Tice Bcg - Bacillus Calmette - Guerin powder, For Suspension prescribing information
WARNING
TICE ® BCG contains live, attenuated mycobacteria. Because of the potential risk for transmission, prepare, handle, and dispose of TICE ® BCG as a biohazard material (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).
BCG infections have been reported in health care workers, primarily from exposures resulting from accidental needle sticks or skin lacerations during the preparation of BCG for administration. Nosocomial infections have been reported in patients receiving parenteral drugs that were prepared in areas in which BCG was reconstituted. BCG is capable of dissemination when administered by the intravesical route, and serious infections, including fatal infections, have been reported in patients receiving intravesical BCG (see WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS sections).
INDICATIONS AND USAGE
TICE ® BCG is indicated for:
- the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder
- the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection (TUR)
Limitations of Use:
- TICE BCG is not recommended for stage TaG1 papillary tumors, unless they are judged to be at high risk of tumor recurrence.
- TICE BCG is not indicated for papillary tumors of stages higher than T1.
DOSAGE AND ADMINISTRATION
The dose for the intravesical treatment of carcinoma in situ and for the prophylaxis of recurrent papillary tumors consists of 1 vial of TICE ® BCG suspended in 50 mL preservative-free saline.
Do not inject subcutaneously or intravenously.
Preparation of Agent
The preparation of the TICE BCG suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG has been prepared. A separate area for the preparation of the TICE BCG suspension is recommended. All equipment, supplies, and receptacles in contact with TICE BCG should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves and take precautions to avoid contact of BCG with broken skin. If preparation cannot be performed in a biocontainment hood, then a mask and gown should be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin.
Draw 1 mL of sterile, preservative-free saline (0.9% Sodium Chloride Injection USP) at 4–25°C into a small syringe (e.g., 3 mL) and add to 1 vial of TICE BCG to resuspend. Ensure that the needle is inserted through the center of the rubber stopper of the vial. Gently swirl the vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause clumping of the mycobacteria.
Dilute the cloudy TICE BCG suspension in sterile, preservative-free saline to a final volume of 50 mL. Mix the suspension gently prior to intravesical instillation.
The reconstituted TICE BCG should be kept refrigerated (2–8°C), protected from exposure to direct sunlight, and used within 2 hours. Discard unused portion.
Note: DO NOT filter the contents of the TICE BCG vial. Precautions should be taken to avoid exposing the TICE BCG to direct sunlight. Bacteriostatic solutions must be avoided. In addition, use only sterile, preservative-free saline, 0.9% Sodium Chloride Injection USP as diluent.
Treatment and Schedule
Allow 7 to 14 days to elapse after bladder biopsy before TICE BCG is administered. Patients should not drink fluids for 4 hours before treatment and should empty their bladder prior to TICE BCG administration. The reconstituted TICE BCG is instilled into the bladder by gravity flow via the catheter. After instillation of the TICE BCG suspension is complete, remove the catheter. The TICE BCG is retained in the bladder for 2 hours and then voided. Patients unable to retain the suspension for 2 hours should be allowed to void sooner, if necessary.
While the BCG is retained in the bladder, the patient ideally should be repositioned from left side to right side and also should lie upon the back and the abdomen, changing these positions every 15 minutes to maximize bladder surface exposure to the agent.
A standard treatment schedule consists of 1 intravesical instillation per week for 6 weeks. This schedule may be repeated once if tumor remission has not been achieved and if the clinical circumstances warrant. Thereafter, intravesical TICE BCG administration should continue at approximately monthly intervals for at least 6 to 12 months. There are no data to support the interchangeability of BCG LIVE products.
CONTRAINDICATIONS
Immunosuppressed Patients
TICE ® BCG should not be used in immunosuppressed patients with congenital or acquired immune deficiencies, whether due to concurrent disease (e.g., AIDS, leukemia, lymphoma) cancer therapy (e.g., cytotoxic drugs, radiation), or immunosuppressive therapy (e.g., corticosteroids).
Patients with Increased Risk of BCG Infection
Treatment should be postponed until resolution of a concurrent febrile illness, urinary tract infection, or gross hematuria. Seven to 14 days should elapse before BCG is administered following biopsy, TUR, or traumatic catheterization.
Active Tuberculosis
TICE BCG should not be administered to persons with active tuberculosis. Active tuberculosis should be ruled out in individuals who are PPD positive before starting treatment with TICE BCG.
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 .
| 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 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 2 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 6 summarizes the most common adverse reactions reported in this trial. 7
| Study arm | ||||
|---|---|---|---|---|
| TICE 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%) |
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.
DESCRIPTION
TICE ® BCG (BCG LIVE) for intravesical use, is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis. 1 The TICE ® seed lot used in this TICE ® BCG preparation was developed at the University of Illinois from two BCG strains originated at the Pasteur Institute.
The medium in which the BCG organism is grown for preparation of the freeze-dried cake is composed of the following ingredients: glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, and iron ammonium citrate. The final preparation prior to freeze drying also contains lactose.
The freeze-dried BCG preparation is delivered in glass vials, each containing 1 to 8 × 10 8 colony forming units (CFU) of TICE BCG which is equivalent to approximately 50 mg wet weight. Determination of in vitro potency is achieved through colony counts derived from a serial dilution assay. A single dose consists of 1 reconstituted vial (see DOSAGE AND ADMINISTRATION ).
For intravesical use the entire vial is reconstituted with sterile saline. TICE BCG is viable upon reconstitution.
No preservatives have been added.
CLINICAL PHARMACOLOGY
TICE ® BCG induces a granulomatous reaction at the local site of administration. Intravesical TICE BCG has been used as a therapy for, and prophylaxis against, recurrent tumors in patients with carcinoma in situ (CIS) of the urinary bladder, and to prevent recurrence of Stage TaT1 papillary tumors of the bladder at high risk of recurrence. The precise mechanism of action is unknown.
CLINICAL STUDIES
Carcinoma in situ (Bladder Cancer)
To evaluate the efficacy of intravesical administration of TICE ® BCG in the treatment of carcinoma in situ , patients were identified who had been treated with TICE BCG under 6 different Investigational New Drug (IND) applications in which the most important shared aspect was the use of an induction plus maintenance schedule. Patients received TICE BCG (50 mg; 1 to 8 x 10 8 CFU) intravesically, once weekly for at least 6 weeks and once monthly thereafter for up to 12 months. A longer maintenance was given in some cases.
The study population consisted of 153 patients, 132 males, 19 females, and 2 unidentified as to gender. Thirty patients lacking baseline documentation of CIS and 4 patients lost to follow-up were not evaluable for treatment response. Therefore, 119 patients were available for efficacy evaluation. The mean age was 69 years (range: 38–97 years).
There were 2 categories of clinical response: (1) Complete Histological Response (CR), defined as complete resolution of carcinoma in situ documented by cystoscopy and cytology, with or without biopsy; and (2) Complete Clinical Response Without Cytology (CRNC), defined as an apparent complete disappearance of tumor upon cystoscopy. The results of a 1987 analysis of the evaluable patients are shown in Table 1 .
| Entered | Evaluable | CR | CRNC | Overall response | |
|---|---|---|---|---|---|
| No. (%) of patients | 153 | 119 (78%) | 54 (46%) | 36 (30%) | 90 (76%) |
A 1989 update of these data is presented in Table 2 . The median duration of follow-up was 47 months.
| 1989 Status of 90 Responders (CR or CRNC) | ||||
|---|---|---|---|---|
| Response | 1987/CR n=54 | 1987/CRNC n=36 | 1987 Response n=90 | Percent |
| CR | 30 | 15 | 45 | 50 |
| CRNC | 0 | 0 | 0 | 0 |
| Unrelated deaths | 6 | 6 | 12 | 13 |
| Failure | 18 | 15 | 33 | 37 |
There was no significant difference in response rates between patients with or without prior intravesical chemotherapy. The median duration of response, calculated from the Kaplan-Meier curve as median time to recurrence, is estimated at 4 years or greater. The incidence of cystectomy for 90 patients who achieved a complete response (CR or CRNC) was 11%. The median time to cystectomy in patients who achieved a complete response (CR or CRNC) exceeded 74 months.
TaT1 Bladder Cancer
The efficacy of intravesical TICE BCG in preventing the recurrence of a TaT1 bladder cancer after complete transurethral resection of all papillary tumors was evaluated in 2 open-label, randomized phase III clinical trials. Initial diagnosis of patients included in the studies was determined by cystoscopic biopsies. One was conducted by the Southwestern Oncology Group (SWOG) in patients at high risk of recurrence. High risk was defined as 2 occurrences of tumor within 56 weeks, any stage T1 tumor, or 3 or more tumors presenting simultaneously. The second study was conducted at the Nijmegen University Hospital; Nijmegen, The Netherlands. In this study patients were not selected for high risk of recurrence. In both studies treatment was initiated between 1 and 2 weeks after transurethral resection (TUR).
SWOG Trial (study 8795)
In the SWOG trial (study 8795) patients were randomized to TICE BCG or mitomycin C (MMC). Both drugs were given intravesically weekly for 6 weeks, at 8 and 12 weeks, and then monthly for a total treatment duration of 1 year. Cystoscopy and urinary cytology were performed every 3 months for 2 years. Patients with progressive disease or residual or recurrent disease at or after the 6 month follow-up were removed from the study and were classified as treatment failures.
A total of 469 patients was entered into the study: 237 to the TICE BCG arm and 232 to the MMC arm. Twenty-two patients were subsequently found to be ineligible, and 66 patients had concurrent CIS, and were analyzed separately. Four patients were lost to follow-up, leaving 191 evaluable patients in the TICE BCG arm and 186 in the MMC arm. Of the patients, 84% were male and 16% were female. The average age of these patients was 65 years old.
The Kaplan-Meier estimates of 2-year disease-free survival are shown in Table 3 . The difference in disease-free survival time between the 2 groups was statistically significant by the log rank test ( P =0.03). The 95% confidence interval of the difference in 2-year disease-free survival was 12% ± 10%. No statistically significant differences between the groups were noted in time to tumor progression, tumor invasion, or overall survival.
| TICE BCG Arm N=191 | MMC Arm N=186 | |
|---|---|---|
| Estimated disease-free survival at 2 years | 57% | 45% |
| 95% Confidence Interval (CI) | (50%, 65%) | (38%, 53%) |
Nijmegen Study
In the Nijmegen study, the efficacy of 3 treatments was compared: TICE substrain BCG, Rijksinstituut voor Volksgezondheid en Milieuhygiene substrain BCG (BCG-RIVM), and MMC.
TICE BCG and BCG-RIVM were given intravesically weekly for 6 weeks. In contrast to the SWOG study, maintenance BCG was not given. Mitomycin C was given intravesically weekly for 4 weeks and then monthly for a total duration of treatment of 6 months. Cystoscopy and urinary cytology were performed every 3 months until recurrence.
A total of 469 patients was enrolled and randomized. Thirty-two patients were not evaluable, 17 were ineligible, 15 were withdrawn before treatment, and 50 had concurrent CIS and were analyzed separately, leaving 387 evaluable patients: 117 in the TICE BCG arm, 134 in the BCG-RIVM arm, and 136 in the MMC arm. Twenty-eight patients (24%) in the TICE BCG arm, 32 patients (24%) in the BCG-RIVM arm, and 24 patients (18%) in the MMC arm had TaG1 tumors. The median duration of follow-up was 22 months (range: 3–54 months).
The Kaplan-Meier estimates of 2-year disease-free survival are shown in Table 4 . The differences in disease-free survival among the 3 arms were not statistically significant by the log-rank test ( P =0.08).
| TICE BCG Arm N=117 | BCG-RIVM Arm N=134 | MMC Arm N=136 | |
|---|---|---|---|
| Estimated disease-free survival at 2 years | 53% | 62% | 64% |
| 95% Confidence Interval (CI) | (44%, 64%) | (53%, 72%) | (55%, 74%) |
In both the SWOG 8795 study and the Nijmegen study, acute toxicity was more common, and usually more severe, with TICE BCG than with MMC (see ADVERSE REACTIONS ).
HOW SUPPLIED
TICE ® BCG is supplied in a box of 1 single-dose vial of TICE BCG. Each vial contains 1 to 8 × 10 8 CFU, which is equivalent to approximately 50 mg (wet weight), as lyophilized (freeze-dried) powder, NDC 0052-0602-02.
STORAGE
The intact vials of TICE ® BCG should be stored refrigerated, at 2–8°C (36–46°F).
This agent contains live bacteria and should be protected from direct sunlight. The product should not be used after the expiration date printed on the label.
