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PACIS™
Faulding
Bacillus Calmette-Guérin (BCG), substrain Montréal
Antineoplastic
 
Action And Clinical 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. tag_IndicationsIndications

Indications And Clinical Uses: For intravesical use in the treatment of initial and recurrent episodes of carcinoma in-situ (CIS), and CIS associated with papillary tumors of the urinary bladder. Also indicated for the treatment of papillary tumors of the urinary bladder following surgical resection and for CIS and/or papillary tumors which have failed to respond to other treatment regimens.

Contra-Indications: 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 PACIS and 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.

Manufacturers' Warnings In Clinical States: 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 1 week 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 1 week. 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 2 days, 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 for 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 2 hours prior to and during PACIS therapy.

Ideally, during the first hour following instillation, the patient should lie for 15 minutes 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 60 minutes for a total of 2 hours. All patients may not be able to retain the suspension for 2 hours 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 6 hours after instillation must be disinfected with an equal volume of 5% sodium hypochlorite solution (undiluted household bleach) and allowed to stand for 15 minutes 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.

Adverse Reactions: PACIS may affect several organs (or parts) of the body in addition to the cancer cells. The data in Table I have been derived from 2 open studies which were continued for several years.

The following events were also reported in one patient each. Vancouver: contracted bladder, epididymitis, flu-like syndrome, arthralgia, increased WBC; Kingston: incontinence, flu-like reaction, lightheadedness, anorexia, arthritis, back pain, sepsis.

The adverse events listed in Table II are taken from a report by Lamm et al (1989) on the complications of treatment with BCG. This report includes data from the use of Montréal (Institut Armand-Frappier), Tice, Connaught, Pasteur and RIVM strains.

This report referred to an earlier publication (Lamm, 1986) in which the incidences of the more common side effects in 1 278 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 2 days, or severe malaise), fast-acting antituberculosis therapy should be initiated and an infectious disease specialist consulted.

Dosage And Administration: Intravesical treatment should begin between 7 to 14 days after biopsy (or transurethral resection if this procedure is done).

The recommended course of PACIS treatment is a single dose of 120 mg instilled into the bladder once weekly for 6 weeks.

Reconstitute the product according to the further directions: Dilute 1 mL of reconstituted product in 50 mL of sterile physiological saline. Insert a urethral catheter into the bladder under aseptic conditions and drain the bladder. Instill the 50 mL of PACIS suspension into the bladder slowly by gravity. Remove the catheter. Advise the patient (see Precautions, Information for the Patient).

Ideally, during the first hour following instillation, the patient should lie for 15 minutes 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 60 minutes for a total of 2 hours. All patients may not be able to retain the suspension for 2 hours 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 24 months following the initial treatment.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.

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. Note that if 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. Reconstitute and dilute using aseptic technique immediately prior to use.

The contents of the PACIS vial should be suspended with a sterile diluent (water for injection, 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 1 mL of sterile diluent (water for injection, without any preservative) and add it to the vial containing the PACIS.

Leave them in contact for about 1 minute. Then mix the suspension by withdrawing it into the syringe and expelling it gently back into the ampul 2 or 3 times. 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.

Availability And Storage: 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 120 mg semi-dry weight (2 to 10´10colony-forming units (CFU)/mg) of BCG and is ready to use following reconstitution with the sterile diluent. Neither the BCG nor the sterile diluent contains a preservative.

Store at -30°C wherever possible. May be stored between 2 and 8°C for a maximum of 6 months. At the time of transfer between 2 and 8°C note the new expiry date (i.e., current date plus 6 months) on the carton label in the space provided.

PACIS should not be transferred between 2 and 8°C after the expiry date printed on the vial and carton. PACIS should not be used more than 6 months after being transferred between 2 and 8°C, even if this is earlier than the printed expiry date.

At no time should the lyophilized preparation be exposed to sunlight, direct or indirect. The product may be kept at 4 or 25°C, under artificial light for a maximum of 6 hours, while still in the lyophilized state.

PACIS is produced by BioChem Vaccins Inc.