Honey Bee Hymenoptera Venom Venomil Diagnostic: Package Insert and Label Information (Page 3 of 4)

OVERDOSAGE

See ADVERSE REACTIONS Section.

DOSAGE AND ADMINISTRATION

(1) General

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitute and dilute the freeze-dried venom as directed below. Sterile Albumin Saline with Phenol (0.4%) must be used to reconstitute and dilute the venoms for skin testing and treatment.

Reconstitute the freeze-dried venoms by adding 1.2 mL Sterile Albumin Saline with Phenol (0.4%) to the vial using a sterile syringe. Swirl or rock the container to dissolve the venom completely. DO NOT SHAKE, since shaking can cause foaming. Dilutions (see table below) must be made in Sterile Albumin Saline with Phenol (0.4%). They must be made accurately and aseptically, using sterile solutions, vials, syringes, etc., and thoroughly mixed by rocking or swirling. DO NOT SHAKE. Maintain stock solutions and dilutions constantly at 2° — 8°C.

Extract of Volume Extract Concentration Diluent Volume Dilution Concentration
1 part of 100 µg/mL + 9 parts = 10 µg/mL
1 part of 10 µg/mL + 9 parts = 1 µg/mL
1 part of 1µg/mL + 9 parts = 0.1µg/mL
1 part of 0.1 µg/mL + 9 parts = 0.01 µg/mL
1 part of 0.01 µg/mL + 9 parts = 0.001 µg/mL
1 part of 0.001 µg/mL + 9 parts = 0.0001 µg/mL

As an example of the above dilution table:

Extract of Volume Extract Concentration Diluent Volume Dilution Concentration
0.2mL of 100 µg/mL + 1.8mL = 10 µg/mL
0.2mL of 10 µg/mL + 1.8mL = 1 µg/mL
0.2mL of 1 µg/mL + 1.8mL = 0.1 µg/mL
0.2mL of 0.1 µg/mL + 1.8mL = 0.01 µg/mL
0.2mL of 0.01 µg/mL + 1.8mL = 0.001 µg/mL
0.2mL of 0.001 µg/mL + 1.8mL = 0.0001 µg/mL

NOTE: Mixed Vespid Venom Protein concentrations will be three times that shown above.

USE OF VENOMIL DIAGNOSTIC SETS

The Venomil Diagnostic Sets from Jubilant HollisterStier contain a vial of freeze dried venom protein that when reconstituted as instructed below will contain 100 µg venom or venom protein/mL.

To use the Venomil Diagnostic set, follow these steps:

1. Open box and remove contents. Be sure to read the complete package Instruction Sheet paying particular attention to the WARNINGS, PRECAUTIONS, CONTRAINDICATIONS, and ADVERSE REACTIONS.
2. Remove the freeze-dried venom vial and the vial of diluent provided with the kit. Withdraw 1.3 mL of Albumin Saline with Phenol (0.4%) from the diluent vial using a 2 or 3 mL disposable syringe. Expel some Albumin Saline with Phenol (0.4%) from the syringe until exactly 1.2 mL are remaining in the syringe. The remaining Albumin Saline with Phenol (0.4%) in the diluent vial may be marked “Control” and used as a negative control for prick testing.
3. Insert the needle of the diluent syringe into the vial of venom and expel the diluent. Remove the syringe. Swirl or rock the vial to dissolve the venom completely. DO NOT SHAKE. Shaking can cause foaming of the extract.
At this point, you have completed the reconstitution of the freeze-dried venom. The reconstituted products contain 100 µg of venom or venom protein per mL. DO NOT USE THIS STRENGTH FOR INTRADERMAL SKIN TESTING. DISCARD AFTER THE DILUTIONS HAVE BEEN PREPARED.
4. Remove six vial labels from the kit and mark them: 10 µg/mL, 1 µg/mL, 0.1 µg/mL, 0.01 µg/mL, 0.001 µg/mL and 0.0001 µg/mL. Withdraw 0.2 mL of venom extract in a 1 mL syringe from the vial reconstituted in step #3. Insert the syringe needle into one vial of 1.8 mL Albumin Saline with Phenol (0.4%). Slowly expel the 0.2 mL venom into it. Swirl or rock to mix, and label 10 µg/mL.
5. Withdraw 0.2 mL of the 10 µg/mL venom extract and inject into another vial of 1.8 mL Albumin Saline with Phenol (0.4%). Mix and label 1 µg/mL.
6. The four additional dilutions should be prepared in the same manner.

(2) Diagnosis
Since the level of insect venom specific IgE may fall to low levels briefly after a reaction to a sting, patients should not be tested until 2 to 4 weeks after any sting. Skin testing should be carried out with all five individual venoms, since many patients have multiple sensitivities.(4) Mixed Vespid venom protein should be used only for therapy — not for diagnosis.
Prick testing should be done before intradermal testing to determine appropriate concentration for intradermal testing. See Intradermal Tests. Skin testing (prick and intradermal) provides information to assist in identifying those patients who are to be classified as extremely sensitive and who may not tolerate the Suggested Dose Schedule. See DOSAGE AND ADMINISTRATION, Immunotherapy CAUTION.
In both the prick and intradermal tests, a negative control test with diluent alone must be performed. A histamine positive control test is also recommended.
The flexor surface of the forearm is the usual location for skin testing. It is important that a separate sterile syringe and needle be used for each extract and each patient.
Prick Tests: Prick tests are accomplished by applying one drop of the 1 µg/mL venom extract to the forearm, and by pricking the skin through the surface of the drop with a sterile 27 gauge needle. The prick is superficial and should not draw blood.
Skin response should be assessed after approximately 15-20 minutes.
For prick tests, a positive reaction (reaction greater than diluent control) at the 1 µg/mL concentration indicates a high level of sensitivity to the test venom.
Intradermal Tests: Patients showing a positive reaction to the prick test at the 1 µg/mL concentration should begin intradermal tests at concentrations of not more than 0.0001 to 0.001 µg/mL. Patients with negative prick tests may begin intradermal tests at a concentration of 0.001 µg/mL.
A 1 mL tuberculin syringe with a short 27-gauge needle should be used to deliver a volume of 0.05 mL for intradermal testing. Introduce the needle into the superficial skin layers, bevel down, until the bevel is completely buried, then slowly inject a 0.05 mL aliquot of the venom dilution, making a small bleb.
Start intradermal tests with the most dilute solution. If after 20 minutes no skin reaction is obtained, continue the intradermal testing using ten-fold increments in the concentration until a reaction of 5-10 mm wheal and 11-20 mm erythema is obtained, or until a concentration of 1 µg/mL has been tested, whichever occurs first.
A patient should be considered sensitive to the test venom when a skin response of 5-10 mm wheal and 11-20 mm erythema (or greater) occurs at a concentration of 1 µg/mL or less,(8)providing that this reaction is greater than that of the diluent control.
(3) Immunotherapy
For proper method and route of injection, see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.
The most common site of injection is the lateral aspect of the upper arm.
Patients who have multiple venom sensitivities should be given each specific venom injection in a separate site. (Except, if the patient has sensitivities to Yellow Jacket, Yellow Hornet, and White-Faced Hornet venoms concurrently, s/he can be injected with Mixed Vespid venom protein, an equal mixture of these three vespid venoms). Note which venom preparation is injected at a specific site, so that dosage of that venom preparation can be adjusted if an excessive local reaction occurs. In patients receiving more than one venom, there is theoretically a greater risk of systemic reactions.
CAUTION: Sensitivity to venom differs from patient to patient. Thus, it is not possible to provide a dosage schedule suitable for all patients. The Suggested Dose Schedule shown below was used in
clinical trials(4)and should be suitable for a majority of patients.
IN EXTREMELY SENSITIVE PATIENTS, however, an individualized dose schedule must be employed which will be dictated by the patient’s sensitivity. This individualized schedule will probably include weaker dilutions and smaller increments between doses in progressing to the maintenance level (100 µg per venom). In identifying those patients to be classified as extremely sensitive, individuals reacting with significant skin test (wheal greater than 5 mm and erythema greater than 20 mm) at intradermal skin test concentrations of 0.01 µg/mL or less, or those patients experiencing a systemic reaction to any venom skin test concentration, should be considered highly sensitive.

Suggested Dose Schedule for a Single Venom:

Dose No. *Volume of 1 µg/mL Dose No. Volume of 10 µg/mL Dose No. Volume of 100 µg/mL
1….. …0.05 mL 5….. …0.05 mL 9….. …0.05mL
2….. …0.10 mL 6….. …0.10 mL 10…. …0.10mL
3….. …0.20 mL 7….. …0.20 mL 11…. …0.20mL
4….. …0.40 mL 8….. …0.40 mL 12…. …0.40mL
13…. …0.60mL
14…. …0.80mL
15…. …1.00mL

Mixed Vespid Venom will contain three times the venom protein per mL shown in this table.
*See preceding CAUTION Section.

ALTERNATE MAINTENANCE DOSE SCHEDULE

If the above suggested dosage schedule has been followed, Dose #15 will have emptied the third vial of venom. There should now be three vials of freeze-dried venom remaining in the maintenance set. If a smaller volume maintenance dose is desired, then the remaining vials of venom may be reconstituted with 0.6 mL of Sterile Albumin Saline with Phenol (0.4%) instead of the previously recommended 1.2 mL. When 0.6 mL is used for reconstitution, the maintenance dose volume then becomes 0.5 mL instead of 1.0 mL. The 0.5 mL injection will still contain 100 micrograms of venom or venom protein.
Precautions should be taken to ensure that maintenance level injections of 0.5 mL are given only from those vials of venom that have been reconstituted with 0.6 mL of diluting fluid. Any other volume used for reconstitution will not give 100 micrograms of venom or venom protein at a dosage of 0.5 mL In proceeding with the Suggested Dose Schedule, or modified schedules (for highly sensitive patients) it is recommended that injections be given at least once per week, as in the clinical studies. (See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). When building the dose, it is important that dose intervals not exceed one week since longer intervals may decrease the patient’s tolerance of the extract.
Based on the clinical studies (4)it is suggested that if a systemic, extremely large local (10 cm or more in duration, or other severe local symptoms), or persistent and severe delayed local reaction occurs during the dose building phase, the dose at the next visit be held constant (or reduced, depending on judgment of the severity of the reaction) as was done at Study Center “A,” which reported the least number of systemic reactions during the course of therapy.
It must be considered important to achieve the 100 µg per venom maintenance dose (the maintenance dose for Mixed Vespid venom protein is 300 µg), since there are no data on effectiveness of maintenance levels below 100 µg per venom. Following the achievement of maintenance level (100 µg per venom), it is recommended that a second maintenance injection be given at a 1-week interval, and a third maintenance injection at a 2-week interval. Administer the next injection at a 3-week interval, and then monthly for ongoing maintenance.
See CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE for further information regarding clinical studies on which the above recommendations are based.
The optimum duration for immunotherapy is not known, so current recommendations are that maintenance injections be continued indefinitely, year around, particularly in patients experiencing life-threatening anaphylaxis after insect stings.

PEDIATRIC USE

The dose for the pediatric population is the same as for adults. (See PRECAUTIONS).

GERIATRIC USE

The dose for elderly patients is the same as for adult patients under 65.(23) (See PRECAUTIONS).

HOW SUPPLIED

Jubilant HollisterStier LLC sterile freeze-dried Hymenoptera Venom Products are supplied in vacuum-sealed vials containing venom extract and excipients: mannitol (for Vespid Venom Protein), and mannitol and sodium chloride (for Honey Bee Venom). (See the chart under DESCRIPTION or the latest Allergy Product Price List for vial sizes and content). Reconstituting fluid [Sterile Albumin Saline with Phenol (0.4%)] is supplied with the Venomil® kits, and is also available separately. (Note: Diagnostic kits also contain Sterile Empty Vials.)

Storage:
Store freeze-dried and reconstituted venom product, and venom dilutions, at 2° — 8° C, and keep at this temperature range during office use.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use.
No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company’s headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Lockey, Richard F., Linda M. Benedict, Paul C. Turkeltaub, Samuel C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79 (4): 660-677, 1987.
2. Jacobs, Robert L., Goeffrey W. Rake, Jr., et. al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol. 68 (2): 125-127, August 1981.
3. Hunt, K. J., M. D. Valentine, A. K. Sobotka, A. W. Benton, F. J. Amodio, L. M. Lichtenstein. A controlled trial of immunotherapy in insect hypersensitivity. New Eng. J. Med. 299: 157-161, July 27, 1978.
4. Summary of data from BB-IND 1292 clinical studies, 1978-79, on Hollister-Stier products.
5. Amodio, F., L. Markley, M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Maintenance immunotherapy for Hymenoptera sensitivity. J. Allergy Clin. Immunol. 61 (3): 134, 1978.
6. Reisman, R. E., Allergy Principles and Practice. E. Middleton, C. E. Reed, E. F. Ellis, ed. C. V. Mosby Co., 1978.
7. Sobotka, A. K., N. F. Adkinson, Jr., M. D. Valentine, L. M. Lichtenstein. Allergy to insect stings. IV. Diagnosis by R.A.S.T. J. Immunol. 121 (6): 2477-2484, 1978.
8. Hunt, K. J., M. D. Valentine, A. K. Sobotka, L. M. Lichtenstein. Diagnosis of allergy to stinging insects by skin testing with Hymenoptera venoms. Annals Int. Med. 85: 56-59, 1976.
9. Annals of Allergy, Asthma and Immunology. Inhibitors of angiotensin II: Potential hazards for patients at risk for anaphylaxis. Editorial. 78: 527-529, June 1997.
10. Pharm. Ind. (Germany). Anaphylactoid reactions in patients treated with ACE inhibitor treatment in combination with desensitization treatment or after insect bites. 56 (9): IX226-227, 1994.
11. Tunon-De-Lara, J. M., et al. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. The Lancet (United Kingdom). 340 (8824): 908, Oct. 10, 1992.
12. Weinstien, A. M., B. D. Dubin, W. K. Podleski, S. L. Spector, R. S. Farr. Asthma and pregnancy. JAMA. 124 (11): 1161-1165, 1979.
13. Reid, M. J., R. F. Lockey, P. C. Turkletaub, T. A. E. Platts-Mills. Survey of fatalities from skin testing and immunotherapy. J. Allergy Clin. Immunol. 92 (1): 6-15, July 1993.
14. Reid, M. J., G. Gurka. Deaths associated with skin testing and immunotherapy. J. Allergy Clin. Immunol. 97 (1) Part 3:231, Abstract 195, January 1996.
15. Thompson, R. A. et al. Report of a WHO/IUIS working group. The current status of allergen immunotherapy (hyposensitization). Allergy. 44: 369-379, 1989.
16. Malling, H.J., B. Weeke, et al. The European Academy of Allergology and Clinical Immunology. Position Papers. Allergy. 48 (Supplement 14): 9-82, 1993.
17. Pipkorn, Ulf. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86, 1988.
18. Andersson, M. U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.
19. Rao, Kamineni S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.
20. Pipkorn, Ulf, M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clinical Allergy. 17: 307-311, 1987.
21. DuBuske, L. M., C. J. Ling, A. L. Sheffer. Special problems regarding allergy immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12 (1): 145-175, 1992.
22. Graft, D., K. Schuberth, A. Kagey-Sobotka, K. Kwiterovich, Y. Niv, L. Lichtenstein, M. Valentine. Assessment of prolonged venom immunotherapy in children. J. Allergy Clin. Immunol. 80 (2): 162-169, August 1987. 23. Peebles, Ray Stokes, Jr., B. Bochner, Howard J. Zeitz, ed. Anaphylaxis in the elderly. Immunol. Allergy Clin. of North Am. 13 (3): 627-646, August 1993.

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