2.1 Dosage

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.

2.2 Administration

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.

2.3 Reading the Skin Test Result

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.

Area of Induration

(shaded area)

3.1 Dosage Form

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

3.2 Skin Test Strength

The skin-test strength of CANDIN® has been determined from dose-response studies in healthy adults (see CLINICAL STUDIES). 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).

5.1 Administer Intracutaneously, Not Intravenously

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 In Persons with Bleeding Tendency, Bruising and Non-Specific Induration May Occur Due to the Trauma of the Skin Test

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 Access to Emergency Equipment, Medications

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.

6.1 Local 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, including rash, vesiculation, bullae, dermal exfoliation and cellulitis are possible in highly allergic persons. 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 .

Local 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. Local 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.

6.2 Systemic Reactions

Systemic reactions to CANDIN® have not been observed. However, all foreign antigens have the remote possibility of causing Type 1 anaphylaxis and even death when injected intradermally.(7) 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.

6.3 Reporting Suspected Adverse Events

To report SUSPECTED ADVERSE REACTIONS, contact Nielsen BioSciences, Inc. at (855) 855-1212 or MEDWATCH, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852-9782. Telephone 1-800-332-1088 or https://www.vaers.hhs.gov/.

7.1 Corticosteroids and Imunosuppressive Drugs

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)

7.2 Beta-Blocking Drugs

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)

8.1 Pregnancy

8.2 Labor and Delivery

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

8.3 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.

8.4 Pediatric Use

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

8.5 Geriatric Use

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. (1)

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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)

13.1 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.

14.1 Cellular Hypersensitivity Response to CANDIN® in Healthy Adults

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.

Table 1. Induration response to CANDIN in healthy adults.

(a) Control group in Table 2.

14.2 Response to CANDIN® in Adults with HIV Infection

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.

Table 2. Cellular hypersensitivity response to CANDIN® in adults with AIDS, adults with HIV infection (no-AIDS-indicator conditions) and adult control subjects. Range and mean of CD4 T-cell count shown in the shaded area of the table.

* (reference 5)
(a) p = 0.01 compared to Control. (b) p < 0.01 compared to Control.
† See Control Group in Table 1.

14.3 Response to CANDIN® in Adults with Cancer

In 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).

Table 3. Cellular Hypersensitivity Response to CANDIN® in adults with Cancer.