Mechanism of Action

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 3-8 weeks, these lymphocytes enter the blood stream and circulate for years. (7) Subsequent restimulation of these sensitized lymphocytes with the same or a similar antigen, such as the intradermal injection of TUBERSOL, evokes a local reaction mediated by these cells. (8)

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. The resultant immune response 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 natural mycobacterial infection or by vaccination with BCG Vaccine.

Hypersensitivity

Allergic reactions may occur following the use of TUBERSOL 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 TUBERSOL. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.

General

Information for Patients

Prior to administration of TUBERSOL, 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 TUBERSOL.

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. (8)

Reactivity to TUBERSOL 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, tuberculin testing should be delayed for >1 month after vaccination. (8) (12) (See Interpretation of the Test.)

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

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

TUBERSOL has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility.

Pregnancy

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.

Nursing Mothers

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

Pediatric Use

There is no contraindication to tuberculin skin testing of infants. Infants <6 months of age who are infected with M. tuberculosis may not react to TUBERSOL. (See Interpretation of the Test.)

Geriatric Use

Clinical studies of TUBERSOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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, angioedema, urticaria

Respiratory, thoracic and mediastinal disorders

 

Stridor, dyspnea

Skin and subcutaneous tissue disorders

 

Rash, generalized rash

Nervous system disorders

 

Presyncope, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) 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

Five (5) tuberculin units (TU) per test dose of 0.1 mL is the standard strength used for intradermal (Mantoux) testing.

Method of Administration

TUBERSOL 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:

1. 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.
2. Clean the skin site with a suitable germicide and allow the site to dry prior to injection of the antigen.
3. Administer the test dose (0.1 mL) of TUBERSOL with a 1 mL syringe calibrated in tenths and fitted with a short, one-quarter to one-half inch, 26 or 27 gauge needle.
4. 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 TUBERSOL 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.
5. 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.
6. 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 tuberculin 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 TUBERSOL. 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.

Booster Effect and Two-Step Testing

If tuberculin 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 tuberculin 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 tuberculin 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 tuberculin reactions change to positive after one year, should be considered to have newly acquired tuberculosis infection and managed accordingly. (7)