Multitest

Candida Albicans Antigen:

• Warnings
• Description
• Clinical pharmacology
• Indications & usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage & administration
• How supplied
• Storage
• Limited warranty
• References
• Multitest (Candida Albicans Antigen) reviews

WARNINGS

This product is intended for use only by licensed medical personnel experienced in administering allergenic extracts and trained to provide immediate emergency treatment in the event of a life-threatening reaction. Allergenic extracts may potentially elicit a severe life threatening systemic reaction, rarely resulting in death.7 Therefore, emergency measures and personnel trained in their use must be available immediately in the event of such a reaction. Patients should be instructed to recognize adverse reaction symptoms and cautioned to contact the physician's office if symptoms occur. Patients on non-selective beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. This product should never be injected intravenously. Refer also to the WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS Sections for further discussion.

DESCRIPTION

Sterile extracts for scratch, prick or puncture testing are supplied in dropper vials containing, in addition to the extract allergens and antigens, 50% (v/v) glycerin as preservative, 0.5% sodium chloride and 0.275% sodium bicarbonate. The strength of these extracts may be expressed in terms of

• Weight to Volume (w/v)
• Protein Nitrogen Units/mL (PNU/mL)
• Amb a 1 Units/mL (Amb a 1/mL)
• Allergy Units/mL (AU/mL)
• Bioequivalent Allergy Units/mL (BAU/mL)
• Concentrate

1. Weight to volume (w/v).

For regular extracts this describes the extraction ratio, i.e., the amount of crude allergen added to the extracting fluid. A 1:10 extract, therefore, indicates that the solution contains the extracted material from one gram of raw material added to each 10 mL of extracting fluid. The amount and composition of extracted materials will vary with the kind of antigen, the extracting fluid, duration of extraction, pH, temperature, and other variables. AP (acetone precipitated) extracts, if present, are prepared by reconstituting dry, allergenically active concentrates produced by precipitation process from extracts of raw materials. For those AP extracts labeled on a weight per volume (w/v) basis, the strength designation indicates the dry weight of finished (acetone) precipitate per volume of reconstituting fluid. For example, 1:50 (w/v) means that each gram of dry precipitate obtained from the original extract is reconstituted in 50 mL of solution.

2. Protein Nitrogen Units per mL (PNU/mL).

One protein nitrogen unit represents 0.00001 mg phosphotungstic acid-precipitable protein nitrogen dissolved in one mL of antigen extract. The PNU content of extracts of the same antigen may vary according to the method of measuring the PNU. Thus, the PNU content of extracts from different manufacturers is not comparable unless the PNU method is known to be the same and reproducible from lot to lot. Also, the amount of protein nitrogen extracted from an antigen is influenced by the same variables as the weight to volume extract. Allergenic materials make up a variable proportion of the total protein of an extract.

3. Amb a 1. Of the many allergens which have been purified and characterized from Short Ragweed (Amb a 1¹², Amb a 2¹³, Ra3¹⁴, Ra4(BPA-R)¹⁵, Ra5¹⁶, Ra6, Ra7, and Ra8¹⁷, and cytochrome C¹⁸), Amb a 1 (also known as Antigen E) is considered the most important and has been selected as the basis for standardization. Extracts of Short Ragweed containing Amb a 1 are diffused in agar against standard anti-serum to Amb a 1, and compared to the diffusion of standard Amb a 1 solutions. The amount of Amb a 1 is expressed as units of Amb a 1 per mL of extract.

If an extract is diluted with a diluent or other allergenic extracts, the Amb a 1 concentration must be determined by calculation.

4. Allergy Units per mL (AU/mL).

The potency of extracts labeled in Allergy Units per mL (AU/mL) is determined by in vitro comparison to a reference standard established by the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA).

5. Bioequivalent Allergy Units per mL (BAU/mL).

When originally licensed, the Reference Preparations for standardized extracts were arbitrarily assigned 100,000 Allergy Units (AU)/mL. Subsequently, quantitative skin testing by the ID₅₀EAL method 13 was used to determine that some Reference Preparations should be assigned 10,000 AU/mL, and others 100,000 AU/mL. To avoid possible confusion about this change in the method of allergy unit assignment, the nomenclature changed for standardized extracts whose allergy units are assigned based on quantitative skin testing, and such products are labeled in Bioequivalent Allergy Units (BAU)/mL. References labeled 10,000 BAU/mL can be diluted one to a half million fold, and references labeled 100,000 BAU/mL can be diluted one to 5 million fold and produce a sum of erythema diameter of 50 mm when Intradermal testing highly reactive subjects.

6. Concentrate.

Concentrate label terminology applies to allergenic extract mixtures, where the individual allergens being combined vary in strength or the designation of strength.

CLINICAL PHARMACOLOGY

Allergenic extracts for scratch, prick or puncture testing, used according to the DOSAGE AND ADMINISTRATION section, produce erythema or erythema and wheal reactions in patients with significant IgE-mediated sensitivity to the relevant allergen. This allergic inflammatory response, although not completely understood, is thought to begin with reaction of antigen with IgE on the surface of basophils or mast cells, which initiates a series of biochemical events resulting in the production of histamine and other mediators. These, in turn, produce the immediate-type "wheal and flare" skin reaction.

INDICATIONS & USAGE

Certain diagnostics carry labeling which states Allergenic Extract for Diagnostic Use Only. Data to support the therapeutic use of products labeled with this statement have not been established. 14

In addition to a carefully taken history, the use of glycerin-containing extracts in scratch, prick or puncture testing is an accepted method in the diagnosis of allergic conditions. 1, 2, 3 Extracts of all allergens do not produce equivalent results in scratch, prick or puncture tests. The intensity of the skin reactions produced will be determined by two factors: the degree of sensitivity of the patient, and the nature of the allergenic extract applied.

Scratch, prick or puncture tests are not as sensitive as the intradermal test, but are safer and cause less discomfort. They may, therefore, be the method of choice when a large number of tests are needed, or when testing the pediatric patient. In some cases, where the relatively insensitive scratch, prick or puncture tests are negative or do not confirm the allergic history, follow-up intradermal tests may be positive. However, ANTIGENS PRODUCING LARGE 3 to 4+ SCRATCH, PRICK OR PUNCTURE TESTS SHOULD NOT BE TESTED INTRADERMALLY.

CONTRAINDICATIONS

There are no known absolute contraindications to allergy skin testing. Patients with cardiovascular diseases or pulmonary diseases such as symptomatic asthma, and/or who are receiving cardiovascular drugs such as beta blockers, may be at higher risk for severe adverse reactions. These patients may also be more refractory to the normal anaphylaxis treatment regimen.

WARNINGS

Excessively large local reactions or systemic reactions are more likely to occur if the patient is skin tested shortly after exposure to large amounts of antigen to which s/he is sensitive. Use caution when skin testing patients during a season when pollen is present. Refer to boxed WARNINGS Section.

PRECAUTIONS

1. General

Always have injectable epinephrine and a tourniquet available when tests are being made. Generally 50 to 60 scratch, prick or puncture tests can be applied safely at one sitting. Patients whose history suggests severe sensitivity should have only 5 to 10 tests applied at a time and these tests applied to the volar surface of one arm. These tests should not all be of the same type of antigen; that is, all grass pollens, all weed pollens, all danders, etc. One or two tests from several classes of antigens should be applied at a time. As soon as a large wheal begins to develop, wipe the antigen from it with a damp cotton sponge. After 10 minutes wipe off all the antigens with a damp cotton sponge, followed by a dry cotton sponge. Be careful not to wipe antigen from a positive reaction onto an adjacent test site.

2 Information for Patients

Patients should be instructed in the recognition of adverse reactions to diagnostic testing. Patients should be made to understand the importance of a 30 minute observation period, and be warned to return to the office promptly if symptoms occur after leaving.

3. Drug Interactions

Patients on non-selective beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.6

Certain medications may lessen the skin test wheal and erythema responses elicited by allergens and histamine for varying time periods. Conventional antihistamines should be discontinued at least 5 days before skin testing. Long acting antihistamines should be discontinued for at least 3 weeks prior to skin testing.9 Topical steroids should be discontinued at the skin test site for at least 2-3 weeks before skin testing.9, 10 Tricyclic antidepressants such as Doxepin should be withheld for at least 7 days before skin testing.11 Topical local anesthetics may suppress the flare responses and should be

avoided in skin test sites.12

4. Carcinogenesis, mutagenesis, Impairment of Fertility

Long-term studies in animals have not been conducted with allergenic extracts to determine their potential for carcinogenicity, mutagenicity or impairment of fertility.

5. Pregnancy

4,5

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

6. Nursing Mothers

There are no current studies on secretion of the allergenic extract components in human milk or effect on the nursing infant. Because many drugs are excreted in human milk, caution should be exercised when allergenic extracts are administered to a nursing woman.

7. Pediatric Use

Wheal sizes in response to allergen skin testing can be smaller in infants than in adults. The skin response to histamine parallels that for allergens; therefore, appropriate positive control skin tests should always be performed.1

8. Geriatric Use

Skin test wheal size decreases with age. The decrease in allergen-induced skin test reaction parallels that to histamine; therefore, appropriate positive skin test controls should always be performed.1

ADVERSE REACTIONS

1. Local Reactions

If a severe local reaction occurs during scratch, prick or puncture testing, WIPE OFF test antigen. Large, persistent local reactions or minor exacerbations of the patient's allergic symptoms may be treated by local cold applications and/or the use of oral antihistamines, but they should be considered a warning of possible severe systemic reactions.

2. Systemic Reactions

With careful attention to dosage and administration, such reactions occur infrequently, but it must be remembered that allergenic extracts are highly potent in sensitive individuals and OVERDOSE could result in anaphylactic symptoms. Therefore, it is imperative that physicians administering allergenic extracts understand and be prepared for the treatment of severe reactions.

Adverse reaction frequency data for allergenic extract administration for testing and treatment show that risk is low.7, 8

It cannot be overemphasized that, under certain unpredictable combinations of circumstances, anaphylactic shock is a possibility. Other possible systemic reaction symptoms include fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis and urticaria. If a systemic or anaphylactic reaction does occur, WIPE OFF test antigen, apply a tourniquet above the site of injection, if tests are performed on the arms, and inject the 1:1,000 epinephrine-hydrochloride intramuscularly or subcutaneously into the opposite arm. Loosen the tourniquet at least every 10 minutes. Do not obstruct arterial blood flow with the tourniquet.

EPINEPHRINE:

ADULT

Dosage: 0.3 to 0.5 mL should be injected. Repeat in 5 to 10 minutes if necessary.

PEDIATRIC DOSAGE: The usual initial dose is 0.01 mg (mL) per kg body weight or 0.3 mg (mL) per square meter of body surface area. Suggested dosage for infants to 2 years of age is 0.05 mL to 0.1 mL; for children 2 to 6 years, 0.15 mL; and children 6 to 12 years, 0.2 mL. Single pediatric doses should not exceed 0.3 mg (mL). Doses may be repeated as frequently as every 20 minutes, depending on the severity of the condition and the response of the patient. After administration of epinephrine, profound shock or vasomotor collapse should be treated with intravenous fluids, and other appropriate drugs. Oxygen should be given by mask. Intravenous antihistamine, theophylline or corticosteroids may be used if necessary after adequate epinephrine and circulatory support have been given. Emergency resuscitation measures and personnel trained in their use should be available immediately in the event of a serious systemic or anaphylactic reaction not responsive to the above measures (Ref. J. Allergy Clin. Immunol. 77 (2): 271-273, 1986). Rarely are all of the above measures necessary; the tourniquet and epinephrine usually produce prompt responses. However, the physician should be prepared in advance for all contingencies. Promptness in beginning emergency treatment measures is of utmost importance.

3. Adverse Event Reporting

Report all adverse events to Jubilant HollisterStier LLC Customer Technical Services Department at 1 (800) 992-1120. A voluntary adverse event reporting system for health professionals is available through the FDA MEDWATCH program. Preprinted forms (FDA Form 3500) are available from the FDA by calling 1 (800) FDA-1088. Completed forms should be mailed to MEDWATCH, 5600 Fisher Lane, Rockville, MD 20852-9787 or Fax to: 1 (800) FDA-0178.

OVERDOSAGE

See ADVERSE REACTIONS Section.

DOSAGE & ADMINISTRATION

1. General

Parenteral Drug Products should be inspected visually for particulate matterand discoloration prior to administration, whenever solution and containerpermit.

2. Scratch, Prick or Puncture Testing Methods

There are two general methods of skin testing. The skin is scarified first,and the extract is then applied. (2) A drop of extract is put onto the skin,and a prick or puncture is made through the drop. Avoid touching tip of dropperto skin. Either method is satisfactory, but the second requires that theinstrument be cleansed between tests or that separate needles be used.

The extracts for scratch, prick or puncture testing are suppliedin dropper vials and should be kept in a rack or box in rows of 10 vialscorresponding to the rows of tests to be applied to the skin.

All skin tests should be validated by appropriate positivecontrol tests (e.g., histamine) and negative control tests (e.g., Glycerin,Albumin Saline with Phenol (0.4%), or Buffered Saline with Phenol). Thenegative control test should be the same material as is used as a dilutingfluid in the tested extracts. Diluting fluid is used in the same way as anactive test extract.

Test sites should be examined at 15 and 30 minutes. To preventexcessive absorption, wipe off antigens producing large reactions as soon asthe wheal appears. Record the size of the reaction. Delayed reactions mayrarely occur from tests, so it may be helpful to examine the test sites in 24hours.

Use of Scarifiers and Spacing. Makescarifications at least 2.5 cm apart. Use more space between pollen tests toprevent smearing into adjacent sites. Hold the scarifier between the thumb andindex finger, press the sharp edge of the instrument against the skin and twirlinstrument rapidly. The scratch should disrupt only the outer layers ofepidermis but should not produce immediate oozing of blood. The amount ofpressure needed to produce a satisfactory scratch will vary between patientsaccording to the thickness or fragility of their skin. Experience will indicatethe proper amount of pressure to exert in making the scratch. If the scarifieris kept sharp and the scratch made quickly, discomfort to the patient isminimized.

Use of Prick Test Needles. The skin iscleaned and single drops of each extract applied to the properly identifiedtest sites. A small, sterile disposable needle, such as a 1/2-inch 26 gaugeneedle (with the bevel up), a bifurcated vaccinating needle, or a PrickLancetter is inserted through the drop superficially into the skin, the skin liftedslightly and the needle withdrawn. No bleeding should be produced. After about 1minute the extract may be wiped away.

3. Most Satisfactory Sites for Testing

Prior to testing, clean the skin area to be tested with ether or alcohol andallow to dry. Use a sterile instrument for each patient. The back or the volarsurface of the arms are the most satisfactory sites for testing. Skin of theposterior thighs or abdomen may be used if necessary. Avoid very hairy areaswhere possible, since the reactions will be smaller and more difficult tointerpret. The most satisfactory areas of the back are from the posterioraxillary fold to 2.5 cm from the spinal column, and from the top of the scapulato the lower rib margins. The best areas of the arms are the volar surfacesfrom the axilla to 2.5 or 5 cm above the wrist, skipping the anti-cubitalspace.

4. Use of Antigen Mixes

The use of complicated mixes of unrelated pollens for testing is notrecommended since in the case of a positive reaction, it does not indicatewhich pollen(s) are responsible, and, in the case of a negative reaction, itfails to indicate whether the individual pollens at full concentration wouldgive a positive reaction.

5. Reading Skin Test Reactions

A positive reaction consists of an urticarial wheal with surrounding erythema(resembling somewhat a mosquito bite reaction) larger than the control site. The smallest reaction considered positive is erythema with a central papule atleast 5 mm in diameter. In some instances with no reaction at the control site,erythema may be considered an indication of sensitivity. In general, the sizeof wheal and erythema response correlates directly with the patient’ssensitivity to that allergen.

Standardized Products

(a) Mites:

The skin test concentration of 30,000 AU/mL in dropper vials is used forscratch, prick or puncture testing. Puncture tests performed on 12 highlysensitive subjects showed the following:

Species	Mean Sum of Wheal ± Std. Dev. (mm)	Mean Sum of Erythema ± Std. Dev. (mm)
D. farinae	22.4 ± 10.7	82.2 ± 21.7
D. pteronyssinus	24.0 ± 9.9	89.3 ± 24.5

The sum of a skin response is the sum of the longest diameter andthe mid-point orthogonal diameter.

(b) Cat Hair and Cat Pelt: The skin test concentration of 10,000BAU/mL (10-19.9 Fel d 1 Units/mL) in dropper vials is used for prick orpuncture testing. Puncture tests performed on 15 highly sensitive subjectsshowed the following:

Product	Mean Sum of Wheal ± Std. Dev (mm)	Mean Sum of Erythema ± Std. Dev (mm)
Standardized Cat Hair	15.1 ± 3.8	73.3 ± 14.3
Standardized Cat Pelt	13.9 ± 4.3	67.3 ± 13.3

The sum of a skin response is the sum of the longest diameterand the mid-point orthogonal diameter.

(c) Ragweed pollen (Short Ragweed or Giant and Short RagweedMixture) Antigen E Assayed: Short Ragweed extract at 1:20 w/v in 50% glycerincontaining approximately 100 to 300 units of Amb a 1mL or Giant and ShortRagweed Mix at 1:20 w/v in 50% glycerin containing approximately 50 to 150units of Amb a 1/mL are usually used for scratch, prick or puncture testing.

Refer to the following table to determine the skin test sensitivitygrade. The corresponding ∑E (sum of the longest diameter and the mid-pointorthogonal diameters of erythema) is also presented.

Grade	Erythema mm	Papule or Wheal mm	Corresponding mm ∑E
0	<5	<5	<10
±	5-10	5-10	10-20
1+	11-20	5-10	20-40
2+	21-30	5-10	40-60
3+	31-40	10-15 (a)	60-80
4+	>40	>15 (b)	>80

(a) or with pseudopods (b) or with many pseudopods

A positive skin reaction to any allergen must be interpreted inlight of the patient’s history of symptoms, time of the year, and known exposures.

THE SKIN TESTS ARE IN NO WAY A SUBSTITUTE FOR A CAREFUL ALLERGIC HISTORY. THEYSERVE AS ADDITIONAL INFORMATION TO AID IN IDENTIFYING CAUSATIVE ALLERGENS INPATIENTS WITH ALLERGIC DISORDERS.

6. Geriatric Use

The dose is the same in patients of all age groups. Because the wheal size in response to allergen skin testing decreases with age, appropriate histamine positive control skin tests must be performed.1

7. Pediatric Use

The dose is the same in patients of all age groups. Wheal size in response to allergen skin testing can be smaller in infants than in adults. Appropriate histamine positive control skin tests must be performed.1

HOW SUPPLIED

In 5 mL dropper bottles of extract at 1:10 w/v except pollen at 1:20, AP extracts at 1:50 w/v, except AP Dog Hair-Dander at 1:100 w/v, AP House Dust at 20,000 PNU/mL, some mixes as Concentrate, and Standardized products at AU/mL (Mite extracts at 30,000 AU/mL) or BAU/mL (Cat Hair and Pelt extracts at 10,000 BAU/mL) value. Strengths are listed on product labels.

STORAGE

The expiration date of the diagnostic extracts is listed on the container label. The extract should be stored at 2° - 8°C and kept at this temperature range during office use.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly, and that the directions be followed carefully during use. No warranty, express or implied, including any warranty of merchantability or fitness, is made. Representatives of the Company are not authorized to vary the terms or the contents of any printed labeling, including the package insert, for this product except by printed notice from the Company’s headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Middleton, Elliott, Jr., C.E. Reed, E.F. Ellis (ed.) Allergy Principles and Practice. Fourth Edition, Vol. 1. C.V. Mosby. 1993.

2. Sheldon, J.M., R.G. Lovell, K.P. Mathews. A Manual of Clinical Allergy. W.B. Saunders. 1967.

3. Tuft, L., H.L. Mueller. Allergy in Children. W.B. Saunders. 1970.

4. DuBuske, L.M., C.J. Ling, A.L. Sheffer. Special problems regarding allergen immunotherapy. Immunol. Allergy Clin. North Am. (USA). 12(1): 145-175, 1992.

5. Weinstein, A.M., B.D. Dubin, W.K. Podleski, S.L. Spector, R.S. Farr. Asthma and pregnancy. JAMA. 124(11): 1161-1165, 1979.

6. Jacobs, Robert L., Geoffrey W. Rake, Jr., et.al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J. Allergy Clin. Immunol. 68(2): 125-127, August 1981.

7. Lockey, Richard F., Linda M. Benedict, Paul C. Turkeltaub, Samuel C. Bukantz. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79(4): 660-677, 1987.

8. Turkeltaub, Paul C., Peter J. Gergen. The risk of adverse reactions from percutaneous prick-puncture allergen skin testing, venipuncture, and body measurements: Data from the second National Health and Nutrition Examination Survey 1976-80 (NHANES II). J. Allergy Clin. Immunol. 84(6): 886-890, Dec. 1989.

9. Pipkorn, Ulf. Pharmacological influence of anti-allergic medication on In Vivo allergen testing. Allergy. 43: 81-86, 1988.

10. Andersson, M., U. Pipkorn. Inhibition of the dermal immediate allergic reaction through prolonged treatment with topical glucocorticosteroids. J. Allergy Clin. Immunol. 79 (2): 345-349, February 1987.

11. Rao, Kamineni S., et al. Duration of suppressive effect of tricyclic anti-depressants on histamine induced wheal and flare reactions on human skin. J. Allergy Clin. Immunol. 82: 752-757, November 1988.

12. Pipkorn, Ulf, M. Andersson. Topical dermal anesthesia inhibits the flare but not the wheal response to allergen and histamine in the skin prick test. Clin. Allergy. 17: 307-311, 1987.

13. Turkeltaub, Paul C., Suresh, C. Rastogi, Harold Baer. Office of Biologics Research and Review skin test method for evaluation of subject sensitivity to standardized allergenic extracts and for assignment of allergy units to reference preparations using the ID₅₀EAL method (Intradermal Dilution for 50 mm Sum of Erythema Determines the Allergy Unit). Methods of the Allergenic Products Branch Office of Biologics Research and Review, FDA, Bethesda, MD 20892. Revised May 9, 1986.

14. Food and Drug Administration. Biological products; Allergenic extracts classified in Category IIIB; Final order; Revocation of licenses. Federal Register. 59(220): 59228ff, November 16, 1994.

Tetanus Toxoid Antigen:

• Multitest (Tetanus Toxoid Antigen) reviews

This medication is given to provide protection (immunity) against tetanus (lockjaw) in adults and children 7 years or older. Vaccination is the best way to protect against this life-threatening disease. Vaccines work by causing the body to produce its own protection (antibodies). Tetanus vaccine is usually first given to infants with 2 other vaccines for diphtheria and whooping cough (pertussis) in a series of 3 injections. This medication is usually used as a "booster" vaccine after this first series. Closely follow the vaccination schedule provided by the doctor. Booster injections may be needed at the time of injury in older children and adults if it has been 5-10 years since the last tetanus vaccine was received. Booster injections should also be given every 10 years even if no injury has occurred. This injection or an injection with tetanus/diphtheria or tetanus/diphtheria/pertussis may be used for the booster.

Tuberculin Antigen:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• References
• Multitest (Tuberculin Antigen) reviews

INDICATIONS AND USAGE

Multitest (Tuberculin Antigen), Multitest (Tuberculin Antigen) Purified Protein Derivative (Mantoux), is indicated to aid diagnosis of tuberculosis infection (TB) in persons at increased risk of developing active disease.

The Centers for Disease Control and Prevention (CDC) have published guidelines regarding populations that would benefit from Multitest (Tuberculin Antigen) skin testing (TST). Current recommendations can be accessed at: http://www.cdc.gov/tb/publications/factsheets/testing.htm.

Previous BCG vaccination is not a contraindication to Multitest (Tuberculin Antigen) testing. The skin-test results of BCG vaccinated persons can be used to support or exclude the diagnosis of TB infection. However, an FDA-approved interferon gamma release assay is preferred over Multitest (Tuberculin Antigen) skin test for persons 5 years of age and older who were previously vaccinated with BCG. (9)

CONTRAINDICATIONS

Allergy to any component of Multitest (Tuberculin Antigen) or an anaphylactic or other allergic reaction to a previous test of Multitest (Tuberculin Antigen) PPD is a contraindication to the use of Multitest (Tuberculin Antigen).

Multitest (Tuberculin Antigen) should not be administered to:

• Persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock or ulcerations) to a previous TST,
• Persons with documented active tuberculosis or a clear history of treatment for TB infection or disease, (10)
• Persons with extensive burns or eczema.

WARNINGS

Hypersensitivity

Allergic reactions may occur following the use of Multitest even in persons with no prior history of hypersensitivity to the product components. (11) Epinephrine injection (1:1,000) and other appropriate agents used for the control of immediate allergic reactions must be immediately available.

Syncope

Syncope (fainting) can occur in association with administration of injectable medicines, including Multitest (Tuberculin Antigen). Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.

PRECAUTIONS

GENERAL

Diagnostic Limitations

False positive or false negative Multitest skin test reactions may occur in some individuals.

False positive Multitest (Tuberculin Antigen) reaction tests occur in individuals who have been infected with other mycobacteria, including vaccination with BCG.

Not all infected persons will have a delayed hypersensitivity reaction to a Multitest (Tuberculin Antigen) test.

Many factors have been reported to cause a decreased ability to respond to the Multitest (Tuberculin Antigen) test in the presence of tuberculous infection.

INFORMATION FOR PATIENTS

Prior to administration of Multitest (Tuberculin Antigen), the patient's current health status and medical history should be reviewed. The physician should review the patient's immunization history for possible sensitivity to components of Multitest (Tuberculin Antigen).

The healthcare provider should inform the patient of the need to return for the reading of the test. Self-reading of the test has been shown to be inaccurate and unreliable.

The healthcare provider should give the patient a permanent personal record. In addition, it is essential that the health professional record the testing history in the permanent medical record of each patient. This permanent office record should contain the name of the product, date given, dose, manufacturer and lot number, as well as the test result in millimeters of induration (including 0 mm, if appropriate). Reporting results only as negative or positive is not satisfactory.

DRUG INTERACTIONS

Reactivity to the test may be depressed or suppressed in persons who are receiving corticosteroids or immunosuppressive agents.

Reactivity to Multitest (Tuberculin Antigen) may be temporarily depressed by certain live virus vaccines (measles, mumps, rubella, oral polio, yellow fever, and varicella). If a parenteral live attenuated virus vaccine has been administered recently, Multitest (Tuberculin Antigen) testing should be delayed for >1 month after vaccination. (8) (12)

When Multitest (Tuberculin Antigen) screening is required at the same time as a measles-containing vaccine or other parenteral live attenuated virus vaccine, simultaneous administration of Multitest (Tuberculin Antigen) and the vaccine at separate sites is the preferred option.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Multitest (Tuberculin Antigen) has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility.

PREGNANCY

Animal reproduction studies have not been conducted with Multitest. It is also not known whether Multitest (Tuberculin Antigen) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Multitest (Tuberculin Antigen) should be given to a pregnant woman only if clearly needed.

NURSING MOTHERS

It is not known whether Multitest (Tuberculin Antigen) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Multitest (Tuberculin Antigen) is administered to a nursing woman.

PEDIATRIC USE

There is no contraindication to Multitest skin testing of infants. Infants <6 months of age who are infected with M. tuberculosis may not react to Multitest (Tuberculin Antigen).

GERIATRIC USE

Clinical studies of Multitest (Tuberculin Antigen) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

ADVERSE REACTIONS

Induration at the Multitest injection site is the expected reaction for a positive skin test.

The information pertaining to adverse events has been compiled from historical clinical studies and post-marketing experience with Multitest (Tuberculin Antigen).

General disorders and administration site conditions

• Injection site pain, injection site pruritus and injection site discomfort.
• Injection site erythema or injection site rash (without induration) occurring within 12 hours of testing. These reactions do not indicate TB infection.
• Injection site hemorrhage and injection site hematoma up to three days after the administration of the test.
• Injection site vesicles, injection site ulcer or injection site necrosis in highly sensitive persons.
• Injection site scar as a result of strongly positive reactions.
• Pyrexia

Immune system disorders

• Hypersensitivity, including anaphylaxis/anaphylactic reactions, angiodema, urticaria

Respiratory, thoracic and mediastinal disorders

• Stridor, dyspnea

Skin and subcutaneous tissue disorders

• Rash, generalized rash

Nervous system disorders

• Presyncope, syncope sometimes resulting in transient loss of consciousness with injury

REPORTING OF ADVERSE EVENTS

To report SUSPECTED ADVERSE REACTIONS, contact the Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463 (1-800-VACCINE) or Food and Drug Administration (FDA) MEDWATCH Program at 1-800-332-1088 and www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

DOSAGE

Five Multitest (Tuberculin Antigen) units (TU) per test dose of 0.1 mL is the standard strength used for intradermal (Mantoux) testing.

METHOD OF ADMINISTRATION

Multitest (Tuberculin Antigen) is indicated for intradermal injection only. Do not inject intravenously, intramuscularly, or subcutaneously. If subcutaneous injection occurs, the test cannot be interpreted.

Inspect for extraneous particulate matter and/or discoloration before use. If these conditions exist, do not administer the product.

Use a separate syringe and needle for each injection. (13)

The following procedure is recommended for performing the Mantoux test:

• The preferred site of the test is the volar aspect of the forearm. Avoid areas on the skin that are red or swollen. Avoid visible veins.
• Clean the skin site with a suitable germicide and allow the site to dry prior to injection of the antigen.
• Administer the test dose (0.1 mL) of Multitest (Tuberculin Antigen) with a 1 mL syringe calibrated in tenths and fitted with a short, one-quarter to one-half inch, 26 or 27 gauge needle.
• Wipe the stopper of the vial with a suitable germicide and allow to dry before needle insertion. Then insert the needle gently through the stopper and draw 0.1 mL of Multitest (Tuberculin Antigen) into the syringe. Avoid injection of excess air with removal of each dose so as not to over pressurize the vial and possibly cause seepage at the puncture site.
• Insert the point of the needle into the most superficial layers of the skin with the needle bevel pointing upward and administer the dose by slow intradermal injection. If the intradermal injection is performed properly, a definite pale bleb will rise at the needle point, about 10 mm (³/₈") in diameter. This bleb will disperse within minutes. Do not dress the site.
• A drop of blood may appear at the administration site following injection. Blot the site lightly to remove the blood but avoid squeezing out the injected Multitest (Tuberculin Antigen) test fluid.

In the event of an improperly performed injection (ie, no bleb formed), repeat the test immediately at another site, at least 2 inches from the first site and circle the second injection site as an indication that this is the site to be read.

Inform the patient of the need to return for the reading of the test by a trained health professional. Self-reading may be inaccurate and is strongly discouraged.

INTERPRETATION OF THE TEST

The skin test should be read by a trained health professional 48 to 72 hours after administration of Multitest. Skin test sensitivity is indicated by induration only; redness should not be measured.

Measure the diameter of induration transversely to the long axis of the forearm and record the measurement in millimeters (including 0 mm). (8) The tip of a ballpoint pen, gently pushed at a 45° angle toward the site of injection, will stop at the edge of induration.

Also record presence and size (if present) of necrosis and edema, although these are not used in the interpretation of the test.

Positive Reactions

Multitest (Tuberculin Antigen) reactivity may indicate latent infection, prior infection and/or disease with M. tuberculosis and does not necessarily indicate the presence of active tuberculous disease. Persons showing positive Multitest (Tuberculin Antigen) reactions should be considered positive by current public health guidelines and referred for further medical evaluation. (8) (10) The repeated testing of uninfected persons does not sensitize them to Multitest (Tuberculin Antigen). (7) (8) (10)

The significance of induration measurements in diagnosing latent TB infection must be considered in terms of the patient's history and the risk of developing active TB disease as indicated in Table 1. (10)

Reaction ≥5 mm of Induration	Reaction ≥10 mm of Induration	Reaction ≥15 mm of Induration
HIV-positive persons Recent contacts of tuberculosis (TB) case patients Fibrotic changes on chest radiograph consistent with prior TB Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥15 mg/d of prednisone for 1 month or more)Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration.	Recent immigrants (i.e., within the last 5 yrs) from high prevalence countries Injection drug users Residents or employeesFor persons who are otherwise at low risk and are tested at the start of employment, a reaction of ≥15 mm induration is considered positive. of the following high-risk congregate settings: prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other healthcare facilities, residential facilities for patients with acquired immunodeficiency syndrome (AIDS) and homeless shelters Mycobacteriology laboratory personnel Persons with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some hematologic disorders (e.g., leukemias and lymphomas), other specific malignancies (e.g., carcinoma of the head or neck and lung), weight loss of ≥10% of ideal body weight, gastrectomy and jejunoileal bypass Children younger than 4 yrs of age or infants, children, and adolescents exposed to adults at high-risk	Persons with no risk factors for TB

A TST conversion is defined as an increase of ≥10 mm of induration within a 2-year period, regardless of age. (10)

The possibility should be considered that the skin test sensitivity may also be due to a previous contact with atypical mycobacteria or previous BCG vaccination. (8) (10)

Negative Reactions

An individual who does not show a positive reaction to 5 TU on the first test, but is suspected of being TB positive, may be retested with 5 TU. Any individual who does not show a positive reaction to an initial injection of 5 TU, or a second test with 5 TU may be considered as Multitest (Tuberculin Antigen) negative.

False Positive Reactions

False positive Multitest (Tuberculin Antigen) reactions can occur in individuals who have been infected with other mycobacteria, including vaccination with BCG. (8) However, a diagnosis of M. tuberculosis infection and the use of preventive therapy should be considered for any BCG-vaccinated person who has a positive TST reaction, especially if the person has been, or is, at increased risk of acquiring TB infection. (14) (15)

False-Negative Reactions

Not all infected persons will have a delayed hypersensitivity reaction to a Multitest test.

In those who are elderly or those who are being tested for the first time, reactions may develop slowly and may not peak until after 72 hours.

Since Multitest (Tuberculin Antigen) sensitivity may take up to 8 weeks to develop following exposure to M. tuberculosis, persons who have a negative Multitest (Tuberculin Antigen) test <8 weeks following possible TB exposure should be retested ≥8-10 weeks following the last known or suspected exposure. (16)

Altered Immune Status

Impaired or attenuated cell mediated immunity (CMI) can potentially cause a false negative Multitest (Tuberculin Antigen) reaction. Many factors have been reported to cause a decreased ability to respond to the Multitest (Tuberculin Antigen) test in the presence of tuberculous infection including viral infections (e.g., measles, mumps, chickenpox and HIV), live virus vaccinations (e.g., measles, mumps, rubella, oral polio and yellow fever), overwhelming tuberculosis, other bacterial infections, leukemia, sarcoidosis, fungal infections, metabolic derangements, low protein states, diseases affecting lymphoid organs, drugs (corticosteroids and many other immunosuppressive agents), and malignancy or stress. (8) (17) (18) A TST should be deferred for patients with major viral infections or live-virus vaccination in the past month. Persons with the common cold may be Multitest (Tuberculin Antigen) tested.

Because TST results in HIV-infected individuals are less reliable as CD4 counts decline, screening should be completed as early as possible after HIV-infection occurs. (18)

BOOSTER EFFECT AND TWO-STEP TESTING

If Multitest (Tuberculin Antigen) testing will be conducted at regular intervals, for instance among healthcare workers or prison workers, two-step testing should be performed as a baseline to avoid interpreting a booster effect as a Multitest (Tuberculin Antigen) conversion. If the first test showed either no reaction or a small reaction, the second test should be performed one to four weeks later. Both tests should be read and recorded at 48 to 72 hours. Patients with a second Multitest (Tuberculin Antigen) test (booster) response of ≥10 mm should be considered to have experienced past TB infection. (14) (19)

Persons who do not boost when given repeat tests at one week, but whose Multitest (Tuberculin Antigen) reactions change to positive after one year, should be considered to have newly acquired tuberculosis infection and managed accordingly. (7)

HOW SUPPLIED

Multitest, Multitest (Tuberculin Antigen) Purified Protein Derivative (Mantoux), bioequivalent to 5 US units (TU) PPD-S per test dose (0.1 mL) is supplied in:

10-test vial, 1 mL. NDC No. 49281-752-78; package of 1 vial, NDC No. 49281-752-21

50-test vial, 5 mL. NDC No. 49281-752-98; package of 1 vial, NDC No. 49281-752-22

The stopper of the vial for this product does not contain natural latex rubber.

STORAGE

Store at 2° to 8°C (35° to 46°F). (20) Do not freeze. Discard product if exposed to freezing.

Protect from light. Multitest (Tuberculin Antigen) PPD solutions can be adversely affected by exposure to light. The product should be stored in the dark except when doses are actually being withdrawn from the vial. (21)

A vial of Multitest (Tuberculin Antigen) which has been entered and in use for 30 days should be discarded. (22)

Do not use after expiration date.

REFERENCES

• Landi S. Preparation, purification, and stability of Multitest (Tuberculin Antigen). Appl Microbiol 1963;11:408-412.
• Landi S, et al. Preparation and characterization of a large batch of Multitest (Tuberculin Antigen) purified protein derivative (PPD-CT68). Ann Scalvo.1980;22:889-907.
• US Code of Federal Regulations, Title 21, Part 610, Subpart C - Standard preparations and limits of potency.
• Landi S, et al. Adsorption of Multitest (Tuberculin Antigen) PPD to glass and plastic surfaces. Bull. WHO 1966;35:593-602.
• Landi S, et al. Disparity of potency between stabilized and nonstabilized dilute Multitest (Tuberculin Antigen) solutions. Am Rev Respir Dis 1971;104:385-393.
• Landi S, et al. Stability of dilute solutions of Multitest (Tuberculin Antigen) purified protein derivative. Tubercle 1978;59:121-133.
• Menzies D. Interpretation of repeated Multitest (Tuberculin Antigen) tests. Am J Respir Crit Care Med 1999;159:15-21.
• American Thoracic Society: Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:1376-1395.
• CDC. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection - United States, 2010. MMWR 2010; 59 (RR-5):1-25.
• CDC. Targeted Multitest (Tuberculin Antigen) testing and treatment of latent tuberculosis infection. MMWR 2000;49(RR-6):23-5.
• Froeschle JE, et al. Immediate hypersensitivity reactions after use of Multitest (Tuberculin Antigen) skin testing. Clin Infect Dis 2002;34:e12-13.
• Brickman HF, et al. The timing of Multitest (Tuberculin Antigen) tests in relation to immunization with live viral vaccines. Pediatrics: 1975;55:392-396.
• CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR-2):1-35.
• CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR 2005;54(RR-17):1-141.
• CDC. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR 1996; 45(RR-4):8-9.
• CDC. Guidelines for the Investigation of Contacts of Persons with Infectious Tuberculosis: Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005;54(RR-15):1-47.
• Mori and Shiozawa. Suppression of Multitest (Tuberculin Antigen) hypersensitivity caused by rubella infection. Am Rev Respir Dis 1985;886-888.
• CDC. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Recommendations from the CDC, the National Institutes of Health, and the HIV Medicine Association of Infectious Diseases Society of America. MMWR 2009;58(RR-4):1-207.
• CDC. Prevention and control of tuberculosis in correctional and detention facilities: Recommendations from the CDC. MMWR 2006;55(RR-9):1-44.
• Landi S, et al. Stability of dilute solution of Multitest (Tuberculin Antigen) purified protein derivative at extreme temperatures. J Biol Stand 1981;9:195-199.
• Landi S, et al. Effect of light on Multitest (Tuberculin Antigen) purified protein derivative solutions. Am Rev Respir Dis 1975;111:52-61.
• Landi S, et al. Effect of oxidation on the stability of Multitest (Tuberculin Antigen) purified protein derivative (PPD) In: International Symposium on Tuberculins and BCG Vaccine. Basel: International Association of Biological Standardization, 1983. Dev Biol Stand 1986;58:545-552.

Manufactured by:

Sanofi Pasteur Limited

Toronto Ontario Canada

Distributed by:

Sanofi Pasteur Inc.

Swiftwater PA 18370 USA

Product Information as of

April 2016

Printed in Canada

R10-0416 USA

Multitest (Tuberculin Antigen) Purified

Protein Derivative

(Mantoux)

Multitest (Tuberculin Antigen)^® 1 mL (10 Tests)

Test dose: 5 TU/0.1 mL ID.

Protect from light.

Discard opened

product after 30 days.

Rx only

Sanofi Pasteur Limited

Date opened