TICE BCG BACILLUS CALMETTE-GUERIN 50 mg/50mL Powder, For Suspension

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

Handling Precautions 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. BCG Infection Instillation of TICE BCG with an actively bleeding mucosa may promote systemic BCG infection. Treatment should be postponed for at least 1 week following transurethral resection, biopsy, traumatic catheterization, or gross hematuria.

Systemic BCG Reaction 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 to 3 days may also suggest active infection (see WARNINGS, Management of Serious BCG Complications section). Laboratory Tests 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.

Antimicrobial Therapy Intravesical instillations of BCG should be postponed during treatment with antibiotics, since antimicrobial therapy may interfere with the effectiveness of TICE BCG (see PRECAUTIONS ). TICE BCG should not be used in individuals with concurrent infections. Bladder Capacity 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 to 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 to 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, 2 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.

ADVERSE REACTIONS Symptoms of bladder irritability, related to the inflammatory response induced, are reported in approximately 60% of patients receiving TICE ® BCG. The symptoms typically begin 4 to 6 hours after instillation and last 24 to 72 hours. The irritative side effects are usually seen following the third instillation, and tend to increase in severity after each administration.

The irritative bladder adverse effects can usually be managed symptomatically with products such as pyridium, propantheline bromide, oxybutynin chloride, and acetaminophen. The mechanism of action of the irritative side effects has not been firmly established, but is most consistent with an immunological mechanism. 3 There is no evidence that dose reduction or antituberculous drug therapy can prevent or lessen the irritative toxicity of TICE BCG. "Flu-like" symptoms (malaise, fever, and chills) which may accompany the localized, irritative toxicities often reflect hypersensitivity reactions which can be treated symptomatically.

Antihistamines have also been used. 5 Adverse reactions to TICE BCG tend to be progressive in frequency and severity with subsequent instillation. Delay or postponement of subsequent treatment may or may not reduce the severity of a reaction during subsequent instillation.

Although uncommon, serious infectious complications of intravesical BCG have been reported. 2,3,6 The most serious infectious complication of BCG is disseminated sepsis with associated mortality. In addition, M. bovis infections have been reported in lung, liver, bone, bone marrow, kidney, regional lymph nodes, and prostate in patients who have received intravesical BCG.

Systemic infections may be manifested by pneumonitis, hepatitis, cytopenia, vasculitis, infective aneurysm and/or sepsis after a period of fever and malaise during which symptoms progressively increase. Some male genitourinary tract infections (orchitis/epididymitis) have been resistant to multiple-drug antituberculous therapy and required orchiectomy. If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG infection, BCG treatment should be discontinued and the patient immediately evaluated and treated for systemic infection (see WARNINGS ).

The local and systemic adverse reactions reported in a review of 674 patients with superficial bladder cancer, including 153 patients with carcinoma in situ , are summarized in Table 5 . Table 5: Summary of Adverse Effects Seen in 674 Patients With Superficial Bladder Cancer, Including 153 With Carcinoma in Situ Percent of patients Percent of patients Adverse event N Overall (Grade ≥3) Adverse event N Overall (Grade ≥3) Dysuria 401 60% (11%) Arthritis/myalgia 18 3% (<1%) Urinary frequency 272 40% (7%) Headache/dizziness 16 2%(0) Flu-like syndrome 224 33% (9%) Urinary incontinence 16 2% (0) Hematuria 175 26% (7%) Anorexia/weight loss 15 2% (<1%) Fever 134 20% (8%) Urinary debris 15 2% (<1%) Malaise/fatigue 50 7% (0) Allergy 14 2% (<1%) Cystitis 40 6% (2%) Cardiac (unclassified) 13 2% (1%) Urgency 39 6% (1%) Genital inflammation/ Nocturia 30 5% (1%) abscess 12 2% (<1%) Cramps/pain 27 4% (1%) Respiratory (unclassified) 11 2% (<1%) Rigors 22 3% (1%) Urinary tract infection 10 2% (1%) Nausea/vomiting 20 3% (<1%) Abdominal pain 10 2% (1%) The following adverse events were reported in ≤1% of patients: anemia, BCG sepsis, coagulopathy, contracted bladder, diarrhea, epididymitis/prostatitis, hepatic granuloma, hepatitis, leukopenia, neurologic (unclassified), orchitis, pneumonitis, pyuria, rash, thrombocytopenia, urethritis, and urinary obstruction.

In SWOG study 8795, toxicity evaluations were available on a total of 222 TICE BCG-treated patients and 220 MMC-treated patients. Direct bladder toxicity (cramps, dysuria, frequency, urgency, hematuria, hemorrhagic cystitis, or incontinence) was seen more often with TICE BCG with 356 events, compared to 234 events for MMC. Grade ≤2 toxicity was seen significantly more…

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.