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PACIS (Bacillus Calmette-Guérin (BCG), Substrain Montréal)
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Pharmacology
PACIS (Bacillus Calmette-Guérin (BCG), substrain Montréal) promotes a local inflammatory reaction with histiocytic and leukocytic infiltration in the urinary bladder. The local inflammatory effects are associated with an apparent elimination or reduction of superficial cancerous lesions of the urinary bladder. The exact mechanism by which this is accomplished is unknown.
PACIS (Bacillus Calmette-Guérin (BCG), substrain Montréal) promotes a local inflammatory reaction with histiocytic and leukocytic infiltration in the urinary bladder. The local inflammatory effects are associated with an apparent elimination or reduction of superficial cancerous lesions of the urinary bladder. The exact mechanism by which this is accomplished is unknown.
Indications
PACIS (Bacillus Calmette-Guérin (BCG), Substrain Montréal) Promotes A Local Inflammatory Reaction With Histiocytic And Leukocytic Infiltration In The Urinary Bladder. The Local Inflammatory Effects Are Associated With An Apparent Elimination Or Reduction Of Superficial Cancerous Lesions Of The Urinary Bladder. The Exact Mechanism By Which This Is Accomplished Is Unknown.
PACIS (Bacillus Calmette-Guérin (BCG), Substrain Montréal) Promotes A Local Inflammatory Reaction With Histiocytic And Leukocytic Infiltration In The Urinary Bladder. The Local Inflammatory Effects Are Associated With An Apparent Elimination Or Reduction Of Superficial Cancerous Lesions Of The Urinary Bladder. The Exact Mechanism By Which This Is Accomplished Is Unknown.
Contraindications
Patients on immunosuppressive therapy or with compromised immune systems should not receive PACIS because of the risk of overwhelming systemic mycobacterial sepsis.
Drug combinations containing bone marrow depressants or immunosuppressants, or radiation, may impair the response to PACISand may increase the risk of osteomyelitis or disseminated BCG infection.
PACIS should not be administered to patients with fever unless the cause of the fever is determined and evaluated. If the fever is due to an infection, PACIS should be withheld until it subsides.
Patients with urinary tract infection should not receive PACIS treatment because of the risk of disseminated BCG infection or of an increase in the severity of bladder irritation.
Patients on immunosuppressive therapy or with compromised immune systems should not receive PACIS because of the risk of overwhelming systemic mycobacterial sepsis.
Drug combinations containing bone marrow depressants or immunosuppressants, or radiation, may impair the response to PACISand may increase the risk of osteomyelitis or disseminated BCG infection.
PACIS should not be administered to patients with fever unless the cause of the fever is determined and evaluated. If the fever is due to an infection, PACIS should be withheld until it subsides.
Patients with urinary tract infection should not receive PACIS treatment because of the risk of disseminated BCG infection or of an increase in the severity of bladder irritation.
Safety Information / Warning
Administration of intravesical PACIS causes an inflammatory response in the bladder and has been associated with hematuria, urinary frequency, dysuria and bacterial urinary tract infection. Careful monitoring of urinary status is required. Although local irritative symptoms and flu-like symptoms are the most common, other systemic adverse reactions, while rare, have been seen in patients receiving BCG immunotherapy. These have included nausea, diarrhea, anemia and leukopenia, prostatitis and ureteral obstruction, and systemic BCG infection with death. Death has occurred following intravesical administration of BCG. If systemic BCG infection is suspected, the patient should be immediately treated with fast-acting antituberculosis antibiotic therapy following consultations with an infectious disease specialist (see Precautions). PACIS therapy should be withheld upon any suspicion of systemic infection, e.g., granulomatous hepatitis.
Patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy will obviate the effects of PACIS.
For patients with small bladder capacity, the increased risk of severe local irritation should be considered in decisions to treat with PACIS.
Since intravesical treatment with PACIS may induce a sensitivity to tuberculin, 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 PACIS may be desirable.
Administration of intravesical PACIS causes an inflammatory response in the bladder and has been associated with hematuria, urinary frequency, dysuria and bacterial urinary tract infection. Careful monitoring of urinary status is required. Although local irritative symptoms and flu-like symptoms are the most common, other systemic adverse reactions, while rare, have been seen in patients receiving BCG immunotherapy. These have included nausea, diarrhea, anemia and leukopenia, prostatitis and ureteral obstruction, and systemic BCG infection with death. Death has occurred following intravesical administration of BCG. If systemic BCG infection is suspected, the patient should be immediately treated with fast-acting antituberculosis antibiotic therapy following consultations with an infectious disease specialist (see Precautions). PACIS therapy should be withheld upon any suspicion of systemic infection, e.g., granulomatous hepatitis.
Patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy will obviate the effects of PACIS.
For patients with small bladder capacity, the increased risk of severe local irritation should be considered in decisions to treat with PACIS.
Since intravesical treatment with PACIS may induce a sensitivity to tuberculin, 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 PACIS may be desirable.
Precautions
Contains viable attenuated mycobacteria. Handle as infectious.
All equipment and materials (e.g., syringes, catheters) used for instillation of the product into the bladder should be placed immediately into plastic bags, labelled “Infectious Waste”, and disposed of accordingly as biohazardous waste.
Care must be taken during administration of intravesical PACIS, to avoid introducing contaminants into the urinary tract or traumatizing unduly the urinary mucosa.
Because fatalities have been reported with use of BCG after traumatic catheterization, it is recommended that intravesical PACIS not be administered any sooner than 1week following transurethral resection or other invasive procedures involving the urinary bladder.
If the physician suspects that bladder catherization has been traumatic (e.g., associated with bleeding or possible false passage), then PACIS should not be administered and treatment should be delayed at least 1week. Subsequent treatment should be resumed as if no interruption in the schedule had occurred; i.e., all remaining doses of PACIS should be administered.
Similarly, the full course of treatment should be completed, whenever possible, when interruptions have occurred for other reasons.
If systemic BCG infection is suspected (i.e., if patients have fever over 39°C, or persistent fever above 38°C over 2days, or severe malaise), fast-acting antituberculosis therapy should be initiated and an infectious disease specialist consulted. It should be noted that presumptive BCG systemic infections can rarely be confirmed by positive cultures.
Concomitant use of ASA may interfere with the attachment of BCG to the bladder mucosa.
Pregnancy: Animal reproduction studies have not been conducted with PACIS. It is also not known whether PACIS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PACIS should be given to a pregnant woman only if clearly needed.
Lactation: A nursing mother with a systemic BCG infection could infect her infant. It is not known whether this drug is excreted in human milk. Therefore, caution should be exercised when PACIS is administered to a nursing mother and nursing should be discontinued.
Children: Safety and effectiveness in children have not been established.
Information to Be Provided to the Patient: Patients must be advised to check with their doctor as soon as possible if there is an increase in their existing symptoms, 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, fever and chills, frequent urge to urinate, increased frequency of urination, joint pain, nausea and vomiting, painful urination. Rare: cough, skin rash.
Note: A cough that develops after administration of PACIS could indicate a life-threatening BCG infection. Possible BCG infection should be treated immediately, in consultation with an infectious disease specialist.
Patients should be asked to avoid drinking liquids for the 2hours prior to and during PACIS therapy.
Ideally, during the first hour following instillation, the patient should lie for 15minutes each in the prone and supine positions and also on each side. The patient is then allowed to be up but retains the suspension for another 60minutes for a total of 2hours. All patients may not be able to retain the suspension for 2hours and should be instructed to void in less time if necessary. At the end of treatment all patients should void in a seated position for safety reasons. Patients should be instructed to drink enough liquid after treatment to maintain adequate hydration.
Urine voided during the 6hours after instillation must be disinfected with an equal volume of 5% sodium hypochlorite solution (undiluted household bleach) and allowed to stand for 15minutes before flushing.
Patients must also be advised that drug combinations containing bone marrow depressants and/or immunosuppressants and/or radiation may impair the response to PACIS or increase the risk of osteomyelitis or disseminated BCG infection. They should also be advised to inform any physicians whom they consult that they are being treated with PACIS.
Contains viable attenuated mycobacteria. Handle as infectious.
All equipment and materials (e.g., syringes, catheters) used for instillation of the product into the bladder should be placed immediately into plastic bags, labelled “Infectious Waste”, and disposed of accordingly as biohazardous waste.
Care must be taken during administration of intravesical PACIS, to avoid introducing contaminants into the urinary tract or traumatizing unduly the urinary mucosa.
Because fatalities have been reported with use of BCG after traumatic catheterization, it is recommended that intravesical PACIS not be administered any sooner than 1week following transurethral resection or other invasive procedures involving the urinary bladder.
If the physician suspects that bladder catherization has been traumatic (e.g., associated with bleeding or possible false passage), then PACIS should not be administered and treatment should be delayed at least 1week. Subsequent treatment should be resumed as if no interruption in the schedule had occurred; i.e., all remaining doses of PACIS should be administered.
Similarly, the full course of treatment should be completed, whenever possible, when interruptions have occurred for other reasons.
If systemic BCG infection is suspected (i.e., if patients have fever over 39°C, or persistent fever above 38°C over 2days, or severe malaise), fast-acting antituberculosis therapy should be initiated and an infectious disease specialist consulted. It should be noted that presumptive BCG systemic infections can rarely be confirmed by positive cultures.
Concomitant use of ASA may interfere with the attachment of BCG to the bladder mucosa.
Pregnancy: Animal reproduction studies have not been conducted with PACIS. It is also not known whether PACIS can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PACIS should be given to a pregnant woman only if clearly needed.
Lactation: A nursing mother with a systemic BCG infection could infect her infant. It is not known whether this drug is excreted in human milk. Therefore, caution should be exercised when PACIS is administered to a nursing mother and nursing should be discontinued.
Children: Safety and effectiveness in children have not been established.
Information to Be Provided to the Patient: Patients must be advised to check with their doctor as soon as possible if there is an increase in their existing symptoms, 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, fever and chills, frequent urge to urinate, increased frequency of urination, joint pain, nausea and vomiting, painful urination. Rare: cough, skin rash.
Note: A cough that develops after administration of PACIS could indicate a life-threatening BCG infection. Possible BCG infection should be treated immediately, in consultation with an infectious disease specialist.
Patients should be asked to avoid drinking liquids for the 2hours prior to and during PACIS therapy.
Ideally, during the first hour following instillation, the patient should lie for 15minutes each in the prone and supine positions and also on each side. The patient is then allowed to be up but retains the suspension for another 60minutes for a total of 2hours. All patients may not be able to retain the suspension for 2hours and should be instructed to void in less time if necessary. At the end of treatment all patients should void in a seated position for safety reasons. Patients should be instructed to drink enough liquid after treatment to maintain adequate hydration.
Urine voided during the 6hours after instillation must be disinfected with an equal volume of 5% sodium hypochlorite solution (undiluted household bleach) and allowed to stand for 15minutes before flushing.
Patients must also be advised that drug combinations containing bone marrow depressants and/or immunosuppressants and/or radiation may impair the response to PACIS or increase the risk of osteomyelitis or disseminated BCG infection. They should also be advised to inform any physicians whom they consult that they are being treated with PACIS.
Side Effects / Adverse Effects
PACIS may affect several organs (or parts) of the body in addition to the cancer cells. The data in TableI have been derived from 2 open studies which were continued for several years.
This report referred to an earlier publication (Lamm, 1986) in which the incidences of the more common side effects in 1278 patients were reported. These were: cystitis 91%, hematuria 43%, low grade fever (£38.5°C) 28%, malaise 24% and nausea 8%.
Rare complications, several of which have never been seen with intravesical administration of BCG, may include immune-complex glomerulonephritis, choroiditis, nephrogenic adenoma, cardiac toxicity, suppurative lymphadenitis, lupus vulgaris, musculoskeletal lesions and abscesses and fistulae.
Irritative bladder side effects associated with PACIS administration can be managed symptomatically (e.g., with phenazopyridine HCl or propantheline bromide, and acetaminophen).
Systemic side effects (such as malaise, fever and chills) may represent hypersensitivity reactions and can be treated with antihistamines and other appropriate therapy. Systemic infection as a result of the spread of BCG organisms has occasionally occurred with intravesical BCG administration. If systemic BCG infection is suspected (i.e., if patients have fever over 39°C, persistent fever above 38°C over 2days, or severe malaise), fast-acting antituberculosis therapy should be initiated and an infectious disease specialist consulted.
PACIS may affect several organs (or parts) of the body in addition to the cancer cells. The data in TableI have been derived from 2 open studies which were continued for several years.
This report referred to an earlier publication (Lamm, 1986) in which the incidences of the more common side effects in 1278 patients were reported. These were: cystitis 91%, hematuria 43%, low grade fever (£38.5°C) 28%, malaise 24% and nausea 8%.
Rare complications, several of which have never been seen with intravesical administration of BCG, may include immune-complex glomerulonephritis, choroiditis, nephrogenic adenoma, cardiac toxicity, suppurative lymphadenitis, lupus vulgaris, musculoskeletal lesions and abscesses and fistulae.
Irritative bladder side effects associated with PACIS administration can be managed symptomatically (e.g., with phenazopyridine HCl or propantheline bromide, and acetaminophen).
Systemic side effects (such as malaise, fever and chills) may represent hypersensitivity reactions and can be treated with antihistamines and other appropriate therapy. Systemic infection as a result of the spread of BCG organisms has occasionally occurred with intravesical BCG administration. If systemic BCG infection is suspected (i.e., if patients have fever over 39°C, persistent fever above 38°C over 2days, or severe malaise), fast-acting antituberculosis therapy should be initiated and an infectious disease specialist consulted.
Overdose
Information not available
Information not available
Recommended Dosage
Intravesical treatment should begin between 7 to 14days after biopsy (or transurethral resection if this procedure is done).
The recommended course of PACIS treatment is a single dose of 120mg instilled into the bladder once weekly for 6weeks.
Reconstitute the product according to the further directions: Dilute 1mL of reconstituted product in 50mL of sterile physiological saline. Insert a urethral catheter into the bladder under aseptic conditions and drain the bladder. Instill the 50mL of PACIS suspension into the bladder slowly by gravity. Remove the catheter. Advise the patient (see Precautions, Information to Be Provided to the Patient).
Ideally, during the first hour following instillation, the patient should lie for 15minutes each in the prone and supine positions and also on each side. The patient is then allowed to be up but retains the suspension for another 60minutes for a total of 2hours. All patients may not be able to retain the suspension for 2hours and should be instructed to void in less time if necessary. At the end of treatment all patients should void in a seated position for safety reasons. Patients should be instructed to drink enough liquid after treatment to maintain adequate hydration.
The induction therapy may be followed by a single instillation given at 3, 6, 12, 18 and 24months following the initial treatment.
After use, all equipment should be sterilized or disposed of properly as with any other biohazardous waste (see Precautions).
Reconstitution of Lyophilized Product: Handle as infectious material. Persons handling product should be masked and gloved. PACIS should not be handled by persons with a known immunologic deficiency. Check the expiry date of the product carefully. Reconstitute and dilute using aseptic technique immediately prior to use. PACIS is available in vials or ampuls.
Vials: Note that if the vial is stored between 2 and 8°C, a new expiry date of 6 months from the start of storage at this temperature supersedes the printed expiry date. Administration of any product past its expiry date is not recommended.
The contents of the PACIS vial should be suspended with a sterile diluent (sterile water for injection USP, without any preservative). Moisten the surfaces of both rubber stoppers with tampons of sterile cotton wool soaked in a suitable antiseptic and allow the antiseptic to act for a few moments, then wipe dry with sterile dry swabs. With a sterile syringe, remove 1mL of sterile diluent and add it to the vial containing the PACIS.
Ampuls: The contents of the PACIS ampul should be suspended with a sterile diluent (Sterile Water for Injection USP, without any preservative): open the ampul carefully, it has been sealed under vacuum. With a sterile syringe, add 1 mL of sterile diluent to the ampul containing the PACIS.
Vials and Ampuls: Leave PACIS and diluent in contact for about 1minute. Then mix the suspension by withdrawing it into the syringe and expelling it gently back into the vial or ampul 2 or 3times. Avoid the production of foam; do not shake.
At no time should the reconstituted product be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.
Intravesical treatment should begin between 7 to 14days after biopsy (or transurethral resection if this procedure is done).
The recommended course of PACIS treatment is a single dose of 120mg instilled into the bladder once weekly for 6weeks.
Reconstitute the product according to the further directions: Dilute 1mL of reconstituted product in 50mL of sterile physiological saline. Insert a urethral catheter into the bladder under aseptic conditions and drain the bladder. Instill the 50mL of PACIS suspension into the bladder slowly by gravity. Remove the catheter. Advise the patient (see Precautions, Information to Be Provided to the Patient).
Ideally, during the first hour following instillation, the patient should lie for 15minutes each in the prone and supine positions and also on each side. The patient is then allowed to be up but retains the suspension for another 60minutes for a total of 2hours. All patients may not be able to retain the suspension for 2hours and should be instructed to void in less time if necessary. At the end of treatment all patients should void in a seated position for safety reasons. Patients should be instructed to drink enough liquid after treatment to maintain adequate hydration.
The induction therapy may be followed by a single instillation given at 3, 6, 12, 18 and 24months following the initial treatment.
After use, all equipment should be sterilized or disposed of properly as with any other biohazardous waste (see Precautions).
Reconstitution of Lyophilized Product: Handle as infectious material. Persons handling product should be masked and gloved. PACIS should not be handled by persons with a known immunologic deficiency. Check the expiry date of the product carefully. Reconstitute and dilute using aseptic technique immediately prior to use. PACIS is available in vials or ampuls.
Vials: Note that if the vial is stored between 2 and 8°C, a new expiry date of 6 months from the start of storage at this temperature supersedes the printed expiry date. Administration of any product past its expiry date is not recommended.
The contents of the PACIS vial should be suspended with a sterile diluent (sterile water for injection USP, without any preservative). Moisten the surfaces of both rubber stoppers with tampons of sterile cotton wool soaked in a suitable antiseptic and allow the antiseptic to act for a few moments, then wipe dry with sterile dry swabs. With a sterile syringe, remove 1mL of sterile diluent and add it to the vial containing the PACIS.
Ampuls: The contents of the PACIS ampul should be suspended with a sterile diluent (Sterile Water for Injection USP, without any preservative): open the ampul carefully, it has been sealed under vacuum. With a sterile syringe, add 1 mL of sterile diluent to the ampul containing the PACIS.
Vials and Ampuls: Leave PACIS and diluent in contact for about 1minute. Then mix the suspension by withdrawing it into the syringe and expelling it gently back into the vial or ampul 2 or 3times. Avoid the production of foam; do not shake.
At no time should the reconstituted product be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.
Supplied / Packaging
Ampuls: Each vacuum-sealed ampul of lyophilized preparation of Bacillus Calmette-Guérin (BCG), an attenuated strain of M.bovis, (substrain Montréal) in a 15% (w/v) lactose base contains: a single dose of 120mg semi-dry weight (2to 10´10 6 colony-forming units (CFU)/mg) of BCG and is ready to use following reconstitution with sterile water for injection USP. The BCG contains no preservative. A file is provided to break the ampul.
Keep in a refrigerator at a temperature between 2 and 8°C. Freezing will not harm the BCG. PACIS should not be used after the expiration date marked on the ampul.
Vials: Each vacuum-sealed vial of lyophilized preparation of Bacillus Calmette-Guérin (BCG), an attenuated strain of M.bovis, (substrain Montréal) in a 15% (w/v) lactose base contains: a single dose of 120mg semi-dry weight (2to 10´10 6 colony-forming units (CFU)/mg) of BCG and is ready to use following reconstitution with sterile water for injection USP. The BCG contains no preservative.
Store at -30°C wherever possible. May be stored between 2and 8°C for a maximum of 6months. At the time of transfer between 2and 8°C note the new expiry date (i.e., current date plus 6months) on the carton label in the space provided.
PACIS should not be transferred between 2and 8°C after the expiry date printed on the vial and carton. PACIS should not be used more than 6months after being transferred between 2and 8°C, even if this is earlier than the printed expiry date.
Ampuls and Vials: At no time should the lyophilized PACIS be exposed to sunlight, direct or indirect. The product may be kept at 4or 25°C, under artificial light for a maximum of 6hours, while still in the lyophilized state.
Ampuls: Each vacuum-sealed ampul of lyophilized preparation of Bacillus Calmette-Guérin (BCG), an attenuated strain of M.bovis, (substrain Montréal) in a 15% (w/v) lactose base contains: a single dose of 120mg semi-dry weight (2to 10´10 6 colony-forming units (CFU)/mg) of BCG and is ready to use following reconstitution with sterile water for injection USP. The BCG contains no preservative. A file is provided to break the ampul.
Keep in a refrigerator at a temperature between 2 and 8°C. Freezing will not harm the BCG. PACIS should not be used after the expiration date marked on the ampul.
Vials: Each vacuum-sealed vial of lyophilized preparation of Bacillus Calmette-Guérin (BCG), an attenuated strain of M.bovis, (substrain Montréal) in a 15% (w/v) lactose base contains: a single dose of 120mg semi-dry weight (2to 10´10 6 colony-forming units (CFU)/mg) of BCG and is ready to use following reconstitution with sterile water for injection USP. The BCG contains no preservative.
Store at -30°C wherever possible. May be stored between 2and 8°C for a maximum of 6months. At the time of transfer between 2and 8°C note the new expiry date (i.e., current date plus 6months) on the carton label in the space provided.
PACIS should not be transferred between 2and 8°C after the expiry date printed on the vial and carton. PACIS should not be used more than 6months after being transferred between 2and 8°C, even if this is earlier than the printed expiry date.
Ampuls and Vials: At no time should the lyophilized PACIS be exposed to sunlight, direct or indirect. The product may be kept at 4or 25°C, under artificial light for a maximum of 6hours, while still in the lyophilized state.
