Candin: Package Insert and Label Information

CANDIN- candida albicans injection, solution
Nielsen BioSciences, Inc.

WARNING

See full prescribing information for complete boxed warning.
  • The expected response to CANDIN® is a local area of inflammation at the site of the skin test. The size of reaction depends upon the sensitivity of the person receiving the test, but is usually dime to quarter size reaching maximum diameter between 24 and 48 hours. Larger accelerated reactions can occur which may require treatment with local cold compresses and anti-inflammatory medication. (2.3, 6.1)
  • Systemic reactions can occur with skin test antigens and in certain individuals these reactions may be life-threatening or cause death. Emergency measures as well as personnel trained in their use should be immediately available in the event of a life-threatening reaction. Patients should be observed for at least 20 minutes following the administration of a skin test. (6.2)
  • CANDIN® should never be given intravenously. See also Warnings and Precautions. (5.1)
  • Serious adverse reactions to CANDIN® should be reported to Nielsen BioSciences, Inc. at (855) 855-1212 or MEDWATCH, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852-9782. Telephone: (800) 332-1088 or www.vaers.hhs.gov. (6.3)

1 INDICATIONS AND USAGE

CANDIN® is indicated for use as a recall antigen for detecting cell-mediated hypersensitivity 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 cell-mediated hypersensitivity skin test antigens is recommended. The product should not be used to diagnose or treat Type 1 allergy to Candida albicans.

2 DOSAGE AND ADMINISTRATION

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)

area-of-induration
(click image for full-size original)

3 DOSAGE FORMS AND STRENGTHS

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).

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 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 ADVERSE REACTIONS

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 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

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)

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 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.

The potency of CANDIN® is measured by DTH skin tests using a validated assay measuring relative potency in Guinea pigs based on induration responses at different dilutions against an Internal Reference standard.

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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.

n Age range (years) Number reactions ≥ 5 mm at 48 hrs Combined male/female Response
Study 1 (a)
Male 16 25 – 83 12 78%
Female 2 61 – 69 2 78%
Study 2
Male 20 23 – 63 13 60%
Female 15 28 – 62 8 60%

(a) Control group in Table 2.

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