Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 29 April 2017

Indication(s)

INDICATIONS AND USAGE TICE® BCG is indicated for the treatment and prophylaxis of carcinoma in 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.

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Advisory information

contraindications
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.
Special warnings and precautions
PRECAUTIONS General TICE® BCG contains live mycobacteria and should be prepared and handled using aseptic technique (see DOSAGE AND ADMINISTRATION, Preparation of Agent section). 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.4 BCG is capable of dissemination when administered by intravesical route, and serious reactions, including fatal infections, have been reported in patients receiving intravesical BCG.3 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 cause tuberculin 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 fluid intake 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 increased fatigue. 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 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. Carcinogenesis, Mutagenesis, Impairment of Fertility TICE BCG has not been evaluated for its carcinogenic, mutagenic potentials, or impairment of fertility. Pregnancy 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
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, 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. Table 5: 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% (<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 Table 6: Most Common Adverse Reactions in SWOG Study 8795The adverse reaction profile of TICE BCG was similar in the Nijmegen study.8 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%)

Usage information

Dosing and administration
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. 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 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. DO NOT depress 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. 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.
Pregnancy and lactation
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.

Interactions

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.

More information

Category Value
Authorisation number BLA102821
Agency product number 2XQ558L16Z
Orphan designation No
Product NDC 0052-0602
Date Last Revised 30-09-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1653484
Storage and handling 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.
Marketing authorisation holder Organon USA Inc.
Warnings 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 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).