INDICATIONS AND USAGE
CANDIN® 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.

CONTRAINDICATIONS
CANDIN® should not be used after a previous unacceptable adverse reaction to this antigen or to a similar product, i.e., extrem e hypersensitivity/allergy.

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®. 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).

Patient Information: Local reactions to CANDIN® can include redness, swelling, pruritus, excoriation and discoloration of the skin. These reactions usually subside within hours or d ays 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.

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). Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been conducted with CANDIN® to determine its potential for carcinogenicity, mutag enicity or impairment of fertility.

Pregnancy Category C: Animal reproduction studies have not been conducted with CANDIN®. It is also not known whether CANDIN® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. CANDIN® should be given to pregnant women only if clearly needed.

Nursing Mothers: It is not known whether CANDIN® 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® have not been established in children.

Geriatric Use: Candin7 has not been adequately studied in geriatric patients. However, the DTH response to CANDIN® may be diminished in geriatric patients, since the aging process is known to alter cell-mediated immunity (1).

ADVERSE REACTIONS
Local reactions to CANDIN® 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® , adverse local reactions were observed in six subjects as follows: pruritus (three), swelling at the test site (one), vesiculation (one) and vesiculation w ith weeping edema (one). Pruritus and swelling cleared within 48 hours; vesiculation with edema req uired approximately 1 week 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® 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 days (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® have not been observed. However, all foreign antigens have the remote possibility of causing Type 1 anaphylaxis (14) and even death w hen 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® 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.

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® 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® 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.

CANDIN^® is supplied in a 1 mL multidose vial containing ten 0.1 mL doses.

STORAGE

Store between 2 - 8°C. Do not freeze.

REFERENCES

1. Middleton, E.Jr., Reed, CE., Ellis, FE., 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, WE., Fundamental Immunology, 3rd Ed., pp 75- 76, Raven Press, New York, 1993.

4. MacPhee, M.J., Gordon, J., Christou, NV., Sanchez- Cantu, L., Rode, H. H., Cells recovered from human DTH reactions: phenotypic and functional analysis. Cellular Immunology, 151: 80-96, 1993.

5. Ahmed, AR., 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., Lieberman, P., Delayed hypersensitivity skin testing for assessing anergy in the mid south. South. Med. J., 69: 424-426, 1976.

7. Kniker, W.T., Anderson, CT., 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 the U.S.A. Ann. Allergy, 52: 75-82, 1984.

8. Gordon, E.H., Krouse, HA., Kinney, J. L., Steihm, ER., 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., Austen, K.F., Cellular reactivity to Candida albicans antigen, New Eng. J. Med., 275: 690-693, 1966.

10. Blatt, S.P., Hendrix, C.W., Butzin, CA., Freeman, TM., Ward, W.W., Hensley, RE., 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: 177-1 83, 1993.

11. Colebunders, R.L., Lebughe, I., Nzila, N., Kalunga, 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.

12. CDC, 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Report. 41: No. RR 17, December 18, 1992.

13. Huebner, RE., Schein, M.F., Hall, CA., 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., Dienst, 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.

16. CDC, Purified protein derivative (PPD) - tuberculin anergy and HIV infection: guidelines for anergy testing and management of anergic persons at risk of tuberculosis. Morbidity and Mortality Weekly Report. 40: No. RR-5, April 26, 1991.

17. Data on file, MedWatch, The FDA Medical Products Reporting Program, Rockville MD 20852.