BCG LIVE (TICE® BCG) is not a vaccine for the prevention of cancer. BCG Vaccine, U.S.P., not BCG LIVE (TICE® BCG), should be used for the prevention of tuberculosis. For vaccination use, refer to BCG Vaccine, U.S.P. prescribing information.

TICE® BCG is an infectious agent. Physicians using this product should be familiar with the literature on the prevention and treatment of BCG-related complications, and should be prepared in such emergencies to contact an infectious disease specialist with experience in treating the infectious complications of intravesical BCG. The treatment of the infectious complications of BCG requires long-term, multiple-drug antibiotic therapy. Special culture media are required for mycobacteria, and physicians administering intravesical BCG or those caring for these patients should have these media readily available.

Instillation of TICE® BCG with an actively bleeding mucosa may promote systemic BCG infection. Treatment should be postponed for at least one week following transurethral resection, biopsy, traumatic catheterization, or gross hematuria.

Deaths have been reported as a result of systemic BCG infection and sepsis. ^2,3 Patients should be monitored for the presence of symptoms and signs of toxicity after each intravesical treatment. Febrile episodes with flu-like symptoms lasting more than 72 hours, fever ≥ 103°F, systemic manifestations increasing in intensity with repeated instillations, or persistent abnormalities of liver function tests suggest systemic BCG infection and may require antituberculous therapy. Local symptoms (prostatitis, epididymitis, orchitis) lasting more than 2-3 days may also suggest active infection (See Management of Serious BCG Complications subsection of

WARNINGS

The use of TICE® BCG may cause tuberculin sensitivity. Since this is a valuable aid in the diagnosis of tuberculosis, it is advisable to determine the tuberculin reactivity by PPD skin testing before treatment.

Intravesical instillations of BCG should be postponed during treatment with antibiotics, since antimicrobial therapy may interfere with the effectiveness of TICE® BCG (see

PRECAUTIONS

Small bladder capacity has been associated with increased risk of severe local reactions and should be considered in deciding to use TICE® BCG therapy.

Management of Serious BCG Complications.

Acute, localized irritative toxicities of TICE® BCG may be accompanied by systemic manifestations, consistent with a "flu-like" syndrome. Systemic adverse effects of 1-2 days' duration such as malaise, fever, and chills often reflect hypersensitivity reactions. However, symptoms such as fever of ≥38.5°C (101.3°F), or acute localized inflammation such as epididymitis, prostatitis, or orchitis persisting longer than 2-3 days suggest active infection, and evaluation for serious infectious complication should be considered.

In patients who develop persistent fever or experience an acute febrile illness consistent with BCG infection, two or more antimycobacterial agents should be administered while diagnostic evaluation, including cultures, is conducted. BCG treatment should be discontinued. Negative cultures do not necessarily rule out infection. Physicians using this product should be familiar with the literature on prevention, diagnosis, and treatment of BCG-related complications and, when appropriate, should consult an infectious disease specialist or other physician with experience in the diagnosis and treatment of mycobacterial infections.

TICE® BCG is sensitive to the most commonly used antituberculous agents (isoniazid, rifampin and ethambutol). TICE® BCG is not sensitive to pyrazinamide.

General

TICE® BCG contains live mycobacteria and should be prepared and handled using aseptic technique (See Preparation of Agent subsection of DOSAGE AND ADMINISTRATION ). BCG infections have been reported in health care workers preparing BCG for administration. Needle stick injuries should be avoided during the handling and mixing of TICE® BCG. Nosocomial infections have been reported in patients receiving parenteral drugs which were prepared in areas in which BCG was prepared. ⁴

BCG is capable of dissemination when administered by intravesical route and serious reactions, including fatal infections, have been reported in patients receiving intravesical BCG. ³ Care should be taken not to traumatize the urinary tract or to introduce contaminants into the urinary system. Seven to 14 days should elapse before TICE® BCG is administered following TUR, biopsy, or traumatic catheterization.

TICE® BCG should be administered with caution to persons in groups at high risk for HIV infection.

Laboratory Tests

The use of TICE® BCG may cause tuberculin sensitivity. It is advisable to determine the tuberculin reactivity of patients receiving TICE® BCG by PPD skin testing before treatment is initiated.

Information for Patients

TICE® BCG is retained in the bladder for 2 hours and then voided. Patients should void while seated in order to avoid splashing of urine. For the 6 hours after treatment, urine voided should be disinfected for 15 minutes with an equal volume of household bleach before flushing. Patients should be instructed to increase fluid intake in order to "flush" the bladder in the hours following BCG treatment. Patients may experience burning with the first void after treatment.

Patients should be attentive to side effects, such as fever, chills, malaise, flu-like symptoms, or increased fatigue. If the patient experiences severe urinary side effects, such as burning or pain on urination, urgency, frequency of urination, blood in urine, or other symptoms such as joint pain, cough, or skin rash, the physician should be notified.

Drug Interaction

Drug combinations containing immunosuppressants and/or bone marrow depressants and/or radiation interfere with the development of the immune response and should not be used in combination with TICE® BCG. Antimicrobial therapy for other infections may interfere with the effectiveness of TICE® BCG. There are no data to suggest that the acute, local urinary tract toxicity common with BCG is due to mycobacterial infection and antituberculosis drugs (e.g. isoniazid) should not be used to prevent or treat the local, irritative toxicities of TICE® BCG.

Carcinogenesis, Mutagenesis, Impairment of Fertility

TICE® BCG has not been evaluated for its carcinogenic, mutagenic potentials or impairment of fertility.

Pregnancy

Teratogenic Effects - Pregnancy Category C

Animal reproduction studies have not been conducted with TICE® BCG. It is also not known whether TICE® BCG can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. TICE® BCG should not be given to a pregnant woman except when clearly needed. Women should be advised not to become pregnant while on therapy.

Nursing Mothers

It is not known whether TICE® BCG is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from TICE® BCG in nursing infants, it is advisable to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of TICE® BCG for the treatment of superficial bladder cancer in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of TICE® BCG, the average age was 66 years old. No overall difference in safety or effectiveness was observed between older and younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individual to BCG cannot be ruled out.

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