ImmuCyst (Bacillus Calmette-Guerin)



Bacillus Calmette-Guerin (BCG), substrain Connaught


Action And Clinical Pharmacology: When administered intravesically as a cancer therapy, BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with histiocytic and leukocytic infiltration in the urothelium and lamina propria of the urinary bladder. The local inflammatory effects are associated with an elimination or reduction of superficial cancerous lesions of the urinary bladder. The antitumor effect appears to be T-lymphocyte-dependent. The exact mechanism by which this is accomplished is unknown, but may involve expression of HLA-DR antigens on bladder urothelium and specific immunity to cells expressing both HLA-DR and BCG antigens on their cell surfaces.

General Discussion of BCG Therapy for Bladder Cancer: Carcinoma In-Situ of the Urinary Bladder: Carcinoma in-situ (CIS) may occur either alone or in association with papillary tumors, particularly those of higher grade. CIS may be multifocal, and may also be associated with multifocal pre-malignant dysplastic lesions. While trans-urethral resection (TUR) is the primary treatment for CIS, it is often not curative: some lesions may be either undetectable or unresectable or both. Furthermore, even with curative TUR, CIS is associated with a high incidence of recurrence and of recurrence of higher-stage lesions, including cancer invasive of the muscle layer of the urinary bladder (stage T2 or higher). Intravesical ImmuCyst has been studied and established as both an alternative to radical surgical treatment for CIS, and as prophylaxis for recurrence of CIS.

Papillary Tumors of the Urinary Bladder: While TUR is the primary treatment of superficial papillary tumors, these tumors have a tendency to recur and to progress. This is particularly true when there are 2 or more co-existing papillary tumors, when there has already been a recurrence of such tumors, or when there is co-existing CIS. In these circumstances, ImmuCyst has been shown to increase significantly the time to recurrence when administered intravesically for prophylactic purposes following TUR.

Efficacy of ImmuCyst: Several published studies have proven the effectiveness of ImmuCyst for patients with superficial bladder cancer at the CIS, Ta and T1 stages, including 2 multicentre controlled, randomized trials.

In the first, ImmuCyst was compared to doxorubicin HCl among patients with either CIS or recurrent papillary tumors or both. ImmuCyst was administered intravesically weekly for 6 weeks, with an additional single instillation at 3, 6, 12, 18 and 24 months following the initiation of treatment (total of 11 instillations). Doxorubicin was administered weekly for 5 weeks, with an additional 11 single monthly treatments. For patients with CIS, the complete response rate (i.e., negative biopsies and urine cytology) within 6 months of the initiation of treatment was 70% with ImmuCyst versus 34% with doxorubicin.

In the second multicenter controlled study, two treatment regimes of ImmuCyst were compared among similar patients to the first study. A 6-week induction course alone (total of 6 instillations) was compared to a more intensive regime consisting of the following: an induction course of 6 weekly treatments; after a 6-week pause, another 3 weekly treatments; and then maintenance therapy consisting of 3 weekly instillations at 6 months after the initiation of treatment, and then every 6 months until 36 months (total of 27 instillations). Comparing the maintenance regime to the no-maintenance regime (i.e., 6-week induction course only), the following results were found: among CIS patients, the complete response rate (defined as the absence of signs of malignancy in the urinary tract at both 3 and 6 months after the first instillation) was 87% in the maintenance group versus 73% in the no-maintenance group (p=0.016). Time to recurrence was significantly increased among all patients in the maintenance group.

Indications And Clinical Uses: For treatment of superficial transitional cell carcinoma (TCC) of the urinary bladder, regardless of antecedent intravesical treatment. Superficial TCC comprises the following: carcinoma in-situ (CIS), papillary tumors limited to the mucosa (stage Ta), papillary tumors involving the lamina propria but not the muscle layer of the bladder (stage T1), or any combination thereof.

For treatment and prophylaxis of primary or recurrent carcinoma in-situ (CIS) of the urinary bladder, and for prophylaxis following TUR of primary or recurrent stage Ta and/or T1 papillary tumors.

Contra-Indications: For patients: receiving immunosuppressive therapy (with drugs or radiation) or with compromised immune systems, because of the danger of a systemic BCG reaction; with active tuberculosis, because of the danger of exacerbation or of concomitant systemic BCG reaction; with current or previous evidence of a systemic BCG reaction (see Warnings and Adverse Effects, Treatment of Adverse Events); with fever, unless the cause of the fever has been determined and evaluated (see Adverse Effects, Treatment of Adverse Events); with bacterial urinary tract infection, until the infection has resolved (see Warnings); who have had a trans-urethral resection or traumatic bladder catheterization (associated with hematuria) in the previous week (see Warnings).

Manufacturers’ Warnings In Clinical States: Systemic BCG Reaction: A systemic BCG reaction is a systemic granulomatous illness which may occur (although rarely) subsequent to exposure to BCG. However, because it is usually difficult to isolate BCG organisms from affected organs, it is often unclear to what extent such a reaction is due to an infectious process versus an inflammatory hypersensitivity reaction: hence the term “systemic reaction”. Based on past clinical experience with intravesical BCG, “systemic BCG reaction” may be defined as the presence of any of the following signs, if no other etiologies for such signs are detectable: fever 39.5°C for 12 hours; fever 38.5°C for 48 hours; pneumonitis; hepatitis; other organ dysfunction outside of the genitourinary tract with granulomatous inflammation on biopsy; or the classical signs of sepsis, including circulatory collapse, acute respiratory distress, and disseminated intravascular coagulation. Although rare, a systemic BCG reaction is much more likely to occur if BCG is administered within 1 week of either trans-urethral resection or traumatic bladder catheterization that was associated with hematuria. One case of systemic BCG reaction has been reported in a patient with a prosthetic aortic valve and a prior history of bacterial endocarditis; it is unknown whether these constitute risk factors for a systemic BCG reaction. Three fatalities have been reported with the use of ImmuCyst, all associated with systemic BCG reaction. One was associated with intravesical instillation in spite of traumatic catheterization in a patient with antecedent alcoholic liver disease. The second case was associated with instillation less than 1 week following transurethral resection. The third case may have been related to continued BCG treatment of a patient with an unrecognized systemic BCG reaction. The appropriate treatment of systemic BCG reaction is discussed in Adverse Effects, Treatment of Adverse Events.

Additional Warnings: Skin rash, arthralgias, and migratory arthritis are rare, and are considered to be strictly allergic reactions. The appropriate treatment is discussed in Adverse Effects, Treatment of Adverse Events.

Administration of intravesical ImmuCyst causes an inflammatory response in the bladder and has been frequently associated with transient fever, hematuria, urinary frequency and dysuria. Such reactions may to some degree be taken as evidence that BCG is evoking the desired response, but careful monitoring of urinary status is required. Infrequent associations include bacterial urinary tract infection, bladder contracture, symptomatic granulomatous prostatitis, epididymo-orchitis, ureteral obstruction, and renal abscess.

For patients with small bladder capacity, increased risk of bladder contracture should be considered in decisions to treat with ImmuCyst.

If a bacterial urinary tract infection (UTI) occurs during the course of ImmuCyst treatment, ImmuCyst instillation should be withheld until complete resolution of the bacterial UTI for 2 reasons: (1) the combination of a UTI and BCG-induced cystitis may lead to more severe adverse effects on the genitourinary tract, and (2) BCG bacilli are sensitive to a wide variety of antibiotics; antimicrobial administration may therefore diminish the efficacy of ImmuCyst. Similarly, patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of ImmuCyst.

Intravesical treatment with ImmuCyst may induce a sensitivity to tuberculin purified protein derivative (PPD) which could complicate future interpretations of skin test reactions to tuberculin in the diagnosis of suspected mycobacterial infections. Determination of a patient’s reactivity to tuberculin prior to administration of ImmuCyst may therefore be desirable.

Precautions: General: Contains viable attenuated mycobacteria. Handle as infectious.

Care must be taken during administration of intravesical ImmuCyst not to introduce contaminants into the urinary tract nor to traumatize unduly the urinary mucosa.

It is recommended that intravesical ImmuCyst not be administered any sooner than 1 week following transurethral resection.

If the physician believes that the bladder catheterization has been traumatic (e.g., associated with bleeding), then ImmuCyst should not be administered and there must be a treatment delay of at least 1 week. Subsequent treatment should be resumed as if no interruption in the schedule had occurred.

Drug Interactions: Patients must also be advised that drug combinations containing bone marrow depressants and/or immunosuppressants and/or radiation may impair the response to ImmuCyst or increase the risk of disseminated BCG reaction.

Pregnancy : Animal reproduction studies have not been conducted with ImmuCyst. It is also not known whether ImmuCyst can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ImmuCyst should be given to a pregnant woman only if clearly needed. Women should be advised not to become pregnant while on therapy.

Lactation: A nursing woman with a systemic BCG infection could infect her infant. It is not known whether this product is excreted in human milk. Therefore, caution should be exercised when ImmuCyst is administered to a nursing woman.

Children: Safety and effectiveness in children has not been established.

Information for the Patient: Patients must be advised to check with their doctor as soon as possible if there is an increase in their existing urinary symptoms (such as frequency of voiding or painful urination), or if their symptoms persist even after receiving a number of treatments, or if any of the following symptoms develop:

More Common: Blood in urine, painful or frequent urination lasting >2 days, fever and chills lasting more than 24 hours, nausea and vomiting. Rare: cough, skin rash, high or persistent fever, joint pains, jaundice.

Urine voided for 6 hours after instillation shall be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to stand for 15 minutes before flushing.

Adverse Reactions: Local: The common adverse events which occurred among recipients of ImmuCyst during induction and during maintenance therapy are listed in Table III.

The most common local reactions are transient dysuria and urinary frequency, which occurred on at least one occasion among 26% and 14%, respectively, of patients during induction, rising to 46% and 34%, respectively, among patients during maintenance therapy. Gross hematuria has occurred among 11 to 19% of ImmuCyst recipients.

Treatment of Adverse Events: Irritative bladder side effects associated with ImmuCyst administration can be managed symptomatically with propantheline bromide. Acetaminophen may be administered for symptomatic relief of transient fever or irritative bladder symptoms.

BCG organisms, including the Connaught strain, are susceptible to all currently used antituberculosis drugs, with the exception of pyrazinamide. Accordingly, for more serious reactions other than the systemic BCG reaction described in Warnings – e.g., severe urinary tract adverse events or allergic reaction – isoniazid with or without rifampin should be administered for 3 to 6 months. If a systemic BCG reaction occurs, an Infectious Diseases consultation should be sought, ImmuCyst should be permanently discontinued, and triple antituberculosis therapy should be initiated promptly and continued for 6 months. Commonly, this will comprise isoniazid (300 mg daily), rifampin (600 mg daily), and ethambutol (1 000 mg daily). In the presence of signs of septic shock as a manifestation of a systemic BCG reaction, the addition of short-term corticosteroids (e.g., prednisolone, 40 mg daily) has been shown to be beneficial both in 5 patients and in an animal model, and should therefore be considered.

ImmuCyst Recommended Treatment of Adverse Events Associated with ImmuCyst

Symptom, Sign or Syndrome Treatment

(1) Irritative bladder symptoms
Symptomatic treatment.

(2) Irritative bladder symptoms ³48 hours duration.

Symptomatic treatment; postpone next ImmuCyst treatment until complete resolution. If complete resolution has not occurred within 1 week, administer isoniazid (INH), 300 mg daily until complete resolution.

(3) Concomitant bacterial UTI.

Postpone next ImmuCyst treatment until completion of antimicrobial therapy and negative urine culture.

(4) Other genitourinary tract adverse events: symptomatic granulomatous prostatitis, epididymo-orchitis, ureteral obstruction, or renal abscess

Discontinue ImmuCyst. Administer INH, 300 mg daily and rifampin, 600 mg daily, for 3-6 months.

(5) Fever
Symptomatic treatment with acetaminophen.

(6) Skin rash, arthralgias, or migratory arthritis.

Antihistamines or nonsteroidal anti-inflammatories. If no response, discontinue ImmuCyst and administer INH, 300 mg daily for 3 months.

(7) Systemic BCG reaction (as defined in Warnings) without signs of septic shock.

Discontinue ImmuCyst. Seek an Infectious Disease Consultation. Administer triple-drug antituberculous therapy for 6 months.

(8) Systemic BCG reaction (as defined in Warnings) with signs of septic shock.

As for (7). Consider addition of short-term high-dose systemic corticosteroids.

Legend: INH=Isoniazide.

If a systemic BCG reaction has occurred, a report should be submitted to both the manufacturer and the appropriate health authorities. The report should include details of the treatment history with ImmuCyst, the symptoms and signs of the BCG reaction, the treatment administered for the reaction, and the response to such treatment.

Dosage And Administration: Treatment Schedule: Intravesical treatment of the urinary bladder should begin between 7 to 14 days after biopsy or transurethral resection. The induction treatment comprises 6 weekly intravesical treatments with ImmuCyst, each treatment dose comprising one 81 mg vial of ImmuCyst. After a 6-week pause, another dose should be given intravesically once weekly for 1 to 3 weeks. Three weekly doses should definitely be given to patients who still have evidence of bladder cancer. Clinical studies have demonstrated that the 3 doses given at 3 months significantly increased the complete response rate from 73 to 87% at 6 months. Based on clinical studies performed with ImmuCyst, maintenance therapy following induction is recommended. This consists of 1 to 3 weekly treatments at 6 months following the initiation of treatment, and then every 6 months thereafter until 36 months.

Administration: Each dose (1 reconstituted vial) is further diluted in an additional 50 mL of sterile, preservative-free saline for a total of 53 mL (see reconstitution instructions below).

A urethral catheter is inserted into the bladder under aseptic conditions, the bladder is drained, and then 53 mL suspension of ImmuCyst is instilled slowly by gravity, following which the catheter is withdrawn.

The patient retains the suspension for as long as possible for a total of up to 2 hours. During the first 15 minutes following instillation, the patient should lie prone. Thereafter, the patient is then allowed to be up. At the end of 2 hours, all patients should void in a seated position for environmental safety reasons. Patients should be instructed to maintain adequate hydration.

Protocols for clinical trials carried out with Connaught’s ImmuCyst included a percutaneous inoculation with each intravesical dose, although not all patients received it. A 0.5 mL portion of the 53 mL intravesical dose of ImmuCyst was injected percutaneously (example: on inside, upper thigh). Some studies have suggested that this may not be necessary, so the percutaneous dose may be omitted. Furthermore, if severe reactions, such as ulceration at the site or regional lymphadenitis occur, the percutaneous treatment should be discontinued.

Reconstitution of Freeze-Dried Product and Withdrawal from Rubber-Stoppered Vial: Do not remove the rubber stoppers from the vials. Handle as infectious material.

Reconstitute and dilute immediately prior to use, using aseptic technique in a high airflow, low traffic area (e.g., in a biocontainment cabinet). Persons handling product should wear gloves. If and when the product is handled outside of a biocontainment cabinet, persons handling the product should also wear a mask and eye protection.

ImmuCyst should not be handled by persons with a known immunologic deficiency.

ImmuCyst should be reconstituted only with the diluent provided to ensure proper dispersion of the organisms.

Apply a sterile piece of cotton moistened with a suitable antiseptic to the surface of the rubber stoppers of the vials of diluent and ImmuCyst.

Using a 5 mL sterile syringe and needle, draw into the syringe a volume of air equal to the volume of diluent in the vial. Pierce the center of the rubber stopper in the vial containing diluent with the sterile needle of the syringe, invert the vial, slowly inject into it the air contained in the syringe. Keeping the point of the needle immersed, withdraw into the syringe 3 mL of diluent. Then holding the syringe-plunger steady, withdraw the needle from the vial.

Using the same syringe and needle, pierce the stopper in the vial of freeze-dried material with the needle. Hold the vial of freeze-dried material upright and pull the plunger of the syringe back to the 5 mL marking on the barrel. This will create a mild vacuum in the vial. Release the plunger and allow the vacuum to pull the diluent from the syringe into the vial of freeze-dried material. After all the diluent has passed into the freeze-dried material, remove the needle and syringe. Shake the vial gently until a fine, even suspension results. Withdraw the entire contents of the reconstituted material from the vial into the same 5 mL syringe. Return the vial to an upright position before removing the syringe from the vial.

Further dilute the reconstituted material from the vial (1 dose) in an additional 50 mL of sterile, preservative-free saline to a final volume of 53 mL for intravesical instillation (and 0.5 mL of the 53 mL for percutaneous injection, if administered).

The product should be used immediately after reconstitution and dilution; however, it must not be used after 2 hours. Any reconstituted product which exhibits flocculation or clumping that cannot be dispersed with gentle shaking should not be used.

At no time should the reconstituted product be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

Special Instructions: After use, unused drug, packaging, and all equipment and materials (e.g., syringes, catheters) used for instillation of the product, should be placed immediately in a container for biohazardous materials, and discarded using suitable methods (e.g., autoclaving).

Availability And Storage: Each vial contains: BCG 81 mg (dry weight) and monosodium glutamate 5% w/v. The reconstituted dose (1 vial) contains: 10.5±8.7´10colony forming units (CFU) over the course of its shelf-life. Single dose packages of 1 vial of the freeze-dried ImmuCyst and one 3 mL vial of diluent.

Instillation medium is also available as a vial containing 50 mL of sterile, preservative-free, phosphate-buffered saline, for dilution of the reconstituted material.

ImmuCyst and the accompanying diluent should be kept in a refrigerator at a temperature between 2 and 8°C. It should not be used after the expiration date marked on the vial. At no time should the freeze-dried ImmuCyst be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

ImmuCyst® Connaught Bacillus Calmette-Guérin (BCG), substrain Connaught Antineoplastic

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