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Symptoms of bladder irritability, related to the inflammatory response induced, are reported in approximately 60% of patients receiving TICE® BCG. The symptoms typically begin 4–6 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 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. 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 V.

TABLE V: SUMMARY OF ADVERSE EFFECTS SEEN IN 674 PATIENTS WITH SUPERFICIAL BLADDER CANCER, INCLUDING 153 WITH CARCINOMA IN SITU

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/Abscess 12 2% ( < 1%)
Nocturia 30 5% (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 frequently following TICE® BCG treatment (p=0.003). No life-threatening toxicity was seen in either arm. Systemic toxicity with TICE® BCG was markedly increased compared to that of MMC, with 181 events for TICE® BCG compared to 80 for MMC. The frequency of toxicity was increased in all grades, particularly for grades 2 and 3. The most common complaints were malaise, fatigue and lethargy, fever, and abdominal pain. Thirty-two TICE® BCG patients were reported to have been treated with isoniazid. Five TICE® BCG patients had liver enzyme elevation, including two with grade 3 elevations. Eighteen of the 222 (8.1%) TICE® BCG patients failed to complete the prescribed protocol compared to 6.2% in the MMC group. Table VI summarizes the most common adverse reactions reported in this trial.7

TABLE VI: MOST COMMON ADVERSE REACTIONS IN SWOG STUDY 8795*

Adverse Event StudyArm
TICE® BCG
(N = 222)
MMC
(N = 220)
All Grades Grade ≥ 3 All Grades Grade ≥ 3
Dysuria 115 (52%) 6 (3%) 77 (35%) 5 (2%)
Urgency/Frequency 112 (50%) 5 (2%) 63 (29%) 7 (3%)
Hematuria 85 (38%) 6 (3%) 56 (25%) 5 (2%)
Flu-Like Symptoms 54 (24%) 1 ( < 1%) 29 (13%) 0
Fever 37 (17%) 1 ( < 1%) 7 (3%) 0
Pain (Not Specified) 37 (17%) 4 (2%) 22 (10%) 1 ( < 1%)
Hemorrhagic Cystitis 19 (9%) 3 (1%) 10 (5%) 0
Chills 19 (9%) 0 2 (1%) 0
Bladder Cramps 18 (8%) 0 9 (4%) 0
Nausea 16 (7%) 0 12 (5%) 0
Incontinence 8 (4%) 0 3 (1%) 0
Myalgia/Arthralgia 7 (3%) 0 0 0
Diaphoresis 7 (3%) 0 1 ( < 1%) 0
Rash 6 (3%) 1 ( < 1%) 16 (7%) 2 (1%)
*The adverse reaction profile of TICE® BCG was similar in the Nijmegen study.8