A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Tice Side Effects, and Drug Interactions - Bacillus of Calmette and Guerin
Tice Side Effects, and Drug Interactions - Bacillus of Calmette and Guerin
SIDE EFFECTS
Symptoms of bladder irritability, related to the inflammatory response induced,
are reported in approximately 60% of patients receiving TICEŽ 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 TICEŽ 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 TICEŽ 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 patient 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
| 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% (<%) |
|
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 TICEŽ
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 TICEŽ BCG, with 356 events compared to 234 events for
MMC. Grade ≤ 2 toxicity was seen significantly more frequently following
TICEŽ BCG treatment (p=0.003). No life-threatening toxicity was seen in either
arm. Systemic toxicity with TICEŽ BCG was markedly increased compared to that
of MMC, with 181 events for TICEŽ 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 TICEŽ BCG patients were reported to have been treated with
isoniazid. Five TICEŽ BCG patients had liver enzyme elevation, including two
with grade 3 elevations. Eighteen of the 222 (8.1%) TICEŽ 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 SIDE EFFECTS
IN SWOG
STUDY 8795 *
|
|
Study Arm |
|
|
TICEŽ BCG (N = 222) |
MMC (N = 220) |
|
Adverse Event
|
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 TICEŽ BCG was similar
in the Nijmegen study. 8
|
DRUG INTERACTIONS
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 TICEŽ BCG. Antimicrobial therapy for other infections
may interfere with the effectiveness of TICEŽ 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 TICEŽ BCG.
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