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Data from Clinical Studies

Administration of TheraCys (bcg live (intravesical)) causes an inflammatory response in the bladder and has been frequently associated with transient fever, hematuria, urinary frequency and dysuria; careful patient monitoring is required. Symptoms of bladder irritability are reported in approximately 50% of patients receiving TheraCys (bcg live (intravesical)) and typically begin 4-6 hours after instillation and last 24-72 hours. The irritative side effects are usually seen following the third instillation and tend to increase in severity after each administration. The mechanism of action of the irritative side effects has not been studied, but is most consistent with an immunological mechanism. There is no evidence that dose reduction or antituberculous drug therapy can prevent or lessen the irritative symptoms ofTheraCys (bcg live (intravesical)) .

The adverse reactions which occurred among 127 recipients of TheraCys (bcg live (intravesical)) during a US clinical trial are listed in Table 2. (4) The adverse reactions are combined totals caused by both the original bladder cancer and the TheraCys (bcg live (intravesical)) treatment.

Table 2: Adverse Reactions: Toxicity Data Derived From a US Clinical Trial (4)

Adverse Event Percent of Patients
(N = 127)
Overall (Grade ≥ 3)
Adverse Event Percent of Patients
(N = 127)
Overall (Grade ≥ 3)
Dysuria 52% (4%) Nausea/Vomiting 16% (0%)
Urinary Frequency 40% (2%) Anorexia 11% (0%)
Malaise 40% (2%) Renal Toxicity (NOS) 10% (2%)
Hematuria 39% (7%) Genital Pain 10% (0%)
Fever (>38°C) 38% (3%) Arthralgia/Myalgia 7% (1%)
Chills 34% (3%) Urinary Incontinence 6% (0%)
Cystitis 29% (0%) Cramps/Pain 6% (0%)
Anemia 21% (0%) Diarrhea 6% (0%)
Urinary Tract Infection 18% (1%) Contracted Bladder 5% (0%)
Urgency 18% (0%) Leukopenia 5% (0%)

The following adverse reactions were reported in < 5% of patients: coagulopathy, abdominal pain, liver involvement, systemic infection, pulmonary infection, cardiac (unclassified), headache, skin rash, tissue in urine, local infection, constipation, dizziness, fatigue, thrombocytopenia, ureteral obstruction and flank pain.

In a US Clinical Trial, 112 patients received TheraCys (bcg live (intravesical)) . The incidence of adverse reactions associated with intravesical TheraCys (bcg live (intravesical)) is given below.

The following adverse events were reported in =1% of patients: tissue in urine, local infection, constipation, dizziness, fatigue, thrombocytopenia and flank pain.

In this study, local irritative symptoms were more common with TheraCys (bcg live (intravesical)) than with doxorubicin; however, grade ≥ 3 irritative toxicity was similar, occurring in approximately 2-7% of patients. Systemic symptoms (fever, chills, malaise, etc.) were also more common with TheraCys (bcg live (intravesical)) . Overall, grade ≥ 3 toxicities were seen in 26 patients (23%) treated with TheraCys (bcg live (intravesical)) and 25 patients (21%) treated with doxorubicin. "Systemic infection" was reported to occur in three patients treated with TheraCys (bcg live (intravesical)) (one grade 2 and two grade 3) and one patient treated with doxorubicin (grade 2). In four patients, treatment was discontinued because of toxicity (two with irritative symptoms, one with severe hematuria and one with possible BCG infection). In addition, six patients refused further treatment because of severe local toxicity and/or chills. Six of these ten patients received TheraCys (bcg live (intravesical)) . Table 3 compares the common adverse events reported in this study.

Table 3: Comparative Toxicity from a US Clinical Trial (4)

  Study Arm
TheraCys (N=112) Doxorubicin (N=119)
All Grades Grade =3 All Grades Grade =3
Dysuria 58 (52%) 4 (4%) 48 (40%) 7 (6%)
Frequency 45 (40%) 2 (2%) 34 (29%) 5 (4%)
Malaise 45 (40%) 2 (2%) 17 (14%) 0
Hematuria 44 (39%) 8 (7%) 33 (28%) 8 (7%)
Fever (>38°C) 43 (38%) 3 (3%) 11 (9%) 0
Chills 38 (34%) 3 (3%) 7 (6%) 0
Cystitis 33 (29%) 0 23 (19%) 1 (<1%)
Urgency 20 (18%) 1 (<1%) 14 (12%) 3 (2%)
Nausea/Vomiting 18 (16%) 0 10 (8%) 1 (<1%)
Bladder Cramps/Pain 7 (6%) 0 6 (5%) 2 (1%)

Acute, localized irritative side effects of TheraCys (bcg live (intravesical)) 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, or acute localized inflammation such as epididymitis, prostatitis, or orchitis, persisting longer than 48 hours suggest active infection and evaluation for serious infectious complication should be considered.

Data from Postmarketing Experience

These events were reported voluntarily from a population of uncertain size, it is not possible to reliably calculate their frequencies.

Symptomatic granulomatous prostatitis, epididymo-orchitis, and renal abscess associated with administration of intravesical BCG have been reported.

Ocular symptoms (including uveitis, conjunctivitis, iritis, keratitis, granulomatous choreoretinitis) alone, or in combination with joint symptoms (arthritis or arthralgia), urinary symptoms and/or skin rash, have been reported following administration of intravesical BCG. The risk appears to be elevated among patients who are positive for HLA-B27. (13)

Skin rash, arthralgia and migratory arthritis may be allergic reactions.

Serious infectious complications of intravesical BCG have been reported. The most serious infectious complication of BCG is disseminated sepsis associated with death. In addition, BCG infections have been reported in eye, lung, liver, bone, bone marrow, kidney, regional lymph nodes, peritoneum and prostate in patients who have received intravesical BCG. Some male genitourinary tract infections (orchitis/epididymitis) have been refractory to multiple drug antimycobacterial therapy and required orchiectomy.

Treatment ofAdverse Reactions

If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG infection, BCG instillations should be permanently discontinued, the patient immediately evaluated and treated for BCG infection and an infectious disease consultation sought. (See WARNINGS and PRECAUTIONS.) Treatment with two or more antimycobacterial agents should be initiated promptly while diagnostic evaluation, including cultures, is conducted. Negative cultures do not necessarily rule out infection. TheraCys (bcg live (intravesical)) is sensitive to the most commonly used antimycobacterial agents (isoniazid, rifampin and ethambutol). TheraCys (bcg live (intravesical)) is not sensitive to pyrazinamide. (14)

Reporting ofAdverse Reactions

Patients should be encouraged to report all adverse events after treatment with TheraCys (bcg live (intravesical)) . Adverse events should be reported by health care providers to MEDWATCH (call 1-800-FDA-1088 or report on line to Physicians, physician assistants, nurses and pharmacists should report adverse occurrences temporally related to the administration of the product to the Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater PA 18370 or call 1-800-822-2463.