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ADVERSE REACTIONS LOCAL REACTIONS Large, persistent local reactions or minor exacerbations of the patient's allergic symptoms may be treated by local cold applications and/or the use of oral anti-histamines. SYSTEMIC REACTIONS Allergenic extracts are highly potent and in highly sensitive individuals can cause systemic symptoms, including anaphylaxis. It cannot be overemphasized that anaphylactic shock is always a possibility under certain unpredictable combinations of circumstances. Other possible systemic reaction symptoms may include fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis and urticaria. Therefore, it is imperative that physicians administering skin tests understand and be prepared to treat severe allergic reactions. If a systemic or anaphylactic reaction occurs during or following skin testing, the patient should be treated with 1:1000 epinephrine hydrochloride. The recommended dose: infants to 2 years of age 0.05 to 0.1 mL, children 2 to 6 years, 0.15 mL, children 6 to 12 years, 0.2 mL, adults 0.3 - 0.5 mL. If necessary, treatment may be repeated up to three times every 10 - 15 minutes. After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids and possibly vasoactive drugs. Oxygen should be given by mask. Intravenous antihistamine, aminophylline, inhaled bronchodilators or adrenal corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given. Emergency resuscitation measures and personnel trained in their use should be available immediately. The physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment is of utmost importance 14 . Serious adverse reactions should be reported to MedWatch: The FDA Safety Information and Adverse Event Reporting Program, Office Of The Center Director, Center for Drug Evaluation and Research, 5515 Security Lane, Suite 5100, Rockville, MD 20852, Telephone (800) 332-1088.

WARNINGS This product is intended for use by physicians who are experienced in the administration of allergenic extracts or for use under the guidance of an allergy specialist. Skin tests should be performed after the patient's physical well being and allergic history have been evaluated. Patients should be instructed to recognize adverse reaction symptoms and cautioned to contact the physician if symptoms occur. As with all allergenic extracts, severe systemic reactions may occur, and in certain individuals these reactions may cause death. Patients should be observed for at least 20 minutes after skin tests have been completed. Emergency measures as well as personnel trained in their use should be immediately available in the event of a life threatening reaction. This product should never be injected intravenously (see DOSAGE AND ADMINISTRATION). Also, see WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and OVERDOSE Sections below.

CLINICAL PHARMACOLOGY In sensitive persons, allergenic extract elicits immediate-type skin reactions consisting of erythema and edema at the test site. This allergic inflammatory response is thought to begin with the reaction of allergen with immunoglobulin E (IgE) on the surface of the mast cell. This antigen-antibody reaction initiates a series of biochemical events that result in the release of histamine and other mediators from the mast cell. These mediators are responsible for the characteristic wheal and flare response associated with a positive skin test. The initial antigen-antibody reaction appears to be a specific response that is dependent upon the presence of allergen-specific IgE attached to the mast cell 2,3 . Delayed-type reactions occur in some individuals following the intradermal administration of Trichophyton extract. This response is due to the presence of sensitized lymphocytes. The reaction is characterized by erythema and induration that peaks between 24 and 48 hours after skin testing 4 .

CONTRAINDICATIONS Conditions under which the administration of allergenic extract may be contraindicated, depending upon individual circumstances, include: EXTREME SENSITIVITY TO AN ALLERGEN - Determined from the allergic history, or from previous anaphylaxis following skin testing or subcutaneous injection; MYOCARDIAL INFARCTION - Patients who have experienced a recent myocardial infarction may be less able to tolerate the life-threatening effects of a serious adverse reaction. ASTHMA - Patients with highly unstable asthma are at greater risk of fatal reactions from skin tests than are patients without asthma, especially during seasonal exacerbations of the disease. Also, the combination of unstable asthma and treatment with B-adrenergic blockers appears to increase this risk 5 . Allergenic extract should be temporarily withheld from patients if any of the following conditions exist: 1) severe symptoms of hay fever and/or asthma; 2) infection or flu accompanied by fever; and 3) exposure to excessive amounts of clinically relevant allergen(s) prior to skin testing.

DESCRIPTION Trichophyton extract for diagnostic skin testing is a sterile solution that is prepared by extracting allergenic source material of equal parts of Trichophyton mentagrophytes and Trichophyton rubrum with an aqueous solution of 0.25% sodium chloride, 0.125% sodium bicarbonate and 50% glycerol v/v. Phenol is added at 0.4% w/v as a preservative. Extract for intradermal administration is diluted with the above solution without glycerol. WEIGHT BY VOLUME (W/V) Weight by volume refers to the weight of raw product added to a measured volume of extraction solution. A 1:500 w/v extract contains 1 gram of source material in 500 mL of solution. The w/v designation refers to concentration rather than potency. Extract labeled w/v has no U.S. Standard of Potency.

DOSAGE AND ADMINISTRATION Prior to administering skin tests, the skin should be cleaned with alcohol and allowed to dry completely. The tests should be placed on the volar surface of the forearm and four rows may be placed on the back. INTRADERMAL TEST The intradermal test is performed by administering 0.1 mL of extract into the skin. The injection should be given as superficially as possible creating a distinct bleb approximately 5 mm in diameter. The tests should be examined after 15 - 20 minutes and read as negative or positive. Test sites that show a wheal and flare response should be measured and reported in mm of edema and erythema or scored as 1+ to 4+ based on a mm reference scale. Induration after 24 - 48 hours can occur in some individuals and also may be recorded in mm.

HOW SUPPLIED One mL of extract for intradermal skin testing is supplied in 2 mL sealed multidose vials. Each vial contains enough extract for 10 tests.

INDICATIONS AND USAGE Intradermal skin tests with Trichophyton extract are indicated for use in persons who are suspected of having Type I hypersensitivity (i.e. allergy) to the fungus.

OVERDOSAGE The signs and symptoms of overdosage are the same as those listed under ADVERSE REACTIONS, paragraphs 1 and 2. The treatment of a systemic allergic reaction resulting from skin tests should include the following: The patient should be placed in the recumbent position to maintain blood flow to the head. Aqueous epinephrine 1:1,000 should be administered subcutaneously. See ADVERSE REACTIONS for dose and other supportive measures. Reassurance should be provided. The above steps should be performed nearly simultaneously and as soon as possible after the reaction begins. Persistent wheezing may necessitate treatment with intravenous aminophylline and inhaled bronchodilators. For profound shock and hypotension, intravenous fluids, vasopressors and oxygen also may be needed. Maintenance of an open airway is critical if upper airway obstruction is present. Corticosteroids may provide benefit if symptoms are prolonged or recurrent.

PRECAUTIONS GENERAL It is recommended that the device used to perform skin tests be disposable to prevent the possibility of accidental transfer of serum hepatitis, HIV and other infectious agents from one person to another. Injectable epinephrine should be available when skin tests are administered (see ADVERSE REACTIONS). PATIENT INFORMATION Skin tests with allergenic extracts are usually safe and effective in the diagnosis of allergic diseases when used properly and when interpreted in conjunction with the allergic history and clinical findings. Patients should be observed in the office for 20 minutes after skin tests have been completed 9 and instructed to return to the office or emergency room if symptoms of an allergic reaction or shock occur. The risk of a serious adverse reaction is always present. However, it is minimized by the use of the prick-puncture procedure as the initial method of testing. In a study of 16,204 persons in the United States between 6 and 74 years of age, no anaphylactic reactions were observed after prick-puncture skin testing with eight different allergenic extracts. The authors concluded that the risk of adverse reactions to prick-puncture skin tests is low and similar to other routine medical procedures, such as venipuncture 10 . Since drugs may affect the reactivity of the skin, patients should be instructed to avoid medications, particularly antihistamines and sympathomimetic drugs prior to skin testing (see DRUG INTERACTION below). DRUG INTERACTION Treatment with beta-blocking drugs may make patients refractory to the usual dose of epinephrine, in the event epinephrine is required to control an adverse reaction 11 . Since drugs may affect the reactivity of the skin, patients should be instructed to avoid medications, particularly antihistamines and sympathomimetic drugs for at least 24 hours prior to skin testing. Non-sedating antihistamine suppresses the erythema/edema response for longer periods and should be withheld according to information included in the package insert. Adrenal corticosteroids and ACTH do not alter the immediate hypersensitivity reaction of the skin but do reduce delayed-type reactions associated with cellular hypersensitivity. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity or impairment of fertility. PREGNANCY CATEGORY C Allergenic Extracts. 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. Since studies indicate no increased risk to the fetus or to the mother who is treated cautiously with immunotherapy during a normal pregnancy, it is unlikely that extract administered by skin test will be harmful. However, on the basis of histamine's known ability to contract uterine muscle, extensive testing with its possibility of histamine release should be avoided during pregnancy. Also, immunologic suppressive action can occur during pregnancy and for this reason it is possible that the results of allergy skin tests may not accurately reflect the allergic state of the pregnant patient 12 . NURSING MOTHERS It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when allergenic extract is administered to a nursing woman. PEDIATRIC USE The procedures and precautions that are observed in skin testing adults should be observed with children 13 .

REFERENCES Turkeltaub, P.C., The allergy unit - clinical relevance: Issues in allergen standardization, In: Lockey, R.F., S.C. Bukantz (Eds), Allergen Immunotherapy, Marcel Dekkar, New York, 171, 1991. Ting, S., E.H. Dunsky, R.M. Lavker, et al., Patterns of mast cell alterations and in vivo mediator release in human allergic skin reactions, J. Allergy Clin. Immunol., 66:417, 1980. Zweiman, B., Mediators of allergic inflammation in the skin, Clin. Allergy, 18:419, 1988. Askenase, Philip W., Effector and regulatory mechanisms in delayed-type hypersensitivity, Allergy Principles and Practice, vol.1, p. 264, third edition, C.V. Mosby, St. Louis, 1988. Lockey, R.F., L.M. Benedict, P.C. Turkeltaub, S.C. Buicantz, Fatalities from immunotherapy (IT) and skin testing (ST), J. Allergy and Clinical Immunol., 79:660, 1987. Nelson, H.S., Diagnostic procedures in allergy: I. Allergy skin testing, Ann. Allergy, 51: 411, 1983. Bierman, C.W., D.S. Pearlman, G.G. Shapiro, W.W. Busse (Eds), Allergic disease from infancy to adulthood, Third edition, W.B. Saunders Co., Philadelphia, 1996. Middleton, E., Jr., C.E. Reed, E.F. Ellis, N.F. Adkinson, J.W. Yunginger (Eds), Allergy principles and practice, Fourth edition, C.V. Mosby, St. Louis, 1993. Executive Committee, The American Academy of Allergy and Clinical Immunology, Position Statement, The waiting period after allergen skin testing and immunotherapy, J. Allergy Clin. Immunol., 85:526, 1990. Turkeltaub, P.C., P.J. Gergen, The risk of adverse reactions from percutaneous prick-puncture allergen skin testing, venipuncture and body measurements: data from the second National Health and Nutrition Examination Survey (NHANES II) 1976-1980, J. Allergy Clin. Immunol., 84:886, 1989. Jacobs, Robert L., Goeffrey W. Rake, Jr., et al., Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade, J. Allergy and Clinical Immunol., 68:125, 1981. Weinstein, A.M., D.B. Dubin, W. K. Podleski, L.L. Spector, R.S. Farr, Asthma and pregnancy, JAMA 134: 1161, 1979. Sly, M.R., Pediatric allergy, Medical Examination Publishing Co., Inc., Second edition, p.352, 1981. Executive Committee, The American Academy of Allergy and Clinical Immunology, Position Statement, Personnel and equipment to treat systemic reactions caused by immunotherapy with allergenic extracts. J. Allergy and Clinical Immunol., 77:271, 1986.

Trichophyton for Intradermal Skin Testing Trichophyton mentagrophytes and Trichophyton rubrum Trichophyton mentagrophytes Trichophyton mentagrophytes Trichophyton rubrum Trichophyton rubrum Sodium chloride Sodium bicarbonate Glycerin Phenol Water

STORAGE Extract should be stored at 2°C to 8°C, since higher temperatures may adversely affect the stability of allergens. Do not freeze.

WARNINGS Physicians who use allergenic extracts should have a knowledge and practical understanding of allergy skin testing as described in the published literature 6,7,8 . Allergenic extracts are manufactured to assure high potency and therefore have the ability to cause serious local and systemic reactions, including death in highly sensitive patients 5 . Patients should be informed of the risks of skin testing and instructed in the recognition of symptoms of an adverse allergic reaction (see PRECAUTIONS and ADVERSE REACTIONS below). Excessively large local reactions or systemic reactions are more likely to occur if the patient is skin tested shortly after exposure to allergens to which he or she is sensitive.