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CLINICAL PHARMACOLOGY Cellular or delayed-type hypersensitivity (DTH) can be assessed by intracutaneous testing with bacterial, viral and fungal antigens to which most healthy persons are sensitized. a positive skin test denotes prior antigenic exposure, T-cell competency and an intact inflammatory response (1,2) The reaction usually peaks 48 hours after antigen is introduced into the skin and is manifest as induration at the test site. Recall antigens may be useful in evaluating delayed-type hypersensitivity by eliciting positive induration reactions 48 to 72 hours after intracutaneous administration. Except for mumps skin test antigen, most commonly used recall antigens were developed for other purposes, and the size of the reaction elicited may not be directly related to cellular immunity because of variability in antigen source and dose and skin test administration and measurement techniques. Useful antigens are those which elicit a reaction size ≥ 5 mm in more than 50% of normal individuals. The combination of results from skin testing with more than one antigen should result in detection of dth in at least 95% of normal subjects (2) The inflammatory response associated with the DTH reaction is characterized by an infiltration of lymphocytes and macrophages at the site of antigen deposition. Specific cell types that appear to play a major role in the dth response include CD4+ and CD8+ T lymphocytes which leave the recirculating lymphocyte pool in response to exogenous antigen (3). Both CD4+ and CD8+ lymphocytes have been recovered from dth reactions elicited by Candida antigen (4). In the literature, the incidence of dth reactions to unstandardized Candida antigens has been reported to vary from 52 - 89%, depending upon the strength of the antigen and the mm induration required for a positive test (5,6,7,8,9). Published studies have reported that antigens of Candida albicans are useful in the assessment of diminished cellular immunity in persons infected with human immunodeficiency virus (10,11). Responses to dth antigens have been reported to have prognostic value in patients with cancer (5). Table 1. Cellular hypersensitivity response to CANDIN® (candida albicans) in healthy adults (15). N Age range (years) Number reactions ≥ 5 mm at 48 hours Response overall Study 1 (a) Male 16 25 - 83 14 Female 2 61 - 69 2 78% Study 2 Male 20 23 - 63 13 Female 15 28 - 62 8 60% (a) Control group in Table 2. Response to CANDIN® (candida albicans) in Healthy Adults (Table 1): In one group of 18 subjects, 14 (78%) of the individuals reacted to Candin® (candida albicans) with an induration response of ≥ 5 mm at 48 hours. In a second study of 35 subjects, 21 (60%) had induration reactions ≥ 5 mm at 48 hours. In this study, 65% of males tested positive compared to 5 3% of females; the mean induration in responding males was 12.8 mm and in responding females was 13.0 mm. When subjects in these studies were tested with two reagents, CANDIN® (candida albicans) and Mumps Skin Test Antigen, 92% were positive to at least one antigen, a higher response rate than to either antigen used alone (15). Table 2. Cellular hypersensitivity response to CANDIN® (candida albicans) in adults with AIDS, adults with HIV infection (no-AIDS-indicator conditions) and adult control subjects (15) Group Classification* N Zidovudine Use CD4 T-cell Count Mean Induration (mm) N ≥ 5 (mm) % Range Mean AIDS A3,B3,C 32 14 4 - 483 145 3.35 (a) 9 28 (b) HIV POS. A1, A2, B1,B2 28 13 201-1065 455 5.67 15 54 CONTROL --- 18 0 554-1876 869 8.03 14 78 * (reference 12) (a) p = 0.01 compared to Control. (b) p < 0.01 compared to Control. Response to CANDIN® (candida albicans) in Adults with HIV Infection: In one study (Table 2), the skin test responses of adults with HIV infection were compared to those of healthy control subjects (age range AIDS 22 - 65, HIV positive 20 - 45, Controls 25 - 69). When HIV-infected subjects were classified by the CDC's 1993 revised classification system for HIV infection (12), a significant difference was found between AIDS patients and normal controls in both mean induration (p = 0.01) and proportion with ≥ 5 mm response (p < 0.01). The responses in HIV-infected patients (without AIDS-indicating conditions or AIDS-indicating CD4 T-cell counts) were less than in normal subjects, but the differences were not statistically significant. In a second study involving 20 male patients (age range 26 - 57) diagnosed with AIDS based on clinical criteria only, one subject responded to CANDIN® (candida albicans) . In the same study 65% of the male control subjects had DTH reactions ≥ 5 mm to CANDIN® (candida albicans) (Table 1, Study 2). The mean induration response at 48 hours for control subjects was 8.33 mm compared to 1.78 mm for the AIDS subject. AIDS vs. control p-values were < 0 01 mean induration and < 0.01 induration ≥ 5 mm. Because HIV infection can modify the DTH response to tuberculin, it is advisable to skin test HIV-infected patients at high risk of tuberculosis with antigens in addition to tuberculin (16). In a published study of DTH anergy, 479 subjects (334 males and 145 females) infected with HIV and being screened for tuberculosis were skin tested with several additional antigens including Candin® (candida albicans) supplied under IND to the investigators. Only 12% reacted to tuberculin ( ≥ 5 mm), 57% reacted to Candin® (candida albicans) ( ≥ 3 mm) and 60% reacted to either tuberculin or CANDIN® (candida albicans) or both. In this study, a 3 mm induration response to CANDIN® (candida albicans) was considered positive. The authors concluded that in HIV-infected subjects, testing with other DTH antigens increases the accuracy of interpretation of negative tuberculin reactions. Table 3. Cellular hypersensitivity response to CANDIN® (candida albicans) in adults with cancer (15). N Age Range Number reactions ≥ 5 mm at 48 hours Response Study 1 18 52 - 75 5 28% Study 2 20 47 - 81 0 0% In one study of 18 patients with lung cancer, CANDIN® (candida albicans) elicited a positive induration response in five patients (28%). In a second series of 20 patients with metastatic cancer, no reactions ≥ 5 mm were observed (Table 3). REFERENCES 1. Middleton, E. Jr., Ree d, C.E., Ellis, F.E., Adkinson, N.F., Jr., Yunginger, J.W., Busse, W.W., Allergy Principles and Practice, 4th Ed., Vol II, pp 963-982, Mosby, St. Louis, 1993. 2. Bernstein, I.L., ed., Proceedings of the task force of guidelines for standardizing old and new technologies used for the diagnosis and treatment of allergy, J. Allergy Clin. Immunol., 82: 487-526, 1988. 3. Paul, W.E., Fundamental Immunology, 3rd Ed., pp 75-76, Raven Press, New York, 1993. 4. MacPhee, M.J., Gordon, J., Christou, N.V., Sanchez-Cantu, L., Rode, H.H., Cells recovered from human DTH reactions: phenotypic and functional analysis. Cellular Immunology, 151: 80-96, 1993. 5. Ahmed, A.R., Blose, D.A., Delayed-type hypersensitivity skin testing. A review. Arch. Dermatol, 119: 934-45, 1983. 6. Stimpson, P.G., Paty, J.G., Jr., Hudson, T., Lieberm an, P., Delayed hypersensitivity skin testing for assessing anergy in the mid-south. South. Med. J., 69: 424-426, 1976. 7. Kniker, W.T., Anderson, C.T., McBryde, J.L., Roumiantzeff, M., Lesourd, B., Multitest CMI for standardized measurement of delayed cutaneous hypersensitivity and cell-mediated immunity. Normal values and proposed scoring system for healthy adults in th e U.S.A . Ann. A llergy, 52: 75-82, 1984. 8. Gordon, E.H., Krouse, H.A., Kinney, J.L., Steihm, E.R., Klaustermeyer, W.B., Delayed cutaneous hypersensitivity in normals: choice of antigens and comparison to in vitro assays of cell-mediated immunity. J. Allergy Clin. Immunol., 72: 487-494, 1983. 9. Shannon, D.C., Johnson, G ., Rosen, F.S., Aus ten, K.F., Cellular reactivity to Candida albicans antigen, New Eng. J. Med., 275: 690-693, 1966. 10. Blatt, S.P., Hen drix, C.W ., Butzin, C .A., Freem an, T.M., Ward, W.W., Hensley, R.E., Melcher, G.P., Donovan, D.I., Boswell, N.R., Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Ann. Int. Med., 119: 177-183, 1993. 11. Colebunders, R.L., Lebughe, I., N zila, N., K alunga, D., Francis, H., Ryder, R., Piot, P., Cutaneous delayed-type hypersensitivity in patients with human immunodeficiency virus infection in Zaire. J. Acq. Immune Def. Synd., 2: 576-578, 1989. 15. Data on file, Allermed Laboratories, Inc. 16. CDC, Purified protein derivative (PPD) C tuberculin anergy and HIV infection: guidelines for anergy testing and management of anergic persons at risk of tubercu losis. Morbidity and Mortality Weekly Report. 40: No. RR-5, April 26, 1991.

Find Lowest Prices on CANDIN® (candida albicans) Skin Test Antigen For Cellular Hypersensitivity DESCRIPTION Candida albicans Skin Test Antigen for Cellular Hypersensitivity (CANDIN® (candida albicans) ) is a clear, colorless, sterile solution with a pH of 8 0 - 8.5. The antigen should be administered intradermally according to the directions included under DOSAGE AND ADMINISTRATION of this package insert. CANDIN® (candida albicans) is made from the culture filtrate and cells of two strains of Candida albicans. The fungi are propagated in a chemically defined medium consisting of inorganic sals, biotin and sucrose. Lyophilized source material is extracted with a solution of 0.25% NaCl, 0.125% NaHCO3 and 50% v/v glycerol. The concentrated extract is diluted with a solution of 0.5% NaCl, 0.25% NaHCO3, 0.03% Albumin (Human) usp, 8 ppm polysorbate 80 and 0.4% phenol. The potency of CANDIN® (candida albicans) is measured by DTH skin tests in humans. The procedure involves concurrent (side-by-side) testing of production lots with an Internal Reference (IR), using sensitive adults who have been previously screened and qualified to serve as test subjects. The induration response at 48 hours elicited by 0.1 mL of a production lot is measured and compared to the response elicited by 0.1 mL of the IR. The test is satisfactory if the potency of the production lot does not differ more than ± 20% from the potency of the IR, when analyzed by the paired t-test (two-tailed) at a p value of 0.05 The potency of the ir is monitored by DTH skin testing. Persons included in the potency assay are qualified as test subjects by receiving four skin tests with the IRfrom which a mean induration response (mm) is calculated. Current skin tests with the IR must show that the potency of the IR has not changed more than ± 20% from the mean qualifying response in the same test subjects, when analyzed by the paired t-test (two-tailed) at a p value of 0.05. The required induration response at 48 hours to the IR is 15 mm ± 20%. Skin Test Strength The skin-test strength of CANDIN® (candida albicans) has been determined from dose-response studies in healthy adults (see CLINICAL PHARMACOLOGY). The product is intended to elicit an induration response ≥ 5 mm in immunologically competent persons with cellular hypersensitivity to the antigen (see DOSAGE AND ADMINISTRATION).

INDICATIONS CANDIN® (candida albicans) is indicated for use as a recall antigen for detecting DTH by intracutaneous (intradermal) testing. The product may be useful in evaluating the cellular immune response in patients suspected of having reduced cellular hypersensitivity. Because some persons with normal cellular immunity are not hypersensitive to Candida, a response rate less than 100% to the antigen is to be expected in normal individuals. Therefore, the concurrent use of other licensed DTH skin test antigens is recommended. The product should not be used to diagnose or treat Type 1 allergy to Candida albicans. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particles or discoloration are observed, the product should not be used and it should be discarded. CANDIN® (candida albicans) should be administered intradermally on the volar surface of the forearm or on the outer aspect of the upper arm. The test dose is 0.1 mL. The skin should be cleansed with 70% alcohol before applying the skin test. The intradermal injection must be given as superficially as possible causing a distinct, sharply defined bleb. An unreliable reaction may result if the product is injected subcutaneously. A positive DTH reaction to CANDIN® (candida albicans) consists of induration ≥ 5 mm. The time required for the induration response to reach maximum intensity varies with the individual. The reaction usually begins within 24 hours and peaks between 24 and 48 hours. The skin test should be read at 48 hours by visually inspecting the test site and palpating the indurated area. Measurements should be made across two diameters as shown in the figure below. The mean of the longest and midpoint orthogonal diameters of the indurated area should be reported as the DTH response. For example, a reaction that is 10 mm (longest diameter) by 8 mm (midpoint orthogonal diameter) has a sum of 18 mm and a mean of 9 mm. The DTH response is therefore 9 mm. HOW SUPPLIED CANDIN® (candida albicans) is supplied in a 1 mL multidose vial containing ten 0.1 mL doses. Storage Store between 2 - 8°C. Do not freeze. Allermed Laboratories, Inc. 7203 Convoy Ct., San Diego, CA 92111. Date of Issue: April 2000

PATIENT INFORMATION Local reactions to CANDIN® (candida albicans) can include redness, swelling, pruritus, excoriation and discoloration of the skin. These reactions usually subside within hours or days after administration of the skin test. In some patients, skin discoloration may persist for several weeks. Progression of the DTH reaction to vesiculation, necrosis and ulceration are possible. Patients should be informed that all foreign antigens have the remote possibility of causing Type I anaphylactic reactions that may require the administration of epinephrine and other drugs or emergency procedures and may be life threatening in some cases. Patients should report any serious adverse reactions to their health care provider.

OVERDOSE No information provided. CONTRAINDICATIONS CANDIN® (candida albicans) should not be used after a previous unacceptable adverse reaction to this antigen or to a similar product, i.e , extreme hypersensitivity/allergy.

SIDE EFFECTS Local reactions to CANDIN® (candida albicans) have included swelling, pruritus and vesiculation. Reactions involving necrosis and ulceration have not been observed, but such reactions are theoretically possible and might occur in persons with exquisite cellular hypersensitivity to the antigen. Local reactions may be treated with a cold compress and topical steroids. Severe local reactions may require additional measures as appropriate. In a published study (13) of 479 HIV positive adults tested with CANDIN® (candida albicans) , adverse local reactions were observed in six subjects as follows: pruritus (three), swelling at the test site (one), vesiculation (one) and vesiculation with weeping edema (one). Pruritus and swelling cleared within 48 hours; vesiculation with edema required approximately 1 wee k to resolve (15). In two studies involving 171 persons discussed under CLINICAL PHARMACOLOGY in Tables 1, 2, 3, and text, one adverse reaction was observed. This reaction consisted of induration 22 x 55 mm at 48 hours which resolved within 1 week (15). Testing of CANDIN® (candida albicans) for consistency of potency is performed in healthy human subjects who are known to be skin-test positive to the antigen. In 58 subjects tested to-date, there have been no cases of Type 1 allergy manifested as either generalized or adverse local reactions. One subject had induration with a central vesicle which subsided within a few da ys (15). Severe local reactions, including rash, vesiculation, bullae, dermal exfoliation and cellulitis, have been reported to MedWatch for unstandardized allergenic extracts of Candida albicans used for anergy testing (17). Systemic reactions to CANDIN® (candida albicans) have not been observed. However, all foreign antigens have the remote possibility of causing Type 1 anaphylaxis (14) and even death when injected intradermally. Systemic reactions usually occur within 30 minutes after the injection o f antigen and may include the following symptoms: sneezing, coughing, itching, shortness of breath, abdominal cramps , vomiting, diarrhea, tachycardia, hypotension and respiratory failure in severe cases. Systemic allergic reactions including anaphylaxis must be immediately treated with Epinephrine HCL 1:1,000. Additional measures may be required, depending upon the severity of the reaction. Immediate Hypersensitivity reactions to CANDIN® (candida albicans) occur in some individuals. These reactions are characterized by the presence of an edematous hive surrounded by a zone of erythema. They occur approximately 15 - 20 minutes after the intradermal injection of the antigen. The size of the immediate reaction varies depending upon the sensitivity of the individual. Immediate hypersensitivity reactions were observed in the control and HIV-infected (AIDS and HIV positive) subjects reported in Table 2 as follows: HIV-infected subjects (20% with erythema of 10 - 21 mm in diameter; 13% with erythema of 5 - 9 mm). Control subjects (22% with erythema of 10 - 15 mm; 5% with erythema of 8.5 mm). Cancer subjects (Group 1, Table 3), 17% with erythema of 10 - 24 mm and 11% with erythema of 6 - 9 mm. DRUG INTERACTIONS Pharmacologic doses of corticosteroids may variably suppress the DTH skin test response after two weeks of therapy. The mechanism of suppression is believed to involve a decrease in monocytes and lymphocytes, particularly T-cells. The skin test response usually returns to the pretreatment level within several weeks after steroid therapy is discontinued (1). REFERENCES 1. Middleton, E. Jr., Ree d, C.E., Ellis, F.E., Adkinson, N.F., Jr., Yunginger, J.W., Busse, W.W., Allergy Principles and Practice, 4th Ed., Vol II, pp 963-982, Mosby, St. Louis, 1993. 13. Huebner, R.E., Schein, M.F., Hall, C.A., Barnes, S.A., Delayed-type hypersensitivity anergy in human immunodeficiency virus-infected persons screened for infection with Mycobacterium tuberculosis. Clin. Infect. Dis., 19: 26-32, 1994. 14. Klotz, S.D., Sweeney, M .J., Diens t, S., Klotz, L.R., Moeller, R.K., Rosenberg, S., Systemic anaphylaxis immediately following delayed hypersensitivity skin tests. Ann. Allergy, 49: 142-144, 1982. 15. Data on file, Allermed Laboratories, Inc. 17. Data on file, MedWatch, The FDA Medical Products Reporting Program, Rockville MD 20852.

WARNINGS As has been observed with other, unstandardized, antigens used for DTH skin testing (14), it is possible that some patients may have exquisite immediate hypersensitivity to CANDIN® (candida albicans) . In persons with bleeding tendency, bruising and non-specific induration may occur due to the trauma of the skin test. PRECAUTIONS General Physicians using this product must have available the facilities and medications necessary to treat all potential local and systemic side effects that can occur from the injection of an antigenic substance Epinephrine (1:1,000) must be immediately available. The patient, or parent or guardian, should be questioned about previous reactions to this product or a similar product. The antigen must be injected intradermally as superficially as possible, causing a distinct, sharply defined bleb at the skin test site. An unreliable reaction may result if the product is injected subcutaneously. It must not be given intravenously; care should be taken to avoid injection into a blood vessel. A separate sterile syringe and needle should be used for each patient to prevent transmission of infectious agents. Needles should be disposed of properly and should not be recapped. Delayed or cellular hypersensitivity reactions can be diminished or completely suppressed if the person has received corticosteroids (see DRUG INTERACTIONS). Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been conducted with CANDIN® (candida albicans) to determine its potential for carcinogenicity, mutagenicity or impairment of fertility. Pregnancy Category C Animal reproduction studies have not been conducted with CANDIN® (candida albicans) . It is also not known whether CANDIN® (candida albicans) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CANDIN® (candida albicans) should be given to pregnant women only if clearly needed. Nursing Mothers It is not known whether CANDIN® (candida albicans) is excreted in human milk. Because drugs may be excreted in human milk, caution should be exercised when this product is administered to a nursing woman. Pediatric Use The safety and effectiveness of intradermally administered CANDIN® (candida albicans) have not been established in children. Geriatric Use Candin (candida albicans) 7 has not been adequately studied in geriatric patients. However, the DTH response to CANDIN® (candida albicans) may be diminished in geriatric patients, since the aging process is known to alter cell-mediated immunity (1). REFERENCES 1. Middleton, E. Jr., Ree d, C.E., Ellis, F.E., Adkinson, N.F., Jr., Yunginger, J.W., Busse, W.W., Allergy Principles and Practice, 4th Ed., Vol II, pp 963-982, Mosby, St. Louis, 1993. 14. Klotz, S.D., Sweeney, M .J., Diens t, S., Klotz, L.R., Moeller, R.K., Rosenberg, S., Systemic anaphylaxis immediately following delayed hypersensitivity skin tests. Ann. Allergy, 49: 142-144, 1982.