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BCG LIVE

(FOR INTRAVESICAL USE)

TICE

BCG

WARNING

TICE

BCG contains live, attenuated mycobacteria. Because of the potential risk for

transmission, it should be prepared, handled, and disposed of as a biohazard material

(see PRECAUTIONS and DOSAGE AND ADMINISTRATIONsections).

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).

DESCRIPTION

TICE

BCG for intravesical use, is an attenuated, live culture preparation of the Bacillus of

Calmette and Guerin (BCG) strain of Mycobacterium bovis.

The TICE strain was developed at

the University of Illinois from a strain 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 x 10

colony forming units (CFU) of TICE BCG which is equivalent to approximately 50

mg wet weight. Determination of invitropotency 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. TICEBCG 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

(FOR INTRAVESICAL USE)

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TaT1 papillary tumors of the bladder at high risk of recurrence. The precise mechanism of

action is unknown.

CLINICAL STUDIES

To evaluate the efficacy of intravesical administration of TICE

BCG in the treatment of

carcinomain 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

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

carcinomain 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.

Table 1: The Response of Patients With CIS Bladder Cancer in6 IND Studies

Entered

Evaluable

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.

Table 2: Follow-upResponse of Patients With CIS Bladder Cancerin 6 IND Studies

1989 Status of 90 Responders (CR or CRNC)

1987/CR

1987/CRNC

1987 Response

Response

n=54

n=36

n=90

Percent

CRNC

Unrelated deaths

Failure

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.

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

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(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).

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.

Table 3: Results of SWOG Study 8795

TICEBCG Arm

MMC Arm

N=191

N=186

Estimated disease-free survival at 2 years

57%

45%

95% Confidence Interval (CI)

(50%, 65%)

(38%, 53%)

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).

Table 4: Results of Nijmegen Study

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TICE BCG Arm

BCG-RIVM Arm

MMC Arm

N=117

N=134

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).

INDICATIONS AND USAGE

TICE

BCG is indicated for the treatment and prophylaxis of carcinomain situ(CIS) of the

urinary bladder, and for the prophylaxis of primary or recurrent stage Ta and/or T1 papillary

tumors following transurethral resection (TUR). 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.

CONTRAINDICATIONS

TICE

BCG should not be used in immunosuppressed patients or persons 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).

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.

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.

WARNINGS

BCG LIVE (TICE

BCG) is not a vaccine for the prevention of cancer. BCG Vaccine USP,

not BCG LIVE (TICE BCG), should be used for the prevention of tuberculosis. For vaccination

use, refer to BCG Vaccine USP prescribing information.

TICE BCG is an infectious agent. Physicians using this product should be familiar with the

literature on the prevention and treatment of BCG-related complications, and should be

prepared in such emergencies to contact an infectious disease specialist with experience in

treating the infectious complications of intravesical BCG. The treatment of the infectious

complications of BCG requires long-term, multiple-drug antibiotic therapy. Special culture media

are required for mycobacteria, and physicians administering intravesical BCG or those caring

for these patients should have these media readily available.

Instillation of TICE BCG with an actively bleeding mucosa maypromote systemic BCG

infection. Treatment should be postponed for at least 1 week following transurethral resection,

biopsy, traumatic catheterization, or gross hematuria.

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Deaths have been reported as a result of systemic BCG infection and sepsis.

2,3

Patients should

be monitored for the presence of symptoms and signs of toxicity after each intravesical

treatment. Febrile episodes with flu-like symptoms lasting more than 72 hours, fever ≥103°F,

systemic manifestations increasing in intensity with repeated instillations, or persistent

abnormalities of liver function tests suggest systemic BCG infection and may require

antituberculous therapy. Local symptoms (prostatitis, epididymitis, orchitis) lasting more than 2

to 3 days may also suggest active infection (see WARNINGS, Management of Serious BCG

Complications section).

The use of TICE BCG may cause tuberculin sensitivity. Since this is a valuable aid in the

diagnosis of tuberculosis, it is advisable to determine the tuberculin reactivity by PPD skin

testing before treatment.

Intravesical instillations of BCG should be postponed during treatment with antibiotics, since

antimicrobial therapy may interfere with the effectiveness of TICE BCG (see PRECAUTIONS).

TICE BCG should not be used in individuals with concurrent infections.

Small bladder capacity has been associated with increased risk of severe local reactions and

should be considered in deciding to use TICE BCG therapy.

Management of Serious BCG Complications.

Acute, localized irritative toxicities of TICE BCG may beaccompanied by systemic

manifestations, consistent with a “flu-like” syndrome. Systemic adverse effects of 1 to 2 days’

duration such as malaise, fever, and chills often reflect hypersensitivity reactions. However,

symptoms such as fever of ≥38.5°C (101.3°F), or acute localized inflammation such as

epididymitis, prostatitis, or orchitis persisting longer than 2to 3 days suggest active

infection, and evaluation for serious infectious complication should be considered.

In patients who develop persistent fever or experience an acute febrile illness consistent with

BCG infection, 2 or more antimycobacterial agents should be administered while diagnostic

evaluation, including cultures, is conducted. BCG treatment should be discontinued.

Negative cultures do notnecessarily rule out infection. Physicians using this product should be

familiar with the literature on prevention, diagnosis, and treatment of BCG-related complications

and, when appropriate, should consult an infectious disease specialist or other physician with

experience in the diagnosis and treatment of mycobacterial infections.

TICE BCG is sensitive to the most commonly used antituberculous agents (isoniazid, rifampin,

and ethambutol). TICE BCG is not sensitive to pyrazinamide.

PRECAUTIONS

General

TICE

BCG contains live mycobacteria and should be prepared and handled using aseptic

technique (see DOSAGE AND ADMINISTRATION, Preparation of Agentsection). BCG

infections have been reported in health care workers preparing BCG for administration. Needle

stick injuries should be avoided during the handling and mixing of TICE BCG. Nosocomial

infections have been reported in patients receiving parenteral drugs which were prepared in

areas in which BCG was prepared.

BCG is capable of dissemination when administered by intravesical route,and serious

reactions, including fatal infections, have been reported in patients receiving intravesical BCG.

Care should be taken not to traumatize the urinary tract or to introduce contaminants into the

urinary system. Seven to 14 days should elapse before TICE BCG is administered following

TUR, biopsy, or traumatic catheterization.

TICE BCG should be administered with caution to persons in groups at high risk for HIV

infection.

Laboratory Tests

The use of TICE BCG may causetuberculin sensitivity. It is advisable to determine the

tuberculin reactivity of patients receiving TICE BCG by PPD skin testing before treatment is

initiated.

Information for Patients

TICE BCG is retained in the bladder for 2 hours and then voided. Patients should void while

seated in order to avoid splashing of urine. For the 6 hours after treatment, urine voided should

be disinfected for 15 minutes with an equal volume of household bleach before flushing.

Patients should be instructed to increase fluidintake in order to “flush” the bladder in the hours

following BCG treatment. Patients may experience burning with the first void after treatment.

Patients should be attentive to side effects, such as fever, chills, malaise, flu-like symptoms, or

increasedfatigue. If the patient experiences severe urinary side effects, such as burning or pain

on urination, urgency, frequency of urination, blood in urine, or other symptoms such as joint

pain, cough, or skin rash, the physician should be notified.

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 mayinterfere 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

TICE BCG has not been evaluated for its carcinogenic, mutagenic potentials,or impairment of

fertility.

Pregnancy

Teratogenic Effects

Animal reproduction studies have not been conducted with TICE BCG. It is also not known

whether TICE BCG can cause fetal harm when administered to a pregnant woman or can affect

reproductive capacity. TICE BCG should not be given to a pregnant woman except when clearly

needed. Women should be advised not to become pregnant while on therapy.

Nursing Mothers

It is not known whether TICE BCG is excreted in human milk. Because many drugs are

excreted in human milk and because of the potential for serious adverse reactions from TICE

BCG in nursing infants, it is advisable to discontinue nursing or to discontinue the drug, taking

into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of TICE BCG for the treatment of superficial bladder cancer in

pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of TICE BCG, the average age was 66 years

old. No overall difference in safety or effectiveness was observed between older and younger

subjects. Other reported clinical experience has not identified differences in response between

elderly and younger patients, but greater sensitivity of some older individuals to BCG cannot be

ruled out.

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 4to 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.

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.

Adverse reactions to TICEBCG 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. bovisinfections 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 persistentfever 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 ina review of 674 patients with superficial

bladder cancer, including 153 patients with carcinomain situ, are summarized in Table 5.

Table 5: Summary of Adverse Effects Seen in 674 Patients

With Superficial Bladder Cancer, Including 153 With Carcinoma in Situ

Percent of patients

Adverse

Overall

Adverse

Overall

event

(Grade ≥3)

event

(Grade ≥3)

Dysuria

401

60% (11%)

Arthritis/myalgia

3% (<1%)

Urinary frequency

272

40% (7%)

Headache/dizziness

2%(0)

Flu-like syndrome

224

33% (9%)

Urinary incontinence

2% (0)

Hematuria

175

26% (7%)

Anorexia/weight loss

2% (<1%)

Fever

134

20% (8%)

Urinary debris

2% (<1%)

Malaise/fatigue

7% (0)

Allergy

2% (<1%)

Cystitis

6% (2%)

Cardiac (unclassified)

2% (1%)

Urgency

6% (1%)

Genital inflammation/

Nocturia

5% (1%)

abscess

2% (<1%)

Cramps/pain

4% (1%)

Respiratory (unclassified) 11

2% (<1%)

Rigors

3% (1%)

Urinary tract infection

2% (1%)

Nausea/vomiting

3% (<1%)

Abdominal pain

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.

Table 6: Most Common Adverse Reactions in SWOG Study 8795*

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%)

Fever

37 (17%)

1 (<1%)

7 (3%)

Pain (not specified)

37 (17%)

4 (2%)

22 (10%) 1 (<1%)

Hemorrhagic cystitis

19 (9%)

3 (1%)

10 (5%)

Chills

19 (9%)

2 (1%)

Bladder cramps

18 (8%)

9 (4%)

Nausea

16 (7%)

12 (5%)

Incontinence

8 (4%)

3 (1%)

Myalgia/arthralgia

7 (3%)

Diaphoresis

7 (3%)

1 (<1%)

Rash

6 (3%)

1 (<1%)

16 (7%) 2 (1%)

*The adverse reaction profile of TICE BCG was similar in the Nijmegen study.

OVERDOSAGE

Overdosage occurs if more than 1 vial of TICE

BCG is administered per instillation. If

overdosage occurs, the patient should be closely monitored for signs of active local or systemic

BCG infection. For acute local or systemic reactions suggesting active infection, an infectious

disease specialist experienced in BCG complications should be consulted.

DOSAGE AND ADMINISTRATION

The dose for the intravesical treatment of carcinoma in situand for the prophylaxis of recurrent

papillary tumors consists of 1 vialof 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 exposureto 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. Gently swirl the

vial until a homogenous suspension is obtained. Avoid forceful agitation which may cause

clumping of the mycobacteria.Dispense the cloudy TICE BCG suspension into the top end of a

catheter-tip syringe which contains 49 mL of saline diluent, bringing the total volume to 50 mL.

To mix, gently rotate the syringe.

The reconstituted TICE BCG should be kept refrigerated (2-8°C), protected from exposure to

direct sunlight, and used within 2 hours. Unused solution should be discarded after 2 hours.

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 7to 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. DO NOTdepress plunger and force the flow of the TICE BCG. The TICE BCG is

retained in the bladder 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.

Astandard 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 6to 12 months. There are no data to support the

interchangeability of BCG LIVE products.

HOW SUPPLIED

TICE

BCG is supplied in a box of 1 vial of TICE BCG. Each vial contains 1 to 8 x 10

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 directsunlight. The product

should not be used after the expiration date printed on the label.

REFERENCES

1. DeJager R, Guinan P, Lamm D, Khanna O, Brosman S, DeKernion J, et al. Long-Term

Complete Remission in Bladder Carcinoma in Situ with Intravesical TICE Bacillus Calmette

Guerin. Urology1991;38:507-513.

2. Rawls WH, Lamm DL, Lowe BA, Crawford ED, Sarosdy MF, Montie JE, Grossman HB,

Scardino PT. Fatal Sepsis Following Intravesical Bacillus Calmette-Guerin Administration

For Bladder Cancer. J Urol1990;144:1328-1330.

3. Lamm DL, van der Meijden APM, Morales A, Brosman SA, Catalona WJ, Herr HW, et al.

Incidence and Treatment of Complications of Bacillus Calmette-Guerin Intravesical Therapy

in Superficial Bladder Cancer. J. Urol1992;147:596-600.

4. Stone MM, Vannier AM, Storch SK, Nitta AT, Zhang Y. Brief Report: Meningitis Due to

Iatrogenic BCG Infection in Two Immunocompromised Children. NEJM1995:333:561-563.

5. Steg A, Leleu C, Debre B, Gibod-Boccon L, Sicard D. Systemic Bacillus Calmette-Guerin

Infection in Patients Treated by Intravesical BCG Therapy for Superficial Bladder Cancer.

EORTCGenitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by

F.M. J. Debruyne, L. Denis and A.P.M. van der Meijden. New York: Alan R. Liss Inc., pp.

325-334.

6. van der Meijden, APM. Practical Approaches to the Prevention and Treatment of Adverse

Reactions to BCG. Eur Urol1995;27(suppl 1):23-28.

7. Lamm DL, Blumenstein BA, Crawford ED, Crissman JD, Lowe BA, Smith JA, Sarosdy MF,

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