DESCRIPTION

The Tuberculin, Old, TINE TEST® is a sterile, simple, multiple-puncture, disposable intradermal test device for the detection of tuberculin reactivity. These convenient devices are especially useful in mass tuberculosis screening programs.

Each test unit consists of a stainless steel disk attached to a white plastic handle. Projecting from the disk are four triangular-shaped prongs (tines) that are 2 mm long and approximately 4 mm apart. The tines have been mechanically dipped into a solution of Old Tuberculin, and then dried. The Old Tuberculin is a harvest filtrate of human-type strains (C, DT, and PN) of Mycobacterium tuberculosis grown in a synthetic medium. The harvest filtrate is concentrated by rotary evaporation, clarified by centrifugation, and stabilized with 7% acacia (gum arabic) and 8.5% lactose. The entire unit has been sterilized by Cobalt 60 irradiation. No preservative has been added. The device is for single dose, single use.

Tuberculin, Old, TINE TEST has been standardized by clinical evaluation in human subjects to elicit at least a 2 mm reaction or more in a person who responds with a 5 mm reaction or more to 5 TU (US tuberculin units) of standard Tuberculin, Old administered intradermally in the Mantoux test. 1

CLINICAL PHARMACOLOGY

Between 1953 and 1985, the number of cases of tuberculosis (TB) reported annually in the US decreased by 74%, from 84,304 to 22,201 cases. 2-5 Between 1985 and 1992, there was a 20% increase in the number of reported TB cases, to 26,673 in 1992. This resurgence was attributed to the emergence of the human immunodeficiency virus (HIV) epidemic, increased immigration from countries with high TB prevalence, social factors such as homelessness and substance abuse, increased numbers of persons in institutionalized settings, and decreased resources allocated to TB control programs. 2-4 Between 1992 and 1995, the reported number of TB cases in the US decreased by 4% to 6% annually. 3 This decline has been attributed to decreased transmission among persons in congregative settings (eg, hospitals, correctional facilities) and improvement in TB control measures. Despite the declining incidence, TB rates remain elevated in certain high-risk groups, such as immigrants, substance abusers, and the homeless.

The classic delayed-type tuberculin skin reaction is elicited in sensitive individuals by intradermal injection of tuberculoprotein antigens (purified protein derivative, old tuberculin). 6 Production of delayed skin reaction involves recognition of antigen by sensitized lymphocytes (T-cells), immobilization of lymphocytes at the site, production and release of lymphocyte mediators, and accumulation of macrophages, with eventual destruction of antigen and resolution of the reaction. 6 Fixed tissue macrophages and basophilic leukocytes, along with fibrin deposition and vessel permeability, also are found. 7 The result is an inflammatory response in the skin with the induration and erythema characteristic of a "positive" reaction.

In clinical studies covering various geographical areas of the United States and all age groups, with a total of 30,588 test subjects, there were 911 (approximately 4%) false positive reactors among 26,236 subjects who were Mantoux negative, and 342 (approximately 8%) false negative reactors among 4,352 subjects who were Mantoux positive. In this population, the sensitivity was 92.1% (95% CI: 91.3%-92.9%) and the specificity was 96.5% (96.3%-96.7%); these correspond to a false negative rate of 7.9% and a false positive rate of 3.5%.

Comparative data were obtained from 589 test subjects using commercial Tuberculin, Purified Protein Derivative (PPD) and US Standard Tuberculin (PPD-S) as Mantoux antigens and the Tuberculin, Old, TINE TEST® units. 8 The Tuberculin, Old, TINE TEST demonstrated a sensitivity of 97.8% (95% CI: 96.4%-99.2%) when compared to PPD-S and 97.3% (95% CI: 95.7%-98.9%) compared to commercial Tuberculin, PPD; these results correspond to false negative rates of 2.2% and 2.7%, respectively. Tuberculin, Old, TINE TEST demonstrated a specificity of 75.8% (95% CI: 69.6%-82.0%) when compared to PPD-S and 82.8% (95% CI: 77.3%-88.3%) compared to commercial Tuberculin, PPD; these results correspond to false positive rates of 24.2% and 17.2%, respectively. Based on these results, the positive predictive value ranges from 31.0% to 97.3% as the prevalence of positive Mantoux PPD-S tests varies from 10% to 90%; and 38.6% to 98.1% as the prevalence of positive Mantoux tests with commercial Tuberculin, PPD ranged from 10% to 90% in different populations. 9 It should be noted that these results are based on the accuracy of the Mantoux test in predicting the presence of TB infections. Mantoux test error rates have been reported to range from 2% to 10%. 8

Tuberculin, Old, TINE TEST reactions are measured at 48 to 72 hours. 1, 8 Various factors may influence the time to maximum reaction or the possibility of a false-negative reaction, including waning sensitivity in older persons. 10 Among individuals with waning sensitivity to homologous or heterologous mycobacterial antigens, however, the stimulus of a tuberculin test may "boost" or increase the size of the reaction to a second test, even causing an apparent development of sensitivity in some cases. 11

The recommended frequency of repeated tuberculin tests depends on risk of exposure of the individual and on the prevalence of tuberculosis in the population group. The repeated testing of uninfected individuals does not sensitize to tuberculin.

INDICATIONS AND USAGE

CONTRAINDICATIONS

Highly sensitive persons may respond to skin testing with vesicular or ulcerating local reactions. These reactions are interpreted as positive. Persons who are known to be tuberculin-positive should not be tested with Tuberculin, Old, TINE TEST® (see WARNINGS ). 12

There is no reliable method to distinguish a tuberculin reaction caused by vaccination with the bacille Calmette-Guérin (BCG) vaccine from those caused by natural mycobacterial infections. Therefore, a previously vaccinated person with a significant reaction to the Tuberculin, Old, TINE TEST should be evaluated for the presence of TB disease and managed accordingly. 12

Previous BCG vaccination is not a contraindication to the use of Tuberculin, Old, TINE TEST.

There are case reports of anaphylactic reactions to the Tuberculin, Old, TINE TEST. Any individual with a known significant immediate-type hypersensitivity to tuberculin or any component of the Tuberculin, Old, TINE TEST, including acacia (gum arabic), should not be tested with the Tuberculin, Old, TINE TEST.

WARNINGS

Tuberculin testing generally should not be administered to individuals with known active tuberculosis. Although activation of quiescent lesions is rare, if a patient has a history of occurrence of vesiculation and necrosis with a previous tuberculin test by any method, tuberculin testing should be avoided.

Skin testing is not to be used as the sole diagnostic factor and patients who have a positive reaction to Tuberculin, Old, TINE TEST® should be evaluated further with additional laboratory tests. Chest radiography is the preferred screening method for persons with current pulmonary TB. 10

PRECAUTIONS

General

Not all persons infected with M. tuberculosis will have a delayed-type hypersensitivity reaction to a tuberculin skin test. Factors which may cause a decreased ability to respond to tuberculin testing include: viral infections (eg, measles, mumps, chicken pox), live virus vaccinations (eg, measles, mumps, rubella, polio), overwhelming tuberculosis or other bacterial infections, drugs (eg, corticosteroids, immunosuppressive agents), metabolic derangements, nutritional factors, age (eg, newborns, elderly), and stress (eg, surgery, burns, mental illness, graft-host reactions). 14-16 Anything that impairs or attenuates cell-mediated immunity potentially can cause a false-negative reaction (eg, viral infections, particularly HIV; live viral vaccines; protein malnutrition; lymphoma; leukemia; sarcoidosis; use of glucocorticoid and other immunosuppressive drugs). Reactivity to the test also may be suppressed in individuals who are anergic.

As with any biological product, allergic reactions including anaphylaxis may occur. Before administration of Tuberculin, Old, TINE TEST®, the healthcare professional should take all known precautions for prevention of allergic or any other reactions. This includes a review of the patient' history for possible sensitivity to this or similar products or any component of Tuberculin, Old, TINE TEST, including acacia. Epinephrine injection (1:1,000) and other appropriate agents used for control of immediate allergic reactions should be available for immediate use. The healthcare professional should also obtain information about the patient' previous immunization history, including immunization with the BCG vaccination.

The utility of the tuberculin skin test depends on the prevalence of M. tuberculosis infection and the relative prevalence of cross-reaction with nontuberculous mycobacteria. 15, 16

The reactivity of the Tuberculin, Old, TINE TEST may be suppressed or depressed in persons who recently received live virus vaccines, who have had a viral infection, or who are receiving corticosteroids or immunosuppressive agents. 12-14

Antituberculous chemotherapy should not be instituted solely on the basis of a single positive Tuberculin, Old, TINE TEST unless vesiculation occurs, in which case management of the patient is the same as that for one classified as positive to the Mantoux test.

Tuberculin, Old, TINE TEST units must never be reused. The units should be discarded into an impenetrable sharps container without recapping.

Information for Patients

Prior to administration of this product, the healthcare professional should inform the patient or parent, guardian, or other responsible adult, of the benefits and risks of tuberculin skin tests. The healthcare professional should inform the patient that pain, pruritus and discomfort may occur at the injection site. Patients, parents or guardians should be instructed to report vesiculation, ulceration or necrosis which may appear at the test site in highly sensitive patients, and any adverse experience to their healthcare professional.

The patient should be given oral instructions regarding how to read the test, the importance of reading the skin test reactions at 48 hours, and the importance of returning the induration indicator card to the healthcare professional. The induration indicator card is an important health record.

Drug Interactions

Reactivity to the test may be suppressed in patients who are receiving corticosteroids or immunosuppressive agents, or those who have recently been immunized with live vaccines such as Measles-Mumps-Rubella vaccine (MMR) and oral polio vaccine. If tuberculin skin testing is indicated, it should be done preceding, or at the time of such immunization, and read 48 to 72 hours later. If the test is not administered in the time suggested, an interval of 4 to 6 weeks should be allowed between tuberculin skin testing and immunization with live measles vaccine or MMR to prevent suppression of tuberculin reaction. 11,17 The effect of live-virus varicella and yellow-fever vaccines on tuberculin skin testing is not known. 17

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tuberculin, Old, TINE TEST® has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.

Pregnancy

Pregnancy Category C.

Animal reproduction studies have not been conducted with Tuberculin, Old, TINE TEST®. It is also not known whether Tuberculin, Old, TINE TEST can cause fetal harm when administered to a pregnant woman or affect reproduction capacity.

Pregnancy is known to cause a physiologic suppression of cell-mediated immunity. 18 Several studies on tuberculin testing have been conducted during pregnancy. 19-23 Earlier studies suggested that a negative response to tuberculin may occur late in pregnancy while tests prior to pregnancy had been positive. 19-21 However, a well-controlled study and a study in which women who tested positive during pregnancy were retested in the postpartum period showed no indication that pregnancy affected the level of tuberculin sensitivity. 22, 23

The Advisory Council for the Elimination of Tuberculosis of the Centers for Disease Control and Prevention (CDC) considers tuberculin skin testing valid and safe throughout pregnancy. 10

Because of the possibility that a false negative response may occur during pregnancy, further diagnostic procedures should be considered if tuberculosis is suspected clinically. The clinical judgement of the healthcare professional should prevail at all times.

Pediatric Use

The American Academy of Pediatrics (AAP) and the Advisory Council for the Elimination of Tuberculosis of the CDC recommend focusing tuberculosis skin testing on children who are at increased risk of acquiring TB infection or disease. 10,24 Children without risk factors who reside in low-TB-prevalence areas, including those under 1 year of age, do not require routine TB skin testing. The AAP states that children who have no risk factors, but who reside in high-prevalence regions, and children whose histories for risk factors are incomplete or unreliable should be considered for tuberculin (Mantoux) skin testing at 4 to 6 and 11 to 16 years of age. Family investigation is indicated whenever a tuberculin skin test result of a parent or child converts from negative to positive (indicating recent infection). Children with HIV infection and those living with HIV-infected persons should receive annual tuberculin (Mantoux) skin testing. 24 Healthcare professionals, in their own judgement, may decide to administer tuberculin skin testing to specific children at earlier ages, if circumstances warrant.

Geriatric Use

Because TB case rates increase with age among all racial and ethnic groups and both sexes, screening for TB in facilities providing long-term care to the elderly is recommended. The incidence of disease is two to seven times higher among nursing home residents in some areas than among demographically similar persons in other settings. Studies indicated that unsuspected transmission of M. tuberculosis in nursing homes/facilities presents a risk to residents and workers. 10

ADVERSE REACTIONS

Postmarketing, voluntary reports of adverse events temporally associated with Tuberculin, Old, TINE TEST® have been received for which an association with the product is unknown. The following local reactions have been reported: rash, pain or discomfort, pruritus, transient bleeding at the puncture site and skin necrosis in highly sensitive persons. Systemic reactions have also been reported. These reactions include infection, dizziness, convulsion, fever, urticaria and allergic reactions, including anaphylactoid reactions. However, there is no indication as to the frequency and severity of reaction relating to these reports.

Healthcare professionals should report suspected adverse events after administration of Tuberculin, Old, TINE TEST to the Centers for Biologics Evaluation and Research of the Food and Drug Administration by submitting a MedWatch form. 25

DOSAGE AND ADMINISTRATION

The volar surface of the upper one third of the forearm, over the fleshy portion of a muscle is the preferred site. Hairy areas, and areas without adequate subcutaneous tissue, eg, concavities over a tendon or bone, should be avoided.

Alcohol, acetone, ether, or soap and water may be used to cleanse the skin. The area must be clean and thoroughly dry before application of the Tuberculin, Old, TINE TEST®.

Expose the four coated tines by removing the protective cap while holding the plastic handle. Grasp the patient' forearm firmly, since the sharp momentary sting may cause the patient to jerk his or her arm, resulting in scratching. Stretch the skin of the forearm tightly and apply the disk with the other hand. Hold at least 1 second. Sufficient pressure should be exerted so that the four puncture sites and circular depression of the skin from the plastic base are visible. Release tension grip on forearm. Withdraw TINE TEST unit.

After administration of the test, local care of the skin is not necessary.

Tuberculin, Old, TINE TEST units must never be reused . The units should be discarded into an impenetrable sharps container without recapping.

Reading Reactions.   Tests should be read at 48 to 72 hours. Vesiculation or the extent of induration are the determining factors. The size of any erythema or necrosis, if present, should be recorded, although not used in the interpretation of the test. Readings should be made in good light with the forearm slightly flexed. The size of the induration in millimeters should be determined by inspection, measuring, and palpation with gentle finger stroking. Identification of the application site is usually easy because of the distinct four-point pattern. The diameter of the largest single reaction around one of the puncture sites should be measured. With pronounced reactions, the areas of induration around the puncture sites may coalesce.

Interpretation:

Positive Reactions

  1. Vesiculation. If vesiculation is present, the test may be interpreted as positive, in which case the management of the patient is the same as that for one classified as positive to the Mantoux test. 11
  2. Induration, 2 mm or greater in diameter or similar in appearance to box 2, 3, or 4 of induration indicator card.

With a positive reaction, further diagnostic procedures must be considered. These may include X-ray of the chest, microbiological examinations of sputa and other specimens, and confirmation of the positive Tuberculin, Old, TINE TEST® reaction (except vesiculation reactions) using the Mantoux method. In general, the Tuberculin, Old, TINE TEST does not need to be repeated.

When vesiculation occurs, the reaction is to be interpreted as strongly positive and a repeat test by the Mantoux method is not required. 12, 15

The Tuberculin, Old, TINE TEST has been standardized by clinical evaluation in human subjects to elicit at least a 2 mm reaction or more in a person who responds with a 5 mm reaction or more to 5 TU of Tuberculin PPD administered intradermally in the Mantoux test. 1 However, there are certain high-risk populations in whom this reaction would not be considered positive including: 10

Appropriate diagnostic procedures, such as the Mantoux test, should be utilized for retesting individuals who display a 2 mm or greater reaction to Tuberculin, Old, TINE TEST.

For interpretation of the Mantoux test in various population groups the healthcare professional should refer to the recommendations of the Advisory Council for the Elimination of Tuberculosis of the CDC. 10

Negative Reaction

Induration less than 2 mm. Persons who are contacts of TB patients or who have clinical evidence of disease should be screened by the Mantoux test or chest radiography, even if they have demonstrated a negative reaction to Tuberculin, Old, TINE TEST®.

Induration indicator cards illustrating typical reactions are enclosed and are considered an important health record. They should be used to record reactions, and become a permanent part of the patient' file. Patients should be instructed to complete and return the card to the healthcare professional.

HOW SUPPLIED

Tuberculin, Old, TINE TEST® is supplied as follows:

  NDC 0005-2722-25 25 individual tests

  NDC 0005-2722-28 100 individual tests

STORAGE

STORE AT CONTROLLED ROOM TEMPERATURE 15°C to 30°C (59°F to 86°F). DO NOT REFRIGERATE.

REFERENCES

  1. Code of Federal Regulations, Food and Drugs; 21 CFR Subpart B--Tuberculin. 1996; 650.10.
  2. Daley CL. Current issues in the pathogenesis and management of HIV-related tuberculosis. AIDS Clin Rev. 1997-1998; 289-321.
  3. McCray E, et al. The epidemiology of tuberculosis in the United States. Clin Chest Med. 1997; 18(1):99-113.
  4. Kaye K, Frieden TR. Tuberculosis control: the relevance of classic principles in an era of acquired immuno-deficiency syndrome and multidrug resistance. Epidemiol Rev. 1996; 18(1):52-63.
  5. CDC: Tuberculosis morbidity--United States, 1995. MMWR. 1996; 45(18):365-370.
  6. Sell S. Immunology, Immunopathology and Immunity. 4th ed. New York, NY: Elsevier. 1987; 476-478.
  7. Dvorak HF, Mihm MC, Dvorak AM, et al. Morphology of delayed type hypersensitivity reactions in man. I. Quantitative description of the inflammatory response. Lab Invest. 1974; 31(2):11-130.
  8. Data on file, Professional Services Brochure, Lederle Laboratories, 1980.
  9. Data on file, Lederle Laboratories.
  10. Advisory Council for the Elimination of Tuberculosis: Screening for tuberculosis and tuberculosis infection in high-risk populations. MMWR. 1995; 44(RR-11):19-35.
  11. Comstock GW, Daniel TM, Snider DE Jr, et al. The tuberculin skin test. Am Rev Respir Dis. 1981; 124:356-363.
  12. Anonymous. Diagnostic standards and classification of tuberculosis. Official statement of the American Thoracic Society. Am Rev Respir Dis. 1990; 142:725-735.
  13. Tager IB, et al. Variability in the intradermal and in vitro lymphocyte responses to PPD in patients receiving isoniazid chemoprophylaxis. Am Rev Respir Dis. 1985; 131:214-220.
  14. Brickman HF, et al. The timing of tuberculin tests in relation to immunization with live viral vaccines. Pediatrics. 1975; 55:392-396.
  15. Huebner RE, et al. The tuberculin skin test. Clin Inf Dis. 1993; 17:968-975.
  16. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics. 1997; 564.
  17. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics. 1997; 354.
  18. Lederman MM. Cell-mediated immunity and pregnancy. Chest. 1984; 86(3, Suppl):65-95.
  19. Rich AR. The pathogenesis of tuberculosis. Springfield, IL: Charles C. Thomas, Publisher; 1944; 513.
  20. Lichtenstein MR. Tuberculosis in pregnancy. Am Rev Tuberc. 1942; 46:89.
  21. Conn RW. Effect of pregnancy upon tuberculin reactions. Am Rev Tuberc. 1942; 46:350.
  22. Present PA, Comstock GW. Tuberculin sensitivity in pregnancy. Am Rev Respir Dis. 1975; 112:413-416.
  23. Montgomery WP, et al. The tuberculin test in pregnancy. Am J Obstet Gyne. 1968; 100(6):829-831.
  24. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics. 1997; 544-547.
  25. Code of Federal Regulations, Food and Drugs; 21 CFR Subpart D-Reporting of Adverse Experiences. 1999; 600.80.

Manufactured by:

LEDERLE LABORATORIES

Division American Cyanamid Company

Pearl River, NY 10965 USA

US GOVERNMENT LICENSE NO. 17

Marketed by:

WYETH LEDERLE

    VACCINES

Wyeth-Ayerst Laboratories

Philadelphia, PA 19101 USA

CI 6398-1                      Issued February 8, 2001

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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