Yellow Jacket Venom Protein

1045063C
PRESCRIBING
I NFORMATION

ALLERGENIC EXTRACTS
HYMENOPTERA
VENOM/VENOM PROTEIN

Pharmalgen®

Honey Bee (Apis mellifera)
Yellow Jacket (Vespula spp.)
Yellow Hornet (Dolichovespula arenaria)
White Faced Hornet (Dolichovespula maculata)
Wasp (Polistes spp.)
Mixed Vespid (Yellow Jacket, Yellow Hornet & White Faced Hornet)

ALK-Abelló A/S
DK-2970 HØRSHOLM, DENMARK

Hymenoptera venom preparations should be used only by or under the direction of physicians experienced in administering allergens to the maximum tolerated dose and only where adequate means for treating severe systemic reactions are immediately available.

Allergenic extracts may potentially elicit a severe life-threatening systemic reaction, rarely resulting in death1. Because of the possibility of severe systemic reactions, the patient should be instructed in the recognition of anaphylactic symptoms, observed in the office for at least 30 minutes after each injection, and warned to return to the office if symptoms of an allergic reaction occur.

Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators, and the risk of severely complicating the treatment of systemic reactions should be carefully considered before a decision to treat is reached.

Treatment with ACE-Inhibitors should be Stopped at least 24 hours Prior to injection due to An increased risk of anaphylactic reaction based on inhibition of the angiotensin metabolism.

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 of mastocytosis may expect less efficacy compared with the general insect venom allergic population.

All patients receiving venom immunotherapy should be instructed in the procedure for emergency self-injection of subcutaneous epinephrine. This self treatment might be necessary before patients have reached a maintenance dose of venom, and partially treated patients should be advised to carry an emergency epinephrine kit during the Hymenoptera season.

Before administering these venom preparations, physicians should be thoroughly familiar with the information in this insert, especially the Warnings, Precautions, and Adverse Reactions sections.

Revision C ()

Six sterile freeze-dried Hymenoptera preparations are available: honey bee venom, and yellow jacket, yellow hornet, white faced (bald faced) hornet, wasp, and mixed vespid venom protein. The mixed vespid preparation consists of equal amounts of yellow jacket, yellow hornet, and white faced hornet venom proteins.

Honey bees, yellow hornets, and white faced hornets are present primarily as the single species designated above, and the source material for those extracts is collected only from those species. There are a number of common species of yellow jackets and wasps in the environment, and those extracts reflect that variety and contain venom protein from a number of species. Information concerning the species included in the yellow jacket and wasp preparations is available on request from ALK customer service (1-800-252-9778; in TX and Canada, 203-877-4782).

Honey bee venom is obtained from live insects by an electric shock method. The other venoms are obtained from dissected venom sacs, which are crushed in a β-alanine/acetic acid buffer to release the venom. The sac residue is then removed by centrifugation and filtration. Allergenic components in the raw honey bee and yellow jacket venom materials have been described ^{2, 3}.

These extracts are available in freeze-dried form, and just prior to use, the contents of each vial should be reconstituted with HAS diluent (see How Supplied), using the volume specified on the vial label. When reconstituted as directed, the single-venom preparations will contain 100 μg/ml of venom or venom protein, and the mixed vespid preparation will contain 300 μg/ml of venom protein. This is the concentration from which full maintenance doses are typically drawn. Other ingredients in the solution reconstituted as directed with HSA diluent are 0.06% albumin human USP, 3.0% mannitol 0.9% sodium chloride, and 0.4% phenol. All these preparations must be diluted before use in diagnosis or in the initial stages of treatment.

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 cells. 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 an initial rise in specific IgE levels, which then decrease as therapy continues.

The Pharmalgen venom preparations are indicated for use in the diagnosis and treatment of Hymenoptera sting allergy. The following general considerations should be applied in determining the proper use of these preparations:

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 an approximately 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.
   
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 counseled on their condition and may benefit from instruction in the self administration of subcutaneously 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.
   
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.
   
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.

No absolute contraindications to venom immunotherapy are known.

However, the risk of serious systemic anaphylactic reactions to venom or any potent allergenic extract suggests a number of preexisting conditions that should be considered relative contraindications. Among those conditions are acute infections, immune disease, malign disorders, severe cardiac disease, and treatment with β-adrenergic antagonist drugs (beta-blockers), angiotensin inhibitors (ACE-inhibitors), tricyclic anti-depressives and monoaminooxidase (MAO) inhibitors. See also Warnings, Precautions, and Adverse Reactions.

See additional warnings given in the box at the beginning of this insert.

Some patients are highly sensitive to Hymenoptera venoms and, for such patients, it must be anticipated that even a small skin test dose could result in a serious systemic reaction. Adequate means to treat such reactions must be immediately available, including the following equipment⁸ stethoscope and sphygmomanometer; tourniquets, syringes, hypodermic needles, and large-bore (14 gauge) needles; aqueous epinephrine HCl, 1:1000; oxygen, intravenous fluids, and the equipment for administering them; oral airway; diphenhydramine or similar antihistamine; aminophylline and corticosteroids for intravenous injection; vasopressor.

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.

Observe the patient for at least 30 minutes after injection, and be alert for the signs of impending reaction. Make sure the patient under stands that serious delayed reactions can occur later on, how to recognize them, and what to do if they occur.Patients who are receiving beta-blocking medication are high-risk patients for immunotherapy, because systemic reactions to the extract may be more severe in such patients⁹, and because the beta-blocker may impair the ability to reverse the reaction¹⁰. In such patients, this risk should be carefully weighed before a decision to treat is reached.

Treatment with ACE-Inhibitors should be Stopped at least 24 hours Prior to injection due to An increased risk of anaphylactic reaction based on inhibition of the angiotensin metabolism ^{12, 13, 14}.

The effect of epinephrine (in cases of anaphylactic shock) on patients being treated with tricyclic anti-depressives or MAO inhibitors can be heightened and the consequences can be fatal. This should be taken into account before initiating specific immunotherapy.

In patients with increased baseline serum tryptase levels and/or mastocytosis , the risk of systemic allergic reactions and the severity of these may be increased¹⁵.

Patients suffering of mastocytosis may expect less efficacy compared with the general insect venom allergic population¹⁵.

Do not inject this or any allergenic extract intravenously. Before injecting the extract subcutaneously, retract the plunger on the syringe slightly and verify that no blood enters the syringe. If it does, remove the syringe and repeat the procedure at a different site.

This and any allergenic extract should be temporarily withheld or its dosage reduced under any of these conditions¹¹.

• When the patient has an 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 the patient has experienced deterioration of atopic dermatitis¹⁶.
  
• If an unusually long time has passed since the previous injection.

Allergic patients differ widely in their sensitivity to this or any allergenic extract, and no single dosage regimen can be recommended for all patients. The treatment schedule described under Dosage and Administration, below, is suitable for the majority of patients, but is based on a rather rapid build-up to the maintenance dosage and will have to be adjusted for sensitive patients. Progression to the next higher dose requires tolerance of the previous one, and the regimen must be modified if any of the conditions described above occur. Such modifications should include weaker dilutions and smaller dosage increments.

Severe anaphylactic reactions to this extract can occur in extremely allergic patients and at any dosage level. Do not use this extract unless you are prepared to deal with these reactions, and until you have read and understood the Warnings, Precautions, and Dosage and Administration sections of this insert.

The most serious systemic reaction that can occur is anaphylactic shock, which, while rare, is life threatening and must be treated immediately. Among other systemic reactions that have occurred are laryngeal edema, headache, fainting, dizziness, paraesthesia, pallor, tachycardia, palpitations, flushing, hypotension, bronchospasm, angioedema, erythema, wheezing, cough, dyspnea, sneezing, asthma, throat irritation, conjunctivitis, rhinitis, urticaria, pruritus, rash, diarrhea, vomiting, nausea, dyspepsia, abdominal pain, joint swelling, arthralgia, chest discomfort, and sensation of foreign body.

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 larger one. 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.

These measures will almost always reverse the reaction, but in the rare instances when they do not, then the full armamentarium of emergency medicine may be required, among them: direct laryngoscopy, direct current cardioversion, tracheotomy, and intracardiac injection of drugs⁸.

The occurrence of a severe systemic reaction to an injection of this extract does not contraindicate further therapy, but the next dose given should be reduced by at least 90%, and raised very slowly thereafter. If a pattern of systemic reactions – even very mild ones – appears, then the benefits of continued treatment must be carefully weighed against the substantial demonstrated risk.

Local reactions, even relatively severe but transient redness, itching, swelling and discomfort, are the normal physiologic response to the allergens and to the volume of the fluid injected, and in their milder form are evidence of the effectiveness of the therapy. Local reactions generally subside quickly and do not require treatment, but application of cold to the injection site or other symptomatic measures may be useful.

However, severe local reactions should be considered a warning of potential systemic reaction if that dosage is continued. Always reduce the dose substantially if such a local reaction occurs.

Reconstitution and Dilution:

A diluent containing 0.03% human serum albumin (HSA), 0.9% sodium chloride, and 0.4% phenol should be used for reconstituting and diluting these preparations.

Reconstitute each vial of freeze-dried venom material by drawing the amount of diluent specified on the label into a syringe, and transfer ring it to the vial of extract using aseptic technique. Swirl or rock the vial gently until all the material has gone into solution. Do not shake the vial or agitate it violently enough to cause the fluid to foam. Note that a needle that has been inserted into a vial of venom must not be reinserted into a stock bottle of diluent, or into a vial containing another type of extract.

When reconstituted as directed on the label, the vial will contain 100 μg of venom per ml (300 μg/ml in the case of the mixed vespid preparation). This is the concentration from which the typical maintenance dose is drawn, but it is not suitable for testing or for the initial stages of immunotherapy.

To obtain the concentrations required for testing or the initial stages of immunotherapy, prepare serial ten-fold dilutions of the concentrate to achieve the concentrations specified in Table 1.

The relatively small 0.2 ml volume conserves the original concentrate, and is convenient because sterile diluent is readily available in prefilled 1.8 ml volumes.

For each vial, record the date of reconstitution or dilution on the label. Then calculate the appropriate shelf life based on the information in Table 4, and write that on the label as well. Note that the calculated shelf life of a dilution must not exceed that of the concentrate from which it was made.

Diagnostic Kit: The diagnostic kit contains 5 vials of freeze-dried venom/venom protein extracts, one vial each of honey bee, yellow jacket, yellow hornet, white faced hornet, and wasp. When reconstituted with 1.2 ml of diluent, each vial contains 100 μg/ml of venom/venom protein.

Treatment Kits: The treatment kits contain 6 unit-dose vials of freeze-dried, venom/venom protein from either honey bee, yellow jacket, yellow hornet, white faced hornet, wasp, or mi- f xed vespid. When reconstituted with 1.2 ml of diluent, each vial of single-venom preparations will contain 100 μg/ml of venom/venom protein, and the mixed vespid products will contain 300 μg/ml of venom/venom protein.

Multi-dose Vials: Multi-dose vials are single vials that contain enough venom/venom protein so that, when reconstituted as directed with 11 ml of diluent, will produce ten full maintenance doses. When reconstituted as directed with 11 ml of diluent, the multi-dose vials contain 100 μg/ml of venom protein for single-venom products, and 300 μg/ml for the mixed vespid product. 

HSA Diluent: A diluent containing 0.03% human serum albumin (HSA), 0.9% sodium chloride, and 0.4% phenol should be used for re-constituting and diluting these preparations. This diluent is available in the US from ALK in

vials containing 1.8 ml (packages of 100), or 30 ml (packages of 1 or 5) of diluent.

1. Van Metre, T.E., and Adkinson, N.F. in: Allergy Principles and Practice, Third Edition, 1327-1343, 1988. C.V. Moseby Co.
   
2. Hoffman, D.R., et al.: J Allergy Clin Immunol 59: 147, 1977.
   
3. Hoffman, D.R.: Ann Allergy 40: 171, 1978.
   
4. Hunt, K.J., et al.: N Engl J Med 299:157, 1978.
   
5. Schuberth, K.C., et al.: J Pediatr 102: 361, 1983.
   
6. Golden, D.B.K., and Valentine, M.D.: Ann Allergy 53: 444-452, 1984.
   
7. Hunt, K.J., et al.: Ann Int Med 85: 56, 1976.
   
8. Anderson, J.A., et al.: J Allergy Clin Immunol 77(2): 271-273, 1986.
   
9. Jacobs, R.L., et al.: J Allergy Clin Immunol 68: 125, 1981.
   
10. Bickel, W.H., Ann Emerg Med 13: 189,1984.
    
11. Norman, P.S., and Van Metre, T.E.: J Allergy Clin Immunol 85: 522, 1990.
    
12. Müller, U & Mosbech, H. Allergy. Suppl 14, Vol 48, 37-43. 1993.
    
13. Ober, A.I. et al..J. Allergy Clin Immunol 112, 1008-1009, 2003.
    
14. Stumpf, J.L. et al. Ann Pharmacother 40, 699-703, 2006.
    
15. Golden, D.B.K. et al. J Allergy Clin Immunol 127(4): 854.e13-854.e15, 2011.
    
16. Alvarez-Cuesta, E. et al. Allergy 61(Suppl. 82): 11, 2006.
    
17. Simons, F.E.R., et al. J Allergy Clin Immunol 127(3): 593.e1-593.e22, 2011.

Warranty Statement

We warrant that this product was prepared according to the applicable regulations of the appropriate regulatory agency; that it is true to label; and that the contents of each unopened, undamaged container are sterile. We have no control over the conditions under which this product is used, the diagnosis of the patient, the dosage, the methods of administration or the handling of the product after it leaves our possession, and we do not warrant either a good effect or against an ill effect following use of this product.

The user of this product should be aware of the inherent danger of injecting any biological product and accept the risk of a serious anaphylactic reaction.

The foregoing warranty is exclusive of all other warranties whether written, oral or implied (including any warranty of merchantability or fitness for use.)

No representative of the company may change any of the foregoing, and the buyer hereby accepts the product subject to all the terms hereof.

Manufactured by:
ALK-Abelló A/S, Hørsholm, Denmark
U.S. Licence 1292
Distributed by:
ALK-Abelló, Inc. Port Washington NY 11050
In NY: 1-800-252-9778

Allergenic Extract
Honey Bee Venom
100 µg/mL
6 x 1 mL Vials
Rx Only

Allergenic Extract Honey Bee Venom 100 µg/mL 6 x 1 mL Vials Rx Only

Allergenic Extract
Mixed Vespid 
Venom Protein
300 µg/mL
6 x 1 mL Vials
Rx Only

Allergenic Extract Mixed Vespid Venom Protein 300 µg/mL 6 x 1 mL Vials Rx Only

Allergenic Extract
Wasp Venom Protein
100 µg/mL
6 x 1 mL Vials
Rx Only

Allergenic Extract Wasp Venom Protein 100 µg/mL 6 x 1 mL Vials Rx Only

Allergenic Extract
White Faced Hornet
Venom Protein
100 µg/mL
6 x 1 mL Vials
Rx Only

Allergenic Extract White Faced Hornet Venom Protein 100 µg/mL 6 x 1 mL Vials Rx Only

Allergenic Extract
Yellow Hornet
Venom Protein
100 µg/mL 
6 x 1 mL Vials
Rx Only

Allergenic Extract Yellow Hornet Venom Protein 100 µg/mL 6 x 1 mL Vials Rx Only

Allergenic Extract
Yellow Jacket
Venom Protein
100 µg/mL 
6 x 1 mL Vials
Rx Only

Allergenic Extract Yellow Jacket Venom Protein 100 µg/mL 6 x 1 mL Vials Rx Only