Candin

3 DOSAGE FORMS AND STRENGTHS

3.1 CANDIN is a solution for intradermal injection supplied in a 1 mL multi-dose vial.

3.2 The skin-test strength of CANDIN has been determined from dose-response studies in healthy adults [see CLINICAL STUDIES (14)]. 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 (2.2)].

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 As has been observed with other, unstandardized, antigens used for DTH skin testing ⁽¹⁰⁾, 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. As with all skin test antigens, local and systemic allergic reactions can occur following administration.

5.3 Physicians using this product must have facilities, equipment and medication necessary to treat potential side effects. Epinephrine and oxygen must be immediately available in the event of a serious systemic response.

6 ADVERSE REACTIONS

6.1 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 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 with weeping edema (one). Pruritus and swelling cleared within 48 hours; vesiculation with edema required approximately 1 week to resolve ⁶

In two studies involving 171 persons discussed under CLINICAL STUDIES 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 ⁸.

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 ⁸.

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

6.2 Systemic reactions to CANDIN have not been observed. However, all foreign antigens have the remote possibility of causing Type 1 anaphylaxis (7) and even death when injected intradermally. Systemic reactions usually occur within 30 minutes after the injection of 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.

6.3 To report SUSPECTED ADVERSE REACTIONS, contact Nielsen Biosciences, Inc. at (855) 855-1212 or FDA at 1-800-833-7967 or www.vaers.hhs.gov.

7 DRUG INTERACTIONS

7.1 Pharmacologic doses of corticosteroids may variably suppress the inflammatory response to DTH skin test antigen after two weeks of therapy. 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.

7.2 Patients receiving beta-blocking drugs may be refractive to the usual dose of epinephrine, in the event that epinephrine is required to control an adverse allergic reaction ¹.

8 USE IN SPECIFIC POPULATIONS

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.

No information is available to assess the effects of CANDIN on childbirth.

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.

The safety and effectiveness of intradermally administered CANDIN have not been established in children.

CANDIN 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.

10 OVERDOSAGE

The recommended dose for CANDIN is 0.1 mL administered intradermally. If a larger dose is administered, or if the dose is accidentally injected intravenously, the potential for a systemic reaction such as anaphylaxis is increased. In this case, Epinephrine HCl at 1:1000 should be made available immediately as well as oxygen and emergency equipment.

Because individuals differ in their sensitivity to CANDIN®, the response to the recommended dose of 0.1 mL can vary in size and intensity. In highly sensitive persons, the result of overdose, or a mistake in the administration of CANDIN may result in a more pronounced local or systemic outcome.

11 DESCRIPTION

Candida albicans Skin Test Antigen for Cellular Hypersensitivity (CANDIN) 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 (2.2) of this package insert.

CANDIN 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 salts, 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.

12 CLINICAL PHARMACOLOGY

Cellular hypersensitivity 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 between 24 and 48 hours after antigen is introduced into the skin and is manifest as induration at the test site.

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.

13 NONCLINICAL TOXICOLOGY

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

14 CLINICAL STUDIES

In one group of 18 subjects, 14 (78%) of the individuals reacted to CANDIN 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 53% of females; the mean induration in responding males was 12.8 mm and in responding females was 13.0 mm.

Response to CANDIN 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(5), 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. In the same study 65% of the male control subjects had DTH reactions ≥ 5 mm to CANDIN (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 (6). 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 supplied under IND to the investigators. Only 12% reacted to tuberculin (≥ 5 mm), 57% reacted to CANDIN (≥ 3 mm) and 60% reacted to either tuberculin or CANDIN or both. In this study, a 3 mm induration response to CANDIN 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.

IIn one study of 18 patients with lung cancer, CANDIN 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).

15 REFERENCES

• Middleton, E. Jr., Reed, 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.
• 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.
• Paul, W.E., Fundamental Immunology, 3rd Ed., pp 75-76, Raven Press, New York, 1993.
• 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.
• 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. RR17, December 18, 1992.
• 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
• 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

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Store between 2° to 8°C (35° to 46°F).

17 PATIENT COUNSELING INFORMATION

Local reactions to CANDIN 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.

^∗Sections or subsections omitted from the full prescribing information are not listed.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - VIAL

Candida albicans Skin Test Antigen For Cellular Hypersensitivity

CANDIN

NDC 59584-138-01 1D barcode: 59584-138-01

Rx Only

Volume: 1 mL Store: 2-8 °C

Dose: 0.1 mL Pres.: 0.4% PHENOL

Nielsen Biosciences, Inc. U.S. Lic. 1903
Mfg. by: Allermed Laboratories, Inc. U.S. Lic. 467
San Diego CA 92111

Lot #: CAxxx
Exp: