< 0.5

0.5 – 1.0

1.1 – 2.0

2.1 – 3.0

3.1 – 4.0

> 4.0

1. 5. If the intradermal reaction is negative at the initial concentration, continue intradermal testing with ten-fold increments in the concentration until a clearly positive response has been obtained or a concentration of a 1 µg/mL has been tested, whichever occurs first. The use of venom concentrations greater than 1 µg/mL for intradermal testing is not recommended because of the risk of false-positive reactions⁴. If there is a positive response at concentrations of 0.01µg/mL or less, the patient should be considered highly sensitive to the venom.

Recommended Dose and Dosage Adjustment

Treatment:

An allergic individual should be treated with each venom extract that provokes a positive skin test. If more than one Hymenoptera venom preparation is indicated the different preparations should be given by separate injections. The mixed vespid preparation should not be substituted for single-venom treatments unless the patient is allergic to all three of the constituent venoms: yellow jacket, yellow hornet, and white faced hornet.

Dosage Schedule:

Dosage of allergenic extracts is a highly individualized matter, and varies according to the degree of sensitivity of the patient, the clinical response, and tolerance of the extract administered previously.

• If a single dose results in more than a moderate local reaction (>5.0 cm wheal) within ½ hour, no additional dose of the venom should be given during that visit, and the same dose should be repeated at the next visit – or visits – until the patient has tolerated it.

• If any systemic manifestation of sensitivity occurs during or following a visit, or if a single dose results in an excessive local reaction (>10 cm wheal) within ½ hour, no additional dose should be administered during the visit and the total dosage for the next visit should be reduced to half of the dose that caused the reaction.

• Delayed local reaction (occurring 24-48 hours after injection) are relatively common, and do not appear to predict difficulties with future doses. As a rule, therefore, dosage adjustment is not required in most instances. However, at the physician’s discretion and for the comfort of the patient, if delayed large local reactions over 10 cm are reported, the subsequent dose should be held at the same level as the one causing the reaction.

Table 2

Representative Treatment Schedule Using a Single Venom Preparation*

Conditions for Proceeding

to Next Dose

1

2

3

0.01

0.1

1.0

0.1

0.1

0.1

0.001

0.01

0.1

1. 1. If a single dose results in more than a moderate local reaction (>5.0 cm wheal) within ½ hour, an additional dose should not be give during that visit. Repeat the same dose at the next visit – or visits – until tolerated.
2. 2. If systemic manifestations of sensitivity occur during or following a visit or a single dose results in an excessive local reaction (>10 cm wheal) within ½ hour, do not administer and additional dose during the visit and reduce the total dose for the next visit to half of the total that produced the reaction.
3. 3. Delayed (24-48 hrs.) local reactions of <10 cm do not require adjusting the dose; for such reactions that are >10 cm, hold dose at previous level.

1

2

3

1.0

1.0

10

0.1

0.5

0.1

0.1

0.5

1.0

1

2

3

10

10

10

0.1

0.5

1.0

1

5

10

1

2

100

100

0.1

0.2

10

20

1

2

100

100

0.2

0.3

20

30

1

2

100

100

0.3

0.3

30

30

1

2

100

100

0.4

0.4

40

40

1

2

100

100

0.5

0.5

50

50

*For the mixed vespid preparation, the total venom protein concentration and the total amount of venom protein injected will be triple the amounts shown, with no changes in injection volumes.

** If a patient on maintenance therapy is stung and has any systemic manifestations of sensitivity, the maintenance dosage should be increased to 200 µg for the relevant venom, increasing at no greater than 50 µg increments.

Administration

Administer the venom solution subcutaneously, using a suitable sterile syringe with 0.1 mL graduations and a 25-27 gauge 1/4 to 5/8 inch needle. The injections are typically given in the lateral aspect of the upper arm.

0.2 mL

0.2 mL

0.2 mL

0.2 mL

0.2 mL

0.2 mL

100 µg/mL

10 µg/mL

1 µg/mL

0.1 µg/mL

0.01 µg/mL

0.001 µg/mL

1.8 mL

1.8 mL

1.8 mL

1.8 mL

1.8 mL

1.8 mL

2.0 mL

2.0 mL

2.0 mL

2.0 mL

2.0 mL

2.0 mL

10 µg/mL

1 µg/mL

0.1 µg/mL

0.01 µg/mL

0.001 µg/mL

0.0001 µg/mL

Mechanism of Action

The mode of action of allergenic extracts is under investigation.

Skin Test:

Superficial injection into the skin of a minute dose of specific allergen will produce a short-lived local reaction in subjects allergic to that allergen.

Treatment:

Escalating dosage according to the schedules described in the DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment section, encourages generation of blocking antibodies to such a level that protection from one or several sting may be developed. Resistance is sustained by maintenance doses.

Geriatrics:

Refer to WARNINGS AND PRECAUTIONS Section.

Duration of Effect

At the present time it appears necessary to continue maintenance injections indefinitely.

Table 4

Maximal Recommended Shelf Life (2-8°C)

Unreconstituted Freeze-Dried Powder

Reconstituted in HSA Diluent to a concentration of:

Proper name: Hymenoptera Venom/Venom Protein

Chemical name: Honey Bee (Apis mellifera)

Yellow Jacket (Vespula spp.)

Yellow Hornet (Dolichovespula arenaria)

White Faced Hornet (Dolichovespula maculate)

Wasp (Polistes spp.)

Product Characteristics

Freeze-dried Hymenoptera preparation of honey bees, yellow jacket, yellow hornets, white faced hornet, wasp, and mixed vespid venom protein. The mixed vespid preparations consist of equal amounts of yellow jacket, yellow hornet and white-faced hornet.

These extracts are available in diagnostic kit, treatment kits, and multi-dose vials. Just prior to use, the contents of each vial should be reconstituted with HSA diluent using the volume specified on the vial label.

The mode of action of allergenic extracts is under investigation.

The skin test reaction occurring in previously sensitized individuals is probably related to the interaction of antigen with IgE antibody and the subsequent release of histamine from mast cells¹. The therapeutic action of allergenic extracts may be related to the production of IgG (blocking) antibodies. Effective immunotherapy with allergenic extracts is usually associated with a rise in serum levels of specific IgG. Immunotherapy also produces and initial rise in specific IgE levels, which then decrease as therapy continues.

Van Metre, T.E., and Adkinson, N.F. in: Allergy Principles and

Practice, Third Edition, 1327-1343, 1988. C.V. Moseby Co.

Norman, P.S. and Van Metre, T.E.: J Allergy Clin Immunol. 85: 522,

1990.