DESCRIPTION

Tuberculin PPD 1 (Mantoux)--Tubersol® for intracutaneous (Mantoux) tuberculin testing is available in stabilized solutions bio-equivalent to 5 U.S. units (TU) PPD-S per test dose (0.1 ml) and stabilized solutions diluted to a calculated bio-equivalance of 1 Tu and 250 TU strengths per test dose (0.1 ml).

Tubersol® is prepared by the Connaught Laboratories Limited from a large Master Batch, Connaught Tuberculin (CT68), which has been obtained from a human strain of Mycobacterium tuberculosis grown on a protein-free synthetic medium. The use of a standard preparation derived from a single batch (CT68) has been recommended 2 in order to eliminate batch to batch variation by the same manufacturer.

Tubersol® is a sterile isotonic solution of Tuberculin in phosphate buffered saline containing Tween 80 (0.0005%) as a stabilizer. Phenol 0.28% is added as a preservative. 3,4,5  Independent studies conducted by the U.S. Public Health Service in humans have determined the amount of CT68 in stabilized solution necessary to produce bio-equivalency with Tuberculin PPD-S (in phosphate buffer without Tween 80) using 5 U.S. units (TU) Tuberculin PPD-S as the standard.

Prior to release, each successive lot is tested for potency in sensitized guinea pigs in comparison with the U.S. Standard Tuberculin PPD-S distributed by the Office of Biologics, Food and Drug Administration, Bethesda, Maryland, U.S.A. 6

CLINICAL PHARMACOLOGY

Intracutaneous tuberculin testing is an accepted aid in the diagnosis of tuberculosis infection.

The reaction to intracutaneously injected tuberculin is a delayed (cellular) hypersensitivity reaction. The reaction which characteristically shows a delayed course, reaching its peak more than 24 hours after administration, consists of induration due to cell infiltration and occasionally vesiculation and necrosis. Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation of previous infection with M. tuberculosis or a variety of non-tuberculosis bacteria.  In most cases sensitization is induced by a natural mycobacterial infection or by vaccination with BCG Vaccine.

The sensitization following infection with mycobacteria occurs primarily in the regional lymph nodes. Small lymphocytes (T lymphocytes) proliferate in response to the antigenic stimulus to give rise to specifically sensitized lymphocytes. After several weeks, these lymphocytes enter the blood stream and circulate for long periods of time. Subsequent restimulation of these sensitized lymphocytes with the same or a similar antigen, such as the intradermal injection of tuberculin, evokes a local reaction mediated by these cells.

The tuberculin reaction is characterized by the early predominance of mononuclear cells (small and medium sized lymphocytes and monocytes). Only a small proportion of these cells appear to be lymphocytes sensitized to tuberculin. Most cells are brought into the reaction through the release of biologically active substances by sensitized lymphocytes. An increase in vascular permeability leading to erythema and edema also occurs in tuberculin reactions.

Characteristically, delayed hypersensitivity reactions to tuberculin begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside over a period of days. 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.  Immediate hypersensitivity reactions to tuberculin or to constituents of the diluent can also occur.

Not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test. A large number of factors has been reported to cause a decreased ability to respond to the tuberculin test in the presence of tuberculous infection including viral infections (measles, mumps, chickenpox), live virus vaccinations (measles, mumps, polio), overwhelming tuberculosis, other bacterial infections, drugs (corticosteroids and many

other immunosuppressive agents), and malignancy. 7

INDICATIONS AND USAGE

Tubersol® is indicated as an aid in the detection of infection with Mycobacterium tuberculosis.

For the initial intracutaneous (Mantoux) tuberculin test it is customary to use 5 U.S. units (TU) per test dose of 0.1 ml. The 1 TU per test dose (0.1 ml) preparation is used for individuals suspected of being highly sensitized since larger initial doses may result in severe skin reactions.  The preparation containing 250 TU per test dose (0.1 ml), should be used exclusively for the testing of individuals who fail to react to a previous injection of 5 TU and under no circumstances is it to be used for the initial injection.

CONTRAINDICATIONS

Tubersol® should not be administered to known tuberculin positive reactors because of the severity of reactions (eg. vesiculation, ulceration or necrosis) that may occur at the test site in highly sensitive persons.

WARNINGS

Tubersol® 250 TU per test dose (0.1 ml) is not, under any circumstances, to be used for the initial injection.

Avoid injecting Tubersol® subcutaneously. If this occurs, no local reaction will develop, but a general febrile reaction and/or acute inflammation around old tuberculosis lesions may occur in highly sensitive individuals.

PRECAUTIONS

a)   General

A separate sterile syringe and needle must be used for each individual injection to prevent the possibility of transmission of viral hepatitis or other infectious agents from one person to another.

The possibility of allergic reactions in individuals sensitive to the components of the product should be borne in mind. Epinephrine Hydrochloride Solution (1:1000) should be readily available for use in case an anaphylactic or acute hypersensitivity reaction occurs.  Failure to store and handle Tubersol® as recommended will result in a loss of potency and inaccurate test results.

b)   Information for Patients

Reactivity to the test may be depressed or suppressed for as long as 5 to 6 weeks in individuals who have received concurrent or recent immunization with certain virus vaccines (measles, influenza), who have had viral infections (rubeola, influenza, mumps and probably others) or who are receiving corticosteroids or immunosuppressive agents.  In those who are elderly or being tested for the first time reactions may develop slowly and may not peak until after 72 hours.

Vesiculation, ulceration or necrosis may appear at the test site in highly sensitive persons. Pain, pruritis and discomfort at the site may also occur.

c)Laboratory Tests

Since a positive tuberculin reaction (10 mm or more) does not necessarily indicate the presence of active tuberculous disease, individuals showing such positive tuberculin reactions should be subjected to other diagnostic procedures, such as X-ray examination of the chest and microbiological examination of the sputum.

In the case of the doubtful tuberculin reactions (5 to 9 mm) to 5 TU, the possibility should not be excluded that the skin sensitivity is due to previous contact with atypical mycobacteria or previous BCG vaccination. In the absence of signs of tuberculous disease, differential diagnosis by means of intracutaneous skin tests with PPD’s derived from atypical mycobacteria may be indicated.

d)   Drug Interactions

Reactivity to the test may be depressed or suppressed in individuals who are receiving corticosteroids or immunosuppressive agents.  Reactivity to PPD may be temporarily depressed by certain live virus vaccines (measles, mumps, rubella). Therefore, if a tuberculin test is to be performed, it should be administered either before or simultaneously with the injection of measles, mumps and rubella vaccines in combined form or as separate antigens.

e)   Carcinogenesis, Mutagenesis, Impairment of Fertility The product is not used for extended treatment over a long period of time.

f)    Pregnancy Category C (Tuberculin)

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

However, the risk of unrecognized tuberculosis and the close post partum contact between a mother with active disease and an infant leaves the infant in grave danger of tuberculosis and complications such as tuberculous meningitis. Therefore, the prescribing physician will want to consider if the potential benefits outweigh the possible risks for performing the tuberculin test on a pregnant woman or a woman of childbearing age, particularly in certain high risk populations.

ADVERSE REACTIONS

In highly sensitized individuals, strongly positive reactions including vesiculation, ulceration or necrosis may occur at the test site. Cold packs or topical steroid preparations may be employed for symptomatic relief of the associated pain, pruritus and discomfort.

Strongly positive reactions may result in scarring at the test site.

Immediate erythematous or other reactions may occur at the injection site.

The reason(s) for these infrequent occurrences are presently unknown.

DOSAGE AND ADMINISTRATION

The Test:   The Mantoux test is performed by intracutaneously injecting, with a syringe and needle, 0.1 ml of Tubersol®. It is customary to use 5 TU per test dose. The 1 TU per test dose preparation is used for individuals suspected of being highly sensitized since larger initial doses may result in severe skin reactions. The preparation containing 250 TU per test dose should be used exclusively for the testing of individuals who fail to react to a previous injection of 5 TU and under no circumstances is it to be used for the initial injection.

The result is read 48 to 72 hours after administration and induration only is considered in interpreting the test.

Method of Administration:   The following procedure is recommended for performing the Mantoux test:

·        The site of the test is the flexor surface of the forearm about 4 inches below the bend of the elbow.

·        The skin of the forearm is first cleansed with alcohol and allowed to dry.

·        The test dose (0.1 ml) of Tuberculin PPD is administered with a 1 ml syringe calibrated in tenths and fitted with a short, one-half inch, 26 or 27 gauge needle.

·        Disposable sterile syringes and needles may be used. Glass syringes and needles should be sterilized by autoclaving (121°C for 30 minutes), by boiling or by the use of dry heat. Do not sterilize by means of alcohol.

·        The rubber cap of the vial should be wiped with sterile piece of cotton moistened with alcohol and allowed to dry. The needle is then inserted gently through the cap and the required amount of Tuberculin PPD is drawn into the syringe.

·        The point of the needle is inserted into the most superficial layers of the skin with the needle bevel pointing upward. If the intracutaneous injection is performed properly, a definite white bleb will rise at the needle point, about 10 mm ( 3 / 8 “) in diameter. This will disappear within minutes. No dressing is required.

In the event of a subcutaneous injection (i.e. no bleb formed), the test should be repeated immediately at another site.

Tubersol® is a stabilized solution of Tuberculin PPD. Data indicates that Tubersol® will remain stable for at least four weeks when prefilled into syringes and stored between 2° and 8°C. 4 However, in order to avoid possible contamination of the product this practice is not recommended.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solutions and container permit.

Interpretation of the Test:   The test should be read 48 to 72 hours after administration of Tubersol®. Sensitivity is indicated by induration, usually accompanied by erythema. The widest diameter of distinctly palpable induration should be recorded in millimeters (mm). Presence of edema and necrosis should also be recorded.

A positive reaction indicates a sensitivity to tuberculin, which may be the result of a previous infection with mycobacteria. This infection, likely due to Mycobacterium tuberculosis, may have occurred years ago or may be of recent origin.

Reactions should be interpreted as follows:

Positive Reaction—Any palpable induration measuring 10 mm or more is considered a positive reaction. In the case of tuberculosis suspects or close contacts of individuals with tuberculosis an induration of 5 mm or even smaller should be interpreted as a positive reaction and appropriate additional follow-up measures indicated.

Doubtful Reaction—Induration measuring 5 to 9 mm indicates a doubtful reaction. Retesting is indicated using a different site and 5 TU per test dose.

The possibility should not be excluded that the skin sensitivity is due to previous contact with atypical mycobacteria or previous BCG vaccination.

Negative Reaction—Induration of less than 5 mm is considered negative. An individual who does not show a positive reaction to either 1 TU or 5 TU on the first test may be retested with 5 TU and if still found negative further testing with 0.1 ml containing 250 TU of Tuberculin PPD (Mantoux) is suggested. If the latter test is employed, it may be given in the other forearm.

An individual who does not show a positive reaction to an initial injection of either 1 TU and 5 TU, or 5 TU alone, and to a subsequent injection of 250 TU of Tuberculin PPD may be considered as tuberculin negative.

Booster Effect—Infection of an individual with tubercle bacilli or other mycobacteria results in a delayed hypersensitivity response to tuberculin which is demonstrated by the skin test. The delayed hypersensitivity response may gradually wane over a period of years. If a person receives a tuberculin test at this time (after several years) the response may be a reaction that is not significant. The stimulus of the test may boost or increase the size of the reaction to a second test, sometimes causing an apparent conversion or development of sensitivity. The booster effect can be seen on a second test done as soon as a week after the initial stimulating test and can persist for a year, and perhaps longer.

When routine periodic tuberculin testing of adults is done, two stage testing should be used to minimize the likelihood of interpreting a boosted reaction as a conversion, 7,8

Since a positive tuberculin reaction does not necessarily indicate the presence of active tuberculosis disease, individuals showing a positive tuberculin reaction should be subjected to other diagnostic procedures.

Those individuals giving a positive tuberculin reaction may or may not show evidence of tuberculosis disease. Chest X-ray examination and microbiological examination of the sputum in these cases are recommended as a means of determining the presence or absence of pulmonary tuberculosis.

HOW SUPPLIED

Tubersol® bioequivalent to 5 U.S. units (TU) PPD-S per test dose (0.1 ml) is available in 1 ml and 5 ml vials. Tubersol® 1 TU and 250 TU per test dose (0.1 ml) are available in 1 ml vials. Tubersol® solutions are ready for immediate use without any further dilution.

STORAGE

Tubersol® should be stored between 2° and 8°C (35° and 46°F). 5,9  Tuberculin 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. 10   A vial of Tuberculin PPD which has been opened and in use for one month should be discarded because oxidation and degradation may have reduced the potency. 11

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’s identity should be verified by chemical analysis.

REFERENCES

·        Landi, S.: Preparation, purification, and stability of tuberculin. Appl.

Microbiol. 11 : 408-412, 1963.

·        Canadian Tuberculosis and Respiratory Disease Association: Classification and reporting of tuberculosis in Canada. Ottawa, the Association, 1972 p. 42.

·        Landi, S., Held, H.R., Hauschild, A. H. W., Hilsheimer, R.: Adsorption of tuberculin PPD to glass and plastic surfaces. Bull. WHO 35 : 593-602, 1966.

·        Landi, S., Held, H.R., Tseng, M. D.: Disparity of potency between stabilized and nonstabilized dilute tuberculin solutions. Am. Rev. Respir.  Dis. 104 : 385-393, 1971.

·        Landi, S., Held, H.R.: Stability of dilute solutions of tuberculin purified protein derivative. Tubercle 59 : 121-133, 1978.

·        U.S. Code of Federal Regulations, Title 21, Part 650, Subpart B—tuberculin, 144-146, April 1, 1981.

·        The Tuberculin Skin Test. Am. Rev. Respir. Dis. 124 : 356-363, 1981.

·        American Thoracic Society: Diagnostic Standards and Classification of Tuberculosis and Other Mycobacterial Diseases (14^th ed.), 1980. Am. Rev.  Respir. Dis. 123 : 343-358, 1981.

·        Landi, S., Held, H.R.: Stability of dilute solution of tuberculin purified protein derivative at extreme temperatures. J. Biol. Stand. 9 : 195-199, 1981.

·        Landi, S., Held, H.R.: Effect of light on tuberculin purified protein derivative solutions. Am. Rev. Respir. Dis. 111 : 52-61, 1975.

·        Landi, S., Held, H.R.: Effect of oxidation on the stability of tuberculin purified protein derivative (PPD) In: International Symposium on Tuberculins and BCG Vaccine. Basel: International Association of Biological Standardization, 1983. (Developments in Biological Standardization) In press.

Manufactured by:

CONNAUGHT LABORATORIES LIMITED

TORONTO, ONTARIO, CANADA

Distributed by:

Connaught Laboratories, Inc.

Swiftwater, Pennsylvania 18370, USA

R2-1097 USA

D15

2000125

A

PASTEUR MÉRIEUX CONNAUGHT

RHÔNE-POULENC GROUP

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