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)
|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 www.fda.gov/medwatch). 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.