Bacillus Calmette-Guerin Live (BCG) is a live, attenuated strain of Mycobacterium bovis used in the treatment of superficial bladder cancer. All BCG strains were derived from the original Calmette-Guerin strain of the Pasteur Institute. Strains currently available for clinical use in the U.S. include the Connaught (TheraCys(R)) and Tice (TICE(R) BCG) strains. In 1998, the FDA required Organon to label the indications for TICE(R) BCG strain separately as two products, BCG Vaccine, USP (see Bacillus Calmette-Guerin Vaccine, BCG monograph), and BCG Live (intravesical). Bacillus Calmette-Guerin Live is not a vaccine against cancer and should not be used as an immunizing agent for tuberculosis prevention. Outcome data from clinical trials and expert opinion support the use of BCG Live or mitomycin C as adjuvant therapy after transurethral resection of carcinoma in situ, T1 bladder cancers, or high grade Ta tumors. Tumor recurrence probability was lower after use of intravesical treatment as compared with resection alone, but there is no evidence that intravesical therapy affects long-term progression to muscle invasive disease. The FDA approved TheraCys(R) in May 1990 for the treatment of carcinoma in situ of the bladder and in November 1999 for the prophylaxis of primary or recurrent carcinoma in situ of the bladder. TICE(R) BCG was approved in August 1990 for the treatment of carcinoma in situ of the bladder and for the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection. Both products are not recommended for stage TaG1 papillary tumors unless the patient is judged to be at high risk of tumor recurrence. The FDA approved PACIS(R) (BCG Live, intravesical) for the treatment of carcinoma in situ of the bladder in the absence of invasive cancer in March 2000, but the product has been discontinued.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
CAUTION: Bacillus Calmette-Guerin (BCG) Live, USP contains live bacteria and should be prepared in a biological safety cabinet and handled using aseptic technique. All equipment, supplies, and receptacles in contact with these products should be disposed of as biohazards. Do not prepare parenteral drugs in areas where BCG has been prepared. Nosocomial infections have been reported in patients receiving parenteral drugs prepared in areas in which BCG was reconstituted.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Removed from the NIOSH list because it is an infectious agent and not classified as a drug by the FDA. For handling recommendations, see the drug package insert.
-Health care professionals should wear gloves, gown, and mask to avoid inadvertent exposure to BCG organisms while preparing and administering the solution. Handling of the product by persons with an immunologic deficiency is not recommended.
Route-Specific Administration
Other Administration Route(s)
Intravesical Administration
-People with latex hypersensitivity may not be appropriate candidates for TheraCys drug preparation, as the vial stopper contains latex.
-Patients should not drink liquids for 4 hours prior to treatment and empty their bladder prior to BCG administration.
Reconstitution (BCG Live, TICE BCG):
-Add 1 mL of sterile, preservative-free NS to one vial of TICE BCG. Do not use bacteriostatic solutions.
-Gently swirl until a homogenous, cloudy suspension is attained; avoid foaming or forceful agitation. NOTE: This solution contains live bacteria.
-Withdraw suspension from the vial and dispense into a catheter-tip syringe containing 49 mL of preservative-free 0.9% Sodium Chloride injection. The final volume should be 50 mL.
-Gently rotate the syringe to mix the suspension. Do not filter. Avoid exposure to direct sunlight.
-Use immediately after preparation. May be refrigerated at 2-8 degrees C (36-46 degrees F) and protected from direct sunlight until use, but discard unused solution after 2 hours.
Reconstitution (TheraCys):
-Do not remove the rubber stopper from the freeze-dried product. Apply a sterile piece of cotton moistened with a suitable antiseptic to the surface of both rubber stoppers (product and diluent). Add 3 mL of the preservative-free 0.9% Sodium Chloride diluent that is provided with the product to the BCG vial. Do not use any other diluent.
-Gently swirl until suspension is attained; avoid foaming. NOTE: This solution contains live bacteria.
-Withdraw suspension from the vial (3 mL) and dispense into a catheter-tip syringe containing 50 mL preservative-free saline. The final volume should be 53 mL.
-Use immediately after preparation. The reconstituted product may be refrigerated until use, but discard solution after 2 hours if not used or if flocculation or clumping that cannot easily be dispersed occurs.
-Avoid exposure to direct or indirect sunlight. Exposure to artificial light should be kept to a minimum.
Bladder instillation (BCG Live, TICE BCG or TheraCys):
-Insert a urethral catheter into the bladder under aseptic conditions. Drain the bladder.
-Instill BCG into the bladder by gravity flow via the catheter. Do NOT depress the plunger and force the solution flow. Try to avoid urinary tract trauma and contaminant introduction. Remove the catheter.
-While BCG is retained in the bladder, patients should repositioned from the left side to right side and may lie upon the back and the abdomen, changing positions every 15 minutes to maximize bladder surface exposure to the agent.
-The BCG solution should be retained in the bladder for 2 hours, if possible, then voided. During the first 24 hours after BCG instillation, the patient should sit down while urinating.
Cardiac toxicity has been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Unspecified cardiac toxicity occurred in less than 5% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Additionally, the incidence of all grade cardiac toxicity was 2% in a review of 674 patients who received TICE BCG; 1% of patients experienced grade 3 or higher cardiac toxicity in this study.
Pain (unspecified) occurred in 17% of patients who received TICE BCG in a randomized, comparative trial (n = 222): grade 3 or higher toxicity occurred in 2% of patients.
Genital pain occurred in 10% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127).
Hepatitis may occur in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who receive intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG). Liver involvement was reported in less than 5% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Hepatitis may be a sign of a systemic granulomatous illness. In a review of 674 patients who received intravesical TICE BCG, hepatic granuloma and hepatitis were reported in 1% of patients or less.
Bladder and urinary system adverse events have been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Bladder irritation (e.g., dysuria, hematuria, urinary frequency) may be caused by inflammation and occurs in approximately 50% and 60% of Theracys- and TICE BCG- treated patients, respectively. Typically, symptoms start 4 to 6 hours after the instillation and last for 24 to 72 hours; irritation symptoms are usually observed following the third instillation and the severity tends to increase with each instillation. Dysuria (all grade, 52%; >= grade 3, 4%), increased urinary frequency (all grade, 40%; >= grade 3, 2%), hematuria (all grade, 39%; >= grade 3, 7%), cystitis (all grade, 29%), urinary urgency (all grade, 18%), unspecified renal toxicity (all grade, 10%; >= grade 3, 2%), urinary incontinence (all grade, 6%), bladder discomfort (e.g., cramps/pain) (all grade, 6%), and contracted bladder (all grade, 5%) occurred in patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Additionally, ureteral obstruction was reported with Theracys use in less than 5% of patients in this study. Bladder and urinary system adverse events reported in a review of 674 patients who received intravesical TICE BCG include dysuria (all grade, 60%; >= grade 3, 11%), increased urinary frequency (all grade, 40%; >= grade 3, 7%), hematuria (all grade, 26%; >= grade 3, 7%), cystitis (all grade, 6%; >= grade 3, 2%), urinary urgency (all grade, 6%; >= grade 3, 1%), nocturia (all grade, 5%; >= grade 3, 1%), bladder cramps/pain (all grade, 4%; >= grade 3, 1%), urinary incontinence (all grade, 2%), urinary debris (all grade, 2%; >= grade 3, < 1%), and urinary tract infection (all grade, 2%; >= grade 3, 1%). Urethritis and urinary obstruction were reported in 1% or less TICE BCG-treated patients in this evaluation. Hemorrhagic cystitis occurred in 9% of patients who received TICE BCG in a randomized, comparative trial (n = 222); grade 3 or higher hemorrhagic cystitis was reported in 1% of patients. Monitor patients receiving BCG for signs and symptoms of bladder irritation.
Gastrointestinal (GI) adverse events have been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Nausea/vomiting (all grade, 16%), anorexia (all grade, 11%), and diarrhea (all grade, 6%) occurred in patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Additionally, abdominal pain and constipation were reported with Theracys use in less than 5% of patients in this study. GI adverse events reported in a review of 674 patients who received intravesical TICE BCG were nausea/vomiting (all grade, 3%; >= grade 3, < 1%), anorexia/weight loss (all grade, 2%; >= grade 3, <1%), and abdominal pain (all grade, 2%; >= grade 3, 1%). Diarrhea was reported in 1% or less TICE BCG-treated patients in this evaluation.
Hematologic adverse events have been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Anemia (21%) and leukopenia (5%) occurred in patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Additionally, thrombocytopenia was reported with Theracys use in less than 5% of patients in this study. In a review of 674 patients who received intravesical TICE BCG, leukopenia and thrombocytopenia were reported in 1% of patients or less.
Central nervous system adverse events have been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Headache and dizziness occurred in less than 5% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). In a review of 674 patients who received intravesical TICE BCG, headache/dizziness and unclassified neurologic toxicity were reported in 1% of patients or less.
Musculoskeletal adverse events have been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Arthralgia/myalgia occurred in 7% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127); grade 3 or higher arthralgia/myalgia was reported in 1% of patients. Additionally, flank pain was reported with Theracys use in less than 5% of patients in this study. In post-marketing surveillance, arthralgia and migratory arthritis have been reported in patients who received intravesical BCG; these adverse events may be allergic reactions. In a review of 674 patients who received intravesical TICE BCG, all grade arthritis/myalgia was reported in 3% of patients; less than 1% of patients experienced grade 3 or higher toxicity.
Infection, some cases serious or fatal, has been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG). BCG infection has occurred in the eye, lung, liver, bone, bone marrow, kidney, lymph nodes, peritoneum, and prostate. Some signs and symptoms of a systemic BCG infection include fever, systemic manifestations increasing with repeat instillations, persistent liver function test elevations, and granulomatous inflammation on biopsy; prostatitis, epididymitis, and orchitis lasting more than 2 or 3 days may be indicative of infection. Fever consisting of a temperature > 38 degrees Celsius (all grade, 38%; >= grade 3, 3%) and urinary tract infection (all grade, 18%; >= grade 3, 1%) occurred in patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Systemic infection, pulmonary infection, and local infection were reported with Theracys use in less than 5% of patients in this study. In post-marketing surveillance, symptomatic granulomatous prostatitis, epididymo-orchitis, and renal abscess have been reported in patients who received intravesical BCG. Fever (all grade, 20%; >= grade 3, 8%) and genital inflammation/abscess (all grade, 2%; >= grade 3, < 1%) were reported in a review of 674 patients who received intravesical TICE BCG. In this evaluation, BCG sepsis, epididymitis/prostatitis, orchitis, and pyuria were reported in 1% or less TICE BCG-treated patients. Monitor patients for signs and symptoms of infection after each BCG instillation. If a patient develops symptoms of a systemic BCG infection, discontinue BCG therapy; antituberculosis treatment (e.g., isoniazid, rifampin, and ethambutol) may be required. Treat BCG-related infectious complications with long-term, multiple-drug antibiotic therapy; withhold BCG during antibiotic therapy.
A flu-like syndrome has been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG). Symptoms lasting 1-2 days include malaise, fever, and chills and may indicate a hypersensitivity reaction. If systemic adverse effects are severe and/or persist for greater than 2-3 days, evaluate patients for serious infectious complications. Malaise (all grade, 40%; >= grade 3, 2%) and chills (all grade, 34%; >= grade 3, 3%) occurred in patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). Additionally, fatigue was reported with Theracys use in less than 5% of patients in this study. Flu-like syndrome (all grade, 33%; >= grade 3, 9%), malaise/fatigue (all grade, 7%), rigors (all grade, 3%; >= grade 3, 1%), and allergy (all grade, 2%; >= grade 3, < 1%) were reported in a review of 674 patients who received intravesical TICE BCG.
Dermatologic toxicity has been reported in patients with carcinoma in situ of the urinary bladder (CIS) or primary or recurrent superficial bladder cancer who received intravesical bacillus calmette-guerin (BCG) live (Theracys, TICE BCG) in clinical studies. Rash (unspecified) occurred in less than 5% of patients who received intravesical Theracys in a multicenter, randomized clinical trial (n = 127). In post-marketing surveillance, skin rash has been reported in patients who received intravesical BCG. In a review of 674 patients who received intravesical TICE BCG, rash was reported in 1% of patients or less. Diaphoresis occurred in 3% of patients who received TICE BCG in a randomized, comparative trial (n = 222).
The incidence of all grade respiratory toxicity was 2% in a review of 674 patients who received intravesical bacillus calmette-guerin (BCG) live (TICE BCG); less than 1% of patients experienced grade 3 or higher toxicity. Pneumonitis was reported in 1% or less TICE BCG-treated patients in this evaluation. Pneumonitis may be a sign of a systemic granulomatous illness.
Coagulopathy occurred in less than 5% of patients who received intravesical bacillus calmette-guerin (BCG) live (Theracys) in a multicenter, randomized clinical trial (n = 127). In a review of 674 patients who received intravesical TICE BCG, coagulopathy was reported in 1% of patients or less.
In post-marketing surveillance, ocular symptoms including uveitis, conjunctivitis, iritis, keratitis, and granulomatous choreoretinitis have been reported in patients who received intravesical bacillus calmette-guerin (BCG) live (Theracys). These symptoms occurred alone or in combination with joint symptoms such as arthritis or arthralgia, urinary symptoms and/or skin rash. The risk of ocular symptoms may be elevated in HLA-B27 positive patients.
BCG is capable of dissemination when administered by the intravesical route and serious infection, including fatal infection, has been reported in patients receiving intravesical BCG. Clinicians should exercise caution to not cause trauma to the urinary tract or introduce contaminants into the urinary system. Seven to 14 days should elapse before BCG is administered following TUR, biopsy, or traumatic catheterization.
Patients with an infection including active mycobacterial infection (i.e., tuberculosis, TB) should not receive BCG Live intravesical therapy. Tuberculin skin testing should be performed prior to intravesical treatment. A positive Mantoux test is a contraindication for BCG Live only if there is evidence of an active tuberculosis infection. Use of BCG Live or vaccination with BCG (See BCG Vaccine monograph) may cause tuberculin sensitivity.
Treatment with BCG Live intravesical therapy should be delayed until resolution of fever, urinary tract infection (UTI), or gross hematuria. Systemic BCG infection may be promoted if BCG Live comes into contact with an actively bleeding mucosa. Intravesical BCG Live administration should be given no sooner than 7-14 days following bladder biopsy, transurethral resection, or catheterization that induced local trauma. Treatment with antibiotics, especially anti-tuberculin agents, should be completed prior to BCG Live treatment because antimicrobial therapy may interfere with the effectiveness of therapy. Patients with an aneurysm or prosthetic device such as prosthetic heart valves may develop an ectopic BCG infection. The risk of infection development is unknown but is considered to be small. Consideration of the benefit and risk of treatment with BCG Live is needed. Patients should be monitored for fever >= 101.3 degrees F (38.5 degrees C) for longer than 48-72 hours or increasing liver function tests that may indicate systemic BCG infection. Local symptoms and inflammation (i.e., epididymitis, prostatitis, or orchitis) lasting more than 2-3 days may also suggest active BCG infection. In patients who develop fever or experience an acute febrile illness consistent with BCG infection, 2 or more antimycobacterial agents should be administered while diagnostic evaluation is being conducted. BCG Live intravesical therapy should be discontinued. Negative culture results do not necessarily rule out infection. BCG Live is sensitive to the most commonly used anti-TB agents with the exception of pyrazinamide.
Elderly patients; patients with diabetes mellitus, renal failure, leukemia, or lymphoma; and patients who are receiving radiation therapy, chemotherapy, or corticosteroid therapy may be immunosuppressed. Use of the BCG Live is contraindicated in patients who are immunosuppressed, as immunosuppression may lead to clinical disease (see Adverse Reactions) and prevent an appropriate immune response to BCG. Patients with bone marrow suppression, severe combined immunodeficiency (SCID), human immunodeficiency virus (HIV) infection, or acquired immunodeficiency syndrome (AIDS) should not receive BCG Live due to the risk of systemic mycobacterium sepsis. Also, patients with immunosuppression may not be able to mount an appropriate immune response to BCG Live intravesical treatment. Carefully consider the use of BCG Live in patients who may become immunosuppressed such as patients with myasthenia gravis and patients on an organ transplant list.
Precautions should be taken to avoid accidental exposure to BCG solutions during preparation and administration, as these solutions contain live, attenuated mycobacterium. After usage, all equipment and materials used for preparation and instillation of the BCG solution should be placed into plastic bags labeled 'Infectious Waste' and disposed of accordingly as biohazardous waste. Patients should be informed that any urine voided within 6 hours of instillation of BCG should be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allow to stand for 15 minutes before flushing. Patients should be advised to sit while urinating during the 24 hours following BCG instillation.
People with latex hypersensitivity may not be appropriate candidates for TheraCys administration. The vial stopper contains latex. Although patients do not handle the drug vial, some latex particles could contaminate the drug suspension. The Tice BCG product does not contain latex.
Bacillus Calmette-Guerin (BCG) Live is indicated for intravesical instillation. Ensure precautions are taken to avoid intravenous administration and subcutaneous administration.
Bacillus Calmette-Guerin (BCG) Live intravesical therapy should be used cautiously in patients with irritable bladder symptoms, including patients with neurogenic bladder. An increased incidence of bladder spasm and spontaneous discharge of the intravesical instillate may occur. Administer cautiously to patients with a small bladder capacity; small bladder capacity has been associated with an increased risk of severe local reactions.
Bacillus Calmette-Guerin (BCG) products are considered FDA pregnancy risk category C agents. It is not known whether BCG Live intravesical causes fetal harm if given to a pregnant woman. Therapy with BCG Live should be given to a pregnant woman only if clearly needed. Females of reproductive age should take precautions against becoming pregnant while on BCG Live therapy.
It is not known whether BCG is excreted in breast milk. Because many drugs are excreted in breast milk and because of the potential for harm in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue BCG therapy taking into account the importance of therapy to the mother. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The safety and effectiveness of BCG Live intravesical therapy for children with superficial bladder cancer has not been established.
For the treatment and prophylaxis of bladder cancer in situ (CIS) or the prophylaxis of primary or recurrent stage Ta or T1 papillary tumors following transurethral resection:
NOTE: The optimal dose and treatment regimen has not been determined. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.
NOTE: There are no data to support the interchangeability of the BCG live products.
NOTE: Neither TICE BCG nor TheraCys are recommended for stage TaG1 papillary tumors unless the patient is judged to be at high risk of tumor recurrence.
Intravesical dosage (BCG Live Intravesical, TICE BCG):
Adults: The contents of 1 vial, appropriately prepared, instilled in the bladder for 2 hours, then voided. Instillation is repeated once weekly for 6 weeks. If tumor remission is not achieved, the schedule may be repeated. Thereafter, BCG instillation should be administered at monthly intervals for 6 to 12 months as maintenance therapy.
Intravesical dosage (BCG Live Intravesical, TheraCys):
Adults: The contents of 1 vial, appropriately prepared, instilled in the bladder for 2 hours, then voided. Instillation is repeated once weekly for 6 weeks. BCG instillation is then given at 3, 6, 12, 18, and 24 months following the initial dose.
Maximum Dosage Limits:
-Adults
One vial/dose intravesically.
-Elderly
One vial/dose intravesically.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Bacillus Calmette-Guerin Live, BCG products.
Bacillus Calmette-Guerin (BCG) is an immunostimulant. BCG treatment is used to mount a local inflammation and immune reaction against superficial cancers, but the exact mechanism of action is unknown. The Calmette-Guerin strain of Mycobacterium bovis present in BCG Live is immunologically similar to M. tuberculosis. Intravesical BCG produces a non-specific, localized immune reaction consisting of granulomatous and inflammation reactions with histocyte and leukocyte infiltration. Following intravesical administration, the live BCG mycobacteria attach to the urothelial lining. The bacterial cell surface glycoproteins act as antigens that stimulate the immune response including macrophages, T-lymphocytes, B-lymphocytes, natural killer cells, and killer cells. This leads the production of interleukin (IL)-1, IL-2, IL-6, interferon gamma, and tumor necrosis factor-alpha (TNF-alpha). The immunotherapeutic effects of BCG in bladder cancer are due to cytokines, which cause cytotoxic effects. Tumor cell motility is also thought to be inhibited. Biopsies following BCG administration show increased expression of human leukocyte antigen (HLA)-Dr on tumor cells and infiltration of tumor and stroma with lymphocytes, mostly T-helper cells, and macrophages. Systemically, an increased immune response to the BCG antigen and production of BCG antibody may be seen.
Pharmacokinetics:
Bacillus Calmette-Guerin is administered as an intravesical solution (BCG Live, intravesical). Specific pharmacokinetic data are not available and may be strain specific.