Systemic Therapy Program

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Document Type

Drug Monographs
Treatment Regimens

Scientific Name:
BCG (Bacillus Calmette-Guérin)
Brand Name(s):
ImmuCyst®, OncoTICE®

Drug Monograph

Pharmacology

Mechanism of Action

Mechanism of action is not clear. A proposed mechanism is that the antitumor effect is related to release of tumour necrosis factor from activated macrophages.  Other proposed mechanisms include the induction of a local granulomatous reaction, activation of histiocytes, and other direct and indirect stimulation of both specific and non-specific immune responses.  Local inflammation follows, leading to destruction of superficial tumour cells by T-lymphocytes.

Pharmacokinetics

Pharmakodynamic/kinetic data have not been reported.

Side Effects

IMMEDIATE ONSET (hours to days)

• anaphylaxis
• flu-like symptoms (fever, chills, malaise, vomiting, arthralgia, myalgia, headache)
• bladder problems (cystitis, frequency, pain on urination, blood in urine, in
   bladder cancer)
• itching (urticaria)

EARLY ONSET  (days to weeks)

• liver problems (elevated liver function tests)
• injection site reactions
• lymph node problems (lymphadenopathy)
• disseminated BCG infection

DELAYED/LATE ONSET  (weeks to years)

• skin problems at injection site (granulomas)
• liver problems (hepatitis, tuberculoid granulomas)

Therapeutics

Approved Indications

• Bladder cancer
OTHER ONCOLOGY USES (Not Approved)
• Malignant melanoma

Routes

Intravesical intravesical (in 50 mL unpreserved NS, 2 hour retention)
Intralesional (rarely) by physician
Scarification (rarely) by physician

Administration

Instillation into the bladder (through an indwelling catheter); held in the bladder for about 30 minutes, with frequent body positioning (to coat inner surface of bladder)
(administering nurse should be certified to administer indwelling bladder instillations with chemotherapy and biologic agents)

IV Compatibility

Normal saline (preservative-free).

Dosing

Intravesical:
• OncoTICETM 1 ampul diluted to 30-50 mL Instil weekly for 6 weeks, then on weeks 8 & 12, then monthly for months 4 to 12 (1 to 8 x 108 CFU/ampul - Organon brand)
• ImmuCystTM 1 ampul diluted to 30-50mL Instil weekly for 6 weeks, then at 3, 6, 12, 18,& 24 months (81 mg/ampul - Connaught brand)
• Severe cystitis may require a 50% dose reduction.  If partial response, consider further 6 week course.  Further BCG for persistent disease after 2 courses or maintenance BCG are not recommended.

Intralesional:
• q1w: 0.005 mg x 4 weeks, then q2-4 weeks for 6-12 months; escalate depending on reactivity

Scarification:
• up to 40 mg

Pediatric: No pediatric indications

Contraindications

• Known hypersensitivity to BCG • Pregnancy or breast feeding • Low WBC, RBC, platelets (myelosuppression) • Significant positive tuberculin skin test • Recent smallpox immunization • Burn patients • Systemic corticosteroids in the previous 6 months • Tuberculin positive patients • AIDS patients

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Watch for signs of urinary infection, especially with prolonged cystitis, hematuria; signs of systemic tuberculosis infections

SUGGESTED CRITERIA
   NO ADDITIONAL TOXICITY RATINGS

Significant Interactions

Antitubercular drugs, immunosuppressive drugs (eg, dexamethasone, prednisone), TB skin test.

Product Information

Commercial Product Description

ImmuCyst® Vials with 81mg BCG for reconstitution OncoTICE® Vials with 1 to 8 x 108 colony forming units of Tice-strain BCG Keep refrigerated, protect from light (Vials of PACIS should be stored at -30oC)

Pharmaceutical Considerations

Handling precautions
BCG preparations contain viable attenuated mycobacteria and should be handled as infectious material. BCG should not be handled by persons with a known immunologic deficiency. Persons handling the product should be masked and gloved. Inadvertent injection can result in a local reaction; inadvertent contact with the eye may result in severe local tissue damage and possible loss of vision. All disposable equipment and materials used for preparation and administration should be handled as biohazardous waste.  Dininfectant solutions should be used to decontaminate vial stoppers before and after needle punctures.  Where available, closed systems should be used.

Injection
BCG vaccine (freeze-dried): 1.5 mg vial (Connaught) plus diluent (buffered saline); 0.75 mg ampul (IAF BioVac) plus diluent.
ImmuCyst (Aventis Pasteur): 1) Package containing 3 vials of freeze-dried BCG, each containing 27 mg dry weight BCG, equivalent to 40 mg moist weight; package also contains 3 vials of preservative-free diluent (0.85% sodium chloride, 0.025% Tween 80, 0.06% w/v sodium di-hydrogen phosphate and 0.25% disodium hydrogen phosphate); a 50 mL vial of phosphate-buffered saline is also available for dilution prior to bladder instillation.
2) Package containing 1 vial of 81mg freeze-dried BCG (equivalent to 10.5 +/- 8.7 x 108 CFU attenuated BCG, M. bovis).  and 1 vial with 3mL diluent solution (same preparations as above)
Reconstitute with diluent solution (3 x 1mL for 27mg vials or 3mL for 81mg vial).  Shake gently to suspend contents; avoid foaming of suspension.  Withdraw into 5mL syringe (3 x 1mL from 27mg vials or 3mL from 81mg vial).  Transfer suspension to a larger syringe and dilute with 50mL sterile normal asline to a total volume of 53mL.
OncoTICE (Organon Teknika): Package with one 2mL vial containing 1 to 8 x 108 CFU Tice strain BCG as a freeze dried cake.  Store in refrigerator at 2-8oC; protect from light.
Reconstitute with 1mL preservative-free normal saline; let stand for a few minutes, then gently swirl until homogenous suspension.  Do not shake or agitate vial.  Suspension may be stored in refrigerator at 2-8oC for up to 2 hours.
Transfer 1mL suspension to a 50mL syringe.  Rinse vial with 1mL saline, and transfer this to the same 50mL syringe.  Dilute suspension in syringe with normal saline to a total volume of 50mL.  Do not filter concentrated or diluted suspension.
PACIS (Shire Biologics)- Removed from Canadian Market: Package with one vial or ampoule containing 120mg BCG lyophilized powder (equivalent to 2 x 108 CFU attenuated BCG, M. bovis substrain Montreal).  Store at –30oC if possible.  When product is transferred to the refrigerator at 2-8oC, the expiry date will be 6 months from the transfer date.  Protect from sunlight.  Powder may be kept at room temperature for up to 6 hours.
Reconstitute with 1mL sterile water for injection.  Gently transfer solution into vial or ampoule; let stand for a few minutes, then withdraw contents into syringe, transfer between syringe and vial/ampoule 2 or 3 times to mix suspension. Dilute suspension in syringe with normal saline to a total volume of 50mL.  Do not filter concentrated or diluted suspension.

Diluted suspension for bladder instillation

Diluted suspension should be used immediately.  If there is a delay, ths diluted suspension may be stored up to 2 hours before use.  If flocculation or clumping is observed in any suspension, the product may be gently shaken; if the product does not re-suspend, this dose should not be used.It is recommended that BCG not be mixed with other drugs.

Safe waste disposal
The manufacturer recommends that urine voided for 6 hours after instillation be disinfected with an equal volume of household bleach and allowed to stand for 15 minutes before flushing. This precaution is intended to protect the person flushing the toilet from splash-back of viable BCG (eg, into the eyes). No environmental impact assessment was performed.

Handling Risk Level

Pregnancy CPOSSIBLE HAZARDOUS DRUG
FDA Pregnancy Risk Factor C

  • Consider handling this drug using precuations outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 3
FDA Pregnancy Risk Factor C
• Consider handling this drug using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

CCNS Provincial Formulary Status- Basic Level Bladder Instillation only • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs Pharmacare Formulary Status- Formulary (red) NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.



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