Standardized Bermuda Grass Pollen

Antigen Laboratories, Inc.

ALLERGENIC EXTRACT

FULL PRESCRIBING INFORMATION

DESCRIPTION
    Antigen Laboratories' Standardized Grass Pollen allergenic extracts are sterile and intended for dilution prior to skin testing and/or immunotherapy. The route of administration for immunotherapy is subcutaneous. The routes of administration for diagnostic purposes are intradermal or prick-puncture of the skin. Standardized Grass Pollen allergenic extract labeled in BAU/ml is not interchangeable with grass pollen extract labeled in AU/ml or with non-standardized grass pollen extract.
    Potency of Standardized Grass Pollen allergenic extract is determined by comparison to a Center for Biologics Evaluation and Research (CBER) approved reference. References are available for pollen extracts of Orchard Grass (Dactylis glomerata), Perennial Rye Grass (Lolium perenne), Timothy Grass (Phleum pratense), Redtop Grass (Agrostis alba), Kentucky (June) Bluegrass (Poa pratensis), Bermuda Grass (Cynodon dactylon), Meadow Fescue Grass (Festuca elatior), and Sweet Vernal Grass (Anthoxanthum odoratum). Quantitative skin testing is used by CBER to establish reference's potency as Bioequivalent Allergy Units (BAU). CBER reference labeled 10,000 BAU/ml produces a sum of erythema diameter of 50 mm with highly puncture reactive subjects at an intradermal dilution of approximately 1:500,000.^11,17 CBER references labeled 100,000 BAU/ml produce a SumE=50 mm at an intradermal dilution of 1:5,000,000. Relative potency of Standardized Grass Pollen allergenic extracts to CBER reference is determined by Enzyme-linked Immunosorbent Assay (ELISA).

    In addition to relative potency testing of Standardized Grass Pollen extract the following testing is performed:
    1. Microscopic examination to confirm identity and purity of source pollens.
    2. lsoelectric focusing (IEF) pattern of source material is compared to respective CBER
reference extract.
    3. lsoelectric focusing pattern of final 100,000 BAU/ml (10,000 BAU/ml Bermuda Grass) product is compared to CBER reference extract.
    4. Ninhydrin Protein Analysis.
    5. Glycerine Analysis. (A minimum of 50% v/v glycerine for optimal stability during the entire
dating period.)
    6. Sterility Testing.
    7. Animal Safety Testing.
    Standardized Grass Pollen allergenic extracts are extracted at 1:10 weight to volume (w/v) ratio of source material to extraction fluid. Bermuda Grass is only available in 10,000 BAU/ml. Standardized Grass Pollen extracts are diluted after extraction to fall in acceptable relative potency range for a 100,000 BAU/ml or 10,000 BAU/ml (Bermuda Grass) product. Standardized Grass Pollen allergenic extracts (except Bermuda) of 10,000 BAU/ml potency are prepared by diluting the 100,000 BAU/ml extract 1:10 with extracting fluid.
    Various mixtures of eight Standardized Grass Pollen extracts are available. Mixtures of Standardized Grass Pollen extracts with non-standardized grass pollen extracts are available. Concentrations of Standardized Grass Pollen extracts (BAU/ml) and non-standardized grass pollen extracts (w/v) in a mixture are printed on the last page of this circular, if applicable.
    Active Ingredients: Allergens are described by common and scientific name on container label or last page of this circular. Preservative is 50% v/v glycerine. Inactive ingredients are 0.95% sodium chloride, 0.24% sodium bicarbonate and water for injection.

CLINICAL PHARMACOLOGY
    Studies indicate allergic individuals produce immunoglobulins of the IgE class in response to exposure to grass pollens. Subsequent exposure to grass pollen results in a combination of allergen with IgE antibody fixed on mast cells or basophil membranes. This cross-linking results in stimulation of mast cell which leads to release and generation of pharmacologically active substances that produce immediate hypersensitivity reaction.¹⁵
    The mode of action of immunotherapy with allergenic extracts is still being investigated. Subcutaneous injections of increasing doses of allergenic extract into patients with allergic disease have been shown to result in both humoral and cellular changes. These include production of allergen specific IgG antibodies, suppression of histamine release from target cells, decrease in circulating levels of antigen specific IgE antibody over long periods of time and suppression of peripheral blood T-Iymphocyte cell responses to antigen. ^5,9,10
    Puncture and intradermal data from skin testing with CBER grass reference is summarized in Table 1. Fifteen patients with clinical symptoms when exposed to grass pollen were included in the study. The mean sum erythema (PSumE) and mean sum wheal (PSumW) from puncture testing is listed in Table 1A. The Intradermal Dilution for 50 mm Sum of Erythema determines Bioequivalent ALlergy Units (ID₅₀EAL) method was used by CBER personnel to calculate intradermal dose (BAU/ml). The calculated mean and ranges of intradermal dose (BAU/ml) for 50 mm sum of erythema using reference extract is summarized in Table 1B. ¹⁷

    B. Calculated Intradermal Dose (BAU50) of CBER Grass Reference for 50mm Sum of Erythema.

    Relative potency value of various lots of non-standardized grass pollen extracts are summarized in Table 2. The acceptable BAU/ml ranges for equivalency to FDA reference for a 100,000 BAU/ml product are 69,900-143,100 at n=3, 73,300-136,400 at n=4 and 75,800-132,000 at n=5. Acceptable equivalency ranges for a 10,000 BAU/ml product are 6,990-14,310 at n=3, 7,330-13,640 at n=4 and 7,580-13,200 at n=5 (n=number of tests performed).

Uses

INDICATIONS AND USAGE
    Allergenic extract is indicated for diagnostic testing and treatment (immunotherapy) of patients whose histories indicate allergic symptoms upon natural exposure to grass allergens. Confirmation is determined by skin testing. 10,000 BAU/ml extracts are intended for percutaneous testing. If negative, 100,000 BAU/ml products can be used for percutaneous test. Dilutions made from 10,000 BAU/ml products are indicated for immunotherapy of previously untreated patients. If 10,000 BAU/ml product is tolerated and symptoms persist, dilutions made from 100,000 BAU/ml can be administered. Standardized Grass Pollen extracts labeled in Bioequivalent Allergy Units (BAU/ml) are not interchangeable with grass pollen extracts labeled In Allergy Units (AU/ml) or with non-standardized grass pollen extracts.

CONTRAINDICATIONS
    Do not administer in the presence of diseases characterized by bleeding diathesis. Individuals with autoimmune disease may be at risk of exacerbating symptoms of underlying disease, possibly due to routine immunization. Recent myocardial infarction patients may not tolerate immunotherapy. Children with nephrotic syndrome probably should not receive injections due to a possibility of immunization causing exacerbation of their nephrotic disease.
    Standardized Grass Pollen extract is not intended for the treatment of patients who do not experience allergic symptoms upon natural exposure to the allergen.
    Allergenic extracts are not intended for diagnosing patients who do not manifest immediate hypersensitivity reactions to the allergenic extract when skin tested.

WARNINGS
    Refer to boxed "WARNINGS", "PRECAUTIONS", "ADVERSE REACTIONS" and "OVERDOSAGE" sections for additional information on serious adverse reactions and steps to be taken, if any occur.
    Extreme caution is necessary when using diagnostic skin tests or injection treatment in highly sensitive patients who have experienced severe symptoms or anaphylaxis by natural exposure, or during previous skin testing or treatment. IN THESE CASES THE POTENCY FOR SKIN TESTS AND THE ESCALATION OF THE TREATMENT DOSE MUST BE ADJUSTED TO THE PATIENTS SENSITIVITY AND TOLERANCE.
    Benefit versus risk needs to be evaluated in steroid dependent asthmatics, patients with unstable asthma or patients with underlying cardiovascular disease.
    Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe allows deep subcutaneous injection. Withdraw plunger slightly after inserting needle to determine if a blood vessel has been entered.
    Proper measurement of dose and caution in making injection will minimize reactions.
Adverse reactions to allergenic extracts are usually apparent within 20-30 minutes following injection of immunotherapy.
    Extract should be temporarily withheld or dosage reduced in case of any of the following conditions: 1) flu or other infection with fever; 2) exposure to excessive amounts of allergen prior to injection; 3) rhinitis and/or asthma exhibiting severe symptoms; 4) adverse reaction to previous injection until cause of reaction has been evaluated by physician supervising patient's immunotherapy program.

PRECAUTIONS

General:
    Immunotherapy must be given under physician's supervision. Sterile solutions, vials, syringes, etc. must be used. Aseptic technique must be observed in making dilutions from stock concentrates. The usual precautions in administering allergenic extracts are necessary, refer to boxed WARNINGS and "WARNINGS" section. Sterile syringe and needle must be used for each individual patient to prevent transmission of serum hepatitis, Human Immunodeficiency Virus (HIV) and other infectious agents.
    Epinephrine 1:1000 should be available. Refer to "OVERDOSAGE" section for description of treatment for anaphylactic reactions.

Information for Patients:
    Patient should remain under observation of a nurse, physician, or personnel trained in emergency measures for at least 20 minutes following immunotherapy injection. Patient must be instructed to report any adverse reactions that occur within 24 hours after injection. Possible adverse reactions include unusual swelling and/or tenderness at injection site, rhinorrhea, sneezing, coughing, wheezing, shortness of breath, nausea, dizziness, or faintness. Immediate medical attention must be sought for reactions that occur during or after leaving physician's office.

Pregnancy Category C:
    Animal reproduction studies have not been conducted with allergenic extracts. It is not known whether allergenic extracts cause fetal harm during pregnancy or affect reproductive capacity. A systemic reaction to allergenic extracts could cause uterine contractions leading to spontaneous abortion or premature labor. Allergenic extracts should be used during pregnancy only if potential benefit justifies potential risk to fetus.⁶

Nursing Mothers:
    It is not known whether allergenic extracts are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

Pediatric Use:
    Allergenic extracts have been used routinely in children and no special problems of safety or specific hazard have been found. Children can receive the same dose as adults. Discomfort is minimized by dividing the dose in half and administering injection at two different sites. ^13,14

Carcinogenicity, Mutagenicity, Impairment of Fertility:
    Long term animal studies have not been conducted with Standardized Grass Pollen allergenic extracts to evaluate carcinogenicity, mutagenicity or fertility impairment.

Drug Interactions:
    Antihistamines. Antihistamines inhibit the wheal and flare reaction. The inhibitory effect of conventional antihistamines varies from 1 day up to 10 days, according to the drug and patient's sensitivity. Long acting antihistamines (e.g., astemizole) may inhibit the wheal and flare for up to forty days.
    Imipramines. phenothiazines, and tranquilizers. Tricyclic antidepressants exert a potent and sustained decrease of skin reactions to histamine. This effect may last for a few weeks. Tranquilizers and antiemetic agents of the phenothiazine class have H, antihistaminic activity and can block skin tests.¹
    Corticosteroids. Short-term (less than 1 week) administration of corticosteroids at the therapeutic doses used in asthmatic patients does not modify the cutaneous reactivity to histamine, compound 48/80, or allergen. Long-term corticosteroid therapy modifies the skin texture and makes the interpretation of immediate skin tests more difficult.¹
    Theophylline. It appears that theophylline need not be stopped prior to skin testing.¹  
    Beta-blockers. PATIENTS RECEIVING BETA-BLOCKERS MAY NOT BE RESPONSIVE TO EPINEPHRINE OR INHALED BRONCHODILATORS. The following are commonly prescribed BETA-BLOCKERS: Levatol, Lopressor, Propanolol Intersol, Propanolol HCL, Blocadren, Propanolol, Inderal-LA, Visken, Corgard, Ipran, Tenormin, Timoptic. Ophthalmic beta-blockers: Betaxolol, Levobunolol, Timolol, Timoptic. Chemicals that are beta-blockers and may be components of other drugs: Acebutolol, Atenolol, Esmolol, Metoprolol, Nadolol, Penbutolol, Pindolol, Propanolol, Timolol, Labetalol, Carteolol.
    Beta-adrenergic agents. Inhaled beta₂ agonists in the usual doses used for the treatment of asthma do not usually inhibit allergen-induced skin tests. However, oral terbutaline and parenteral ephedrine were shown to decrease the allergen-induced wheal.
    Cromolyn. Cromolyn inhaled or injected prior to skin tests with allergens or degranulating agents does not alter the skin whealing response.¹
    Other drugs. Other drugs have been shown to decrease skin test reactivity. Among them, dopamine is the best-documented compound.¹
    Specific immunotherapy. A decreased skin test reactivity has been noticed by many authors for patients undergoing specific immunotherapy with pollen extracts, grass pollen allergoids, mite, or hymenoptera venoms, or in professional beekeepers who are spontaneously desensitized. Finally, it was shown that specific immunotherapy in patients treated with ragweed pollen extract induced a decreased late-phase reaction.¹

ADVERSE REACTIONS
    Adverse reactions include, but are not limited to urticaria; itching; edema of extremities; respiratory wheezing or asthma; dyspnea; cyanosis; tachycardia; lacrimation; marked perspiration; flushing of face, neck or upper chest; mild persistent clearing of throat; hacking cough or persistent sneezing.

1) Local Reactions
    A mild burning immediately after injection is expected; this usually subsides in 10-20 seconds. Prolonged pain or pain radiating up arm is usually the result of intramuscular injection, making this injection route undesirable. Subcutaneous injection is the recommended route.
    Small amounts of erythema and swelling at the site of injection are common.
Reactions should not be considered significant unless they persist for at least 24 hours or exceed 50 mm in diameter.
    Larger local reactions are not only uncomfortable, but indicate the possibility of a severe systemic reaction if dosage is increased. In such cases dosage should be reduced to the last level not causing reaction and maintained for two or three treatments before cautiously increasing.
    Large, persistent local reactions or minor exacerbations of the patient's allergic symptoms may be treated by local cold applications and/or use of oral antihistamines.

2) Systemic Reactions
    Systemic reactions range from mild exaggeration of patient's allergic symptoms to anaphylactic reactions.¹² Very sensitive patients may show a rapid response. It cannot be overemphasized that, under certain unpredictable combinations of circumstances, anaphylactic shock is always a possibility. Fatalities are rare but can occur.¹⁶ Other possible systemic reaction symptoms are fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis, and urticaria.^8,9
    Careful attention to dosage and administration limit such reactions. 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 prepare for treatment of severe reactions. Refer to "OVERDOSAGE" section.

OVERDOSAGE
    Refer to "WARNINGS", "PRECAUTIONS", and "ADVERSE REACTIONS" sections for signs and symptoms of overdose.
    If a systemic or anaphylactic reaction does occur, apply tourniquet above the site of allergenic extract injection and inject intramuscularly or subcutaneously 0.3 to 0.5 ml of 1:1000 Epinephrine-hydrochloride into the opposite arm or gluteal area. Repeat dose in 5-10 minutes if necessary. Loosen tourniquet briefly at 5 minute intervals to prevent circulatory impairment. Discontinue use of the tourniquet after  hour.
    The epinephrine HCL 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml; for children 2 to 6 years it is 0.15 ml; for children 6 to 12 years it is 0.2 ml.     Symptoms of progressive anaphylaxis include airway obstruction and/or vascular collapse. After administration of epinephrine, profound shock and vasomotor collapse should be treated with intravenous fluids and possibly vasoactive drugs. Monitor airways for obstruction. Oxygen should be given by mask if indicated.
    Antihistamines, H₂ antagonist, bronchodilators, steroids and theophylline may be used as indicated after giving adequate epinephrine and circulatory support.¹²
    Patients who have been taking a beta-blocker may be unresponsive to epinephrine or beta-adrenergic drugs (Alupent). These drugs should be administered even though a beta-blocker may have been taken. The following treatment will be effective whether or not patient is taking a beta-blocker: Aminophylline IV, slow push or drip, Atrovent (Ipratropium bromide) Inhaler, 3 inhalations repeated, Atropine, 0.4 mg/ml, 0.75 to 1.5 ml lM or IV, Solu-Cortef, 100-200 mg IM or IV, Solu-Medrol, 125 mg IM or IV, Glucagon, 0.5-1 mg IM or IV, Benadryl, 50 mg IM or IV, Cimetidine, 300 mg IM or IV, Oxygen via ambu bag.

DOSAGE AND ADMINISTRATION
    Refer to "STORAGE" section for proper storage condition for allergenic extract.
    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.
    Precaution is necessary when using grass pollen extract mixtures. Potency may be additive and may equal the total potency of the grass pollen extracts in the mixture. Careful attention to container label and/or package insert in regard to BAU/ml of grass pollen extracts from which mixture is derived is important.
    Physicians undertaking immunotherapy should be concerned with patient's degree of sensitivity. The initial dilution of allergenic extract, starting dose and progression of dosage must be carefully determined on the basis of the patient's history and results of skin tests. (SEE "INDICATIONS AND USAGE" section.) Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.
    PRICK-PUNCTURE TESTING: To identify grass sensitive individuals and as a safety precaution, it is recommended that a prick or puncture test be performed prior to initiating very dilute intradermal testing. Prick (puncture) testing is performed by placing a drop of extract on skin and puncturing skin through the drop with a prick-puncture device. The most satisfactory sites on the back for skin testing are from posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. It is recommended that 10,000 BAU/ml Standardized Grass Pollen extract be used for initial puncture testing because 100,000 BAU/ml extracts produce very large puncture reactions in highly reactive individuals.¹⁸ A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal.
    Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to allergen. Less sensitive individuals can be tested intradermally with appropriately diluted extract. (See Intradermal Testing.)
    A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

HOW SUPPLIED
    Standardized Grass Pollen allergenic extract concentration is expressed in BAU/ml. It is supplied in 100,000 BAU/ml and 10,000 BAU/ml in 10, 30 and 50 ml containers. Standardized Bermuda Grass is only available as 10,000 BAU/ml concentrate. Stock mixtures of Standardized Grass Pollens and mixtures of standardized and non-standardized grass pollens are available at various concentrations. Extracts in 5 ml dropper bottles are available for prick-puncture testing. To insure maximum potency for the entire dating period, all stock concentrates contain 50% v/v glycerine.

STORAGE
    Store all stock concentrates and dilutions at 2-8 degrees C. Keep at this temperature during office use. The expiration date of allergenic extracts is listed on the container label. Dilutions of allergenic extracts containing less than 50% v/v glycerine are less stable than those containing at least 50% v/v glycerine. If loss of potency is suspected, potency can be checked using side by side skin testing with freshly prepared dilutions of equal concentration on individuals with known sensitivity to the allergen.

REFERENCES
1.  Bousquet, Jean: "In vivo methods for study of allergy: Skin tests" Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. I, Chap. 19, pp 419-436, 1988.
2.  Matthews, K., et al; Rhinitis, Asthma and the Other Allergic Diseases, NIAID Task Force Report, U.S. Dept. HEW, NIH Publication No. 79-387, Chapter 4, pp. 213-217, May 1979.
3.  Ishizaka, K.: Control of IgE Synthesis, Third Edition, Allergy Principles and Practices, C.V. Mosby Co.,Vol. I, Chap. 4, p. 52, 1988.
4.  Nelson, H.S.: "The Effect of Preservatives and Dilution on the Deterioration of Russian Thistle (Salsola pestifer), a pollen extract." The Journal of Allergy and Clinical Immunology, Vol. 63, No.6, pp. 417-425, June 1979.
5.  Rocklin, R.E., Sheffer, A.L., Grainader, D.K. and Melmon, K.: "Generation of antigen-specific suppressor cells during allergy desensitization", New England Journal of Medicine, Vol. 302, pp. 1213-1219, May 29,1980.
6.  Seebohm, P.M., et al: Panel on Review of Allergenic Extracts, Final Report, Food and Drug Administration, pp. 9-48, March 13, 1981.
7.  Stevens, E.; Cutaneous Tests, Regulatory Control and Standardization of Allergenic Extracts, First International Paul Ehrlich Seminar, Frankfurt, Germany, pp. 133-138, May 20-22,1979.
8.  Van Metre, T., Adkinson, N., Amodio, F., Lichtenstein, L., Mardinay, M., Norman, P., Rosenberg, G., Sobotka, A., Valentine, M.: "A Comparative Study of the Effectiveness of the Rinkel Method and the Current Standard Method of Immunology for Ragweed Pollen Hay Fever," The Journal of Clinical Allergy and Immunology, Vol. 66, No. 6, p. 511, December 1980.
9.  Wasserman, S.: The Mast Cell and the Inflammatory Response. The Mast Cell its role in health and disease. Proceedings of an International Symposium, Davos, Switzerland, Pitman Medical Publishing Co., pp. 9-20, 1979.
10.  Perelmutter, L.: IgE Regulation During Immunotherapy of Allergic Diseases. Annals of Allergy, Vol. 57, August 1986.
11.  Baer, H., Anderson, M.C., Turkeltaub, P.C.: Allergenic Extracts, Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. I, Chap. 17, 1988.
12.  Wasserman, S., Marquart, D.: Anaphylaxis, Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. 1, Chap. 58, pp. 1365-1376, 1988.
13.  Bullock, J., Frick, O.: Mite Sensitivity in House Dust Allergic Children, Am. J. Dis. Child., pp.123-222, 1972.
14.  Willoughby, J.W.: Inhalant Allergy Immunotherapy with Standardized and Nonstandardized Allergenic Extracts, American Academy of Otolaryngology-Head and Neck Surgery: Instructional Courses, C.V. Mosby Co., Vol. 1, Chapter 15, September 1988.
15.  Holgate, S.T., Robinson, C., Church, Mike: Mediators of Immediate Hypersensitivity, Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. I and II, pp 135-163, 1988.
16.  Reid, Michael J., Lockey, Richard F., Turkeltaub, Paul C., M.D., Platts-Mills, Thomas: "Survey of Fatalities from Skin Testing and Immunotherapy 1985-1989", Journal of Allergy and Clinical Immunology, Vol. 92, No.1, pp. 6-15, 1993.
17.  Turkeltaub, Paul C., M.D., Rastogi, Saresh, Ph.D.: Center for Biologics Research and Review. "Quantitative Intradermal Procedure for Evaluation of Subject Sensitivity of Standardized Allergenic Extracts and for Assignment of Bioequivalent Allergy Units to Reference Preparations Using the ID₅₀EAL Method (Intradermal Dilution for 50 mm Sum of Erythema Determines Bioequivalent ALlergy Units), Nov., 1994.
18.  Turkeltaub, Paul C., M.D.: "Standardized Extracts in Practice", Immunotherapy, A Practical Guide to Current Procedures, Sponsored by American Academy of Allergy and Immunology, 1994.