purified protein derivative of tuberculin 100 UNT/ML Injectable Solution

INDICATIONS AND USAGE TUBERSOL Tuberculin 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 tuberculin 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 tuberculin 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 tuberculin skin test for persons 5 years of age and older who were previously vaccinated with BCG. (8)

DOSAGE AND ADMINISTRATION Aplisol vials should be inspected visually for both particulate matter and discoloration prior to administration and discarded if either is seen. Vials in use for more than 30 days should be discarded. The 0.1 mL dose of Aplisol (tuberculin PPD, diluted) is equivalent to the 5 tuberculin units (TU) dose of Tuberculin PPD, which is the standard strength used for intradermal Mantoux testing. Standard Method (Mantoux Test) The Mantoux test is performed by intradermally injecting, on the volar aspect of the forearm, with a syringe and needle, exactly 0.1 mL of Aplisol. The result is read 48 to 72 hours later and palpable induration only is considered in interpreting the test . Induration is a hard, raised area with clearly defined margins at and around the injection site (see Interpretation of Tuberculin Reaction ). Erythema may develop at the injection site but has no diagnostic value. The standard test is performed as follows: The site of the test is usually the volar or dorsal surface of the forearm about 4" below the elbow. Other skin sites may be used, but the volar surface of the forearm is preferred. The use of a skin area free of lesions and away from any veins is recommended. 7 The skin at the injection site is cleansed with 70% alcohol and allowed to dry. The test material is administered with a tuberculin syringe (0.5 or 1.0 mL) fitted with a short (1/4 to 1/2") 27 gauge needle. A separate, sterile, single-use disposable syringe and needle should be used for each individual patient. The diaphragm of the vial-stopper should be wiped with 70% alcohol. The needle is inserted through the stopper diaphragm of the inverted vial. Exactly 0.1 mL is filled into the syringe with care being taken to exclude air bubbles and to maintain the lumen of the needle filled. The point of the needle is inserted into the most superficial layers of the skin with the needle bevel pointed upward. As the Tuberculin solution is injected, a pale bleb 6 to 10 mm in size (1/3") will rise over the point of the needle. This is quickly absorbed and no dressing is required. There may be a drop of blood when the needle is withdrawn. This is normal. Use a gauze pad and gently dab to remove the blood. Do not press down as this may squeeze out the tuberculin thereby disrupting the test. In the event the injection is delivered subcutaneously (i.e., no bleb will form), or if a significant part of the dose leaks from the injection site, the test should be repeated immediately at another site at least 5 cm (2") removed from the initial injection site. Interpretation of Tuberculin Reaction Readings of Mantoux reactions should be made by a trained health professional during the period from 48 to 72 hours after the injection. Induration only should be considered in interpreting the test. The diameter of induration should be measured transversely to the long axis of the forearm and recorded in millimeters. Erythema has no diagnostic value and should be disregarded. The presence and size of necrosis and edema if present should be recorded although not used in the interpretation of the test. In the absence of induration, an area of erythema greater than 10 mm in diameter may indicate the injection was made too deeply and retesting is indicated. Find the margins of the induration by drawing the index or middle finger lightly across the reaction. The tip of a ballpoint pen pushed at a 45° angle toward the site of injection will also stop at the edges of induration. The diameter of induration should be measured (preferable with a caliper) transversely to the long axis of the forearm and recorded in millimeters. Erythema has no diagnostic value and should be disregarded. The absence of induration should be recorded as "0 mm" not "negative". Reactions should be interpreted as follows (Please refer to most recent guidelines): Based on current guidelines, 3,7,14, 19 interpretation of reactions is as follows: Positive reactions: Reaction ≥ 5 mm of Induration Reaction ≥ 10 mm of Induration Reaction ≥ 15 mm of Induration Human immunodeficiency virus (HIV)-positive persons Recent immigrants (i.e., within the last 5 yr) from high prevalence countries Persons with no risk factors for TB Recent contacts of tuberculosis (TB) case patients Injection drug users Fibrotic changes on chest radiograph consistent with prior TB Residents and employees For 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 health care facilities, residential facilities for patients with acquired immunodeficiency syndrome (AIDS), and homeless shelters Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of ≥ 15 mg/d of prednisone for 1 mo or more) Risk of TB in patients treated with corticosteroids increases with higher dose and longer duration. 19 Mycobacteriology laboratory personnel Persons with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some hematological 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 yr of age or infants, children, and adolescents exposed to adults at high-risk Skin test conversions For persons with negative skin test reactions who undergo repeat skin testing (e.g., health care workers), an increase in reaction size ≥ 10 mm within a period of 2 years should be considered a skin test conversion indicative of recent infection with M. tuberculosis . 19 In some individuals who have been infected with nontuberculous mycobacteria or have undergone BCG vaccination, the skin test may show some degree of induration. For these individuals, a conversion to "positive" is defined as an increase in induration by 10 mm on subsequent tests. 7 Healthcare facilities and other high-risk settings For health care workers and employees in other high-risk settings with no other risk factors for TB, a cut-off of 15 mm of induration (rather than 10 mm) on the tuberculin skin test should be used to define a positive baseline test at the time of initial employment. An increase of ≥10 mm in reaction size is generally accepted as a positive test result on subsequent testing unless the worker is a contact of a TB case or has HIV infection or is otherwise immunocompromised, in which case a result of ≥5 mm is considered positive. 21 Negative Reaction A negative reaction is an induration of less than 15 mm in persons with no risk factors for TB. This indicates a lack of hypersensitivity to tuberculoprotein and tuberculous infection is highly unlikely. 7 It should be noted that reactivity to tuberculin may be depressed or suppressed for as long as 5–6 weeks by viral infections, live virus vaccines (i.e., measles, smallpox, polio, rubella and mumps), or after discontinuation of therapy with corticosteroids or immunosuppressive agents. Malnutrition may also have a similar effect (see WARNINGS ). When of diagnostic importance, a negative test should be accepted as proof that hypersensitivity is absent only after normal reactivity to non-specific irritants has been demonstrated. A primary injection of tuberculin may possibly have a boosting effect on subsequent tuberculin reactions. A pediatric patient who is known to have been exposed to a person with tuberculosis must not be adjudged free of infection until that patient has a negative tuberculin reaction at least ten weeks after contact with tuberculous person has ceased. 17 Annual testing is generally recommended for pediatric patients in high risk populations, such as persons from countries with a high prevalence of tuberculosis and low-income groups

WARNINGS Aplisol should not be administered to persons who previously experienced a severe reaction (e.g., vesiculation, ulceration, or necrosis) because of the severity of reactions that may occur at the test site (see CONTRAINDICATIONS ). Not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test. A number of factors have been reported to cause a decreased ability to respond to the tuberculin test, such as the presence of infections, viral infections (measles, mumps, chickenpox, HIV), live virus vaccinations (measles, mumps, rubella and other live vaccines), bacterial infections (typhoid fever, brucellosis, typhus, leprosy, pertussis, overwhelming tuberculosis, tuberculous pleurisy), fungal infections (South American blastomycosis), drugs (corticosteroids and other immunosuppressive agents), metabolic derangements (chronic renal failure), low protein states (severe protein depletion, afibrinogenemia), age (newborns, elderly patients with waned sensitivity), stress (surgery, burns, mental illness, graft-versus-host reactions), diseases affecting lymphoid organs (Hodgkin's disease, lymphoma, chronic leukemia, sarcoidosis), and malignancy. 7,8,9 Any condition that impairs or attenuates cell mediated immunity potentially can cause a false negative reaction, including aging. 10,11 Tuberculin skin test results are less reliable in HIV-infected individuals as CD4 counts decline (see CLINICAL PHARMACOLOGY ). 3 Avoid injecting tuberculin subcutaneously. If this occurs, no local reaction develops, but a general febrile reaction and/or acute inflammation around old tuberculous lesions may occur in highly sensitive individuals.

CONTRAINDICATIONS Allergy to any component of TUBERSOL or an anaphylactic or other allergic reaction to a previous test of tuberculin PPD is a contraindication to the use of TUBERSOL. (See DESCRIPTION and HOW SUPPLIED .) TUBERSOL 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, (9) Persons with extensive burns or eczema.

CLINICAL PHARMACOLOGY In the United States, the prevalence of Mycobacterium tuberculosis infection and active disease varies for different segments of the population; however, the risk for M. tuberculosis infection in the overall population is low. Tuberculosis (TB) case rates declined steadily for decades in the United States. However, in 1985 the TB case rate stabilized and subsequently increased through 1992, accompanied by a 14% increase in the TB mortality rate in 1988. This has been attributed to several complex social and medical factors, including the human immunodeficiency virus (HIV) epidemic, the occurrence of TB in foreign-born persons from countries that have a high prevalence of TB, the emergence of drug-resistant strains of TB, and the transmission of M. tuberculosis in congregate settings (e.g., health-care facilities, correctional facilities, drug-treatment centers, and homeless shelters). Because the overall risk of acquiring M. tuberculosis is low for the total U.S. population, the primary strategy for preventing and controlling TB in the United States is to minimize the risk of transmission by the early identification and treatment of patients who have active infectious TB, finding and screening persons who have been in contact with active infectious TB patients and screening high risk populations. Tuberculin PPD is indicated as an aid in the detection of infection with Mycobacterium tuberculosis . 3,4 After a person becomes infected with mycobacteria, T lymphocytes proliferate and become sensitized. These sensitized T cells enter the bloodstream and circulate for months or years. This sensitization process occurs principally in the regional lymph nodes and may take 2–10 weeks to develop following infection. Once acquired, tuberculin sensitivity tends to persist, although it often wanes with time and advancing age. The injection of tuberculin into the skin stimulates the lymphocytes and activates the series of events leading to a delayed-type hypersensitivity (DTH) response. This response is called "delayed" because the reaction becomes evident hours after injection. Dermal reactivity involves vasodilation, edema, and the infiltration of lymphocytes, basophils, monocytes, and neutrophils into the site of antigen injection. Antigen-specific T lymphocytes proliferate and release lymphokines, which mediate the accumulation of other cells at the site. The area of induration reflects DTH activity. 5 In most tuberculin-sensitive individuals, the delayed hypersensitivity reaction is evident 5–6 hours after administration of a tuberculin skin test and is maximal 48–72 hours. In geriatric patients or in patients receiving a tuberculin skin test for the first time, the reaction may develop more slowly and may not be maximal until after 72 hours. 6,7 Because their immune systems are immature, many neonates and infants <6 weeks of age, who are infected with M. tuberculosis , do not react at all to tuberculin tests. 5 Immediate erythematous or other hypersensitivity reactions to tuberculin or the constituents of the diluent may occur at the injection site. A possible decrease in responsiveness to skin testing may occur in the presence of infections, viral infections (measles, mumps, chickenpox, HIV), live virus vaccinations (measles, mumps, rubella, oral polio, varicella, yellow fever), bacterial infections (typhoid fever, brucellosis, typhus, leprosy, pertussis, overwhelming tuberculosis, tuberculous pleurisy), fungal infections (South American blastomycosis), drugs (corticosteroids and other immunosuppressive agents), metabolic derangements (chronic renal failure), low protein states (severe protein depletion, afibrinogenemia), age (newborns, elderly patients with waned sensitivity), stress (surgery, burns, mental illness, graft-versus-host reactions), diseases affecting lymphoid organs (Hodgkin's disease, lymphoma, chronic leukemia, sarcoidosis) and malignancy (see WARNINGS ). Tuberculin skin-test results are also less reliable as CD4 counts decline in HIV infected individuals. 3 The 5TU dose of Tuberculin PPD intradermally (Mantoux) is indicated as an aid in the detection of infection with Mycobacterium tuberculosis . Reactions to the Mantoux test are interpreted on the basis of a quantitative measurement of the response to a specific dose (5 TU PPD-S or equivalent) of Tuberculin PPD. 7 To determine that the Tuberculin PPD is clinically bioequivalent in potency to standard 5TU PPD-S*, 3 dose-response studies were conducted in the following populations (1) persons with a history of bacteriologically confirmed TB; (2) healthy volunteers; and (3) volunteers with active or previously active nontuberculosis mycobacterial lung disease.