The product is presented as a lyophilisate, which is a white powder. This is reconstituted in sterile preservative-free normal saline.

ImmuCyst^® 81 mg is freeze-dried preparation made from a culture of the Connaught strain of Bacillus of Calmette and Guérin (BCG), which is an attenuated strain of living bovine tubercle bacillus, Mycobacterium bovis. The bacilli are lyophilised (freeze-dried) and are viable upon reconstitution. The product contains no preservative.

ImmuCyst^® 81 mg is supplied as a lyophilisate for intravesicular use.

ImmuCyst^® 81 mg is indicated for intravesicular use in the treatment and prophylaxis of primary or recurrent carcinoma in situ (CIS) of the urinary bladder, and for the prophylaxis following transurethral resection (TUR) of primary or recurrent stage Ta and/or T1 papillary tumours, or any combination thereof, regardless of antecedent intravesicular treatment.

Adults

A urethral catheter is inserted into the bladder under aseptic conditions. It is important to note that a sufficient quantity of lubricant is used to reduce the chance of traumatising the urinary mucosa and therefore the risk of severe complications including BCG infection and also to reduce the discomfort of the patient. From the limited evidence, bacteriostatic urethral lubricants have been shown to have an association with a reduction in the viability of BCG (see Section 4.5). As a precaution, to minimise the amount of lubricant in the bladder, it is recommended that catheterisation should be performed when the bladder is full. The bladder is drained, rinsing out with the urine any lubricant which may have reached the bladder. The 53ml suspension of ImmuCyst^® 81mg is instilled slowly by gravity, following which the catheter is withdrawn.

The patient retains the suspension for as long as possible for up to two hours. During the first 15 minutes following instillation, the patient should lie prone. Thereafter, the patient is 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.

Clinical trials carried out with ImmuCyst^® 81 mg included a percutaneous inoculation with each intravesicular dose. A 0.5 ml portion of the 53 ml intravesical dose of ImmuCyst^® 81 mg was administered percutaneously (e.g., on inner, upper thigh). Some studies have suggested that there is no additional benefit of administering BCG systemically. If severe reactions occur, such as ulceration at the site of regional lymphadenitis, the percutaneous treatment should be discontinued.

Treatment Schedule

Intravesicular treatment of the urinary bladder should begin 10 to 14 days after biopsy or TUR, and consists of induction and maintenance treatments.

The induction treatment consists of one intravesicular instillation of ImmuCyst^® 81mg each week for 6 weeks. After a 6 week pause, one intravesical instillation should be given once each week for 1-3 weeks. Clinical studies have demonstrated that 3 weekly instillations significantly increase the complete response rate from 73% to 87% at 6 months, compared with no additional treatment given at 3 months. Three weekly instillations should definitely be given to patients who still have evidence of bladder cancer.

Based on clinical studies performed with ImmuCyst^® 81 mg, maintenance therapy following induction is highly recommended. This consists of one dose given each week for 1 to 3 weeks at 6 months following the initial dose, and then every 6 months thereafter until 36 months.

Children

Safety and effectiveness in children have not been established.

ImmuCyst^® 81 mg is contraindicated for patients:

• who have had a TUR or traumatic bladder catheterisation (associated with hematuria) in the previous 10 days,

• who are immunosuppressed as a result of malignancies or receiving immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, or who are otherwise immunocompromised (including HIV-infected individuals),

• with active tuberculosis, because of the danger of exacerbation or of concomitant systemic BCG infection,

• with current or previous evidence of a systemic BCG infection,

• with fever, unless the cause of the fever has been determined and evaluated, and

• with bacterial urinary tract infection, until all the infection has resolved.

Contains viable attenuated mycobacteria. Handle as infectious.

ImmuCyst^® 81 mg should not be handled by persons with immune deficiency.

It is recommended that intravesicular ImmuCyst^® 81 mg not be administered any sooner than 10 days following TUR. Given the specialised nature of BCG intravesical treatment, ImmuCyst^® 81 mg should be administered under the supervision of a qualified physician, such as a urologist, experienced in the use of anti-cancer agents.

Care must be taken during administration of intravesicular ImmuCyst^® 81 mg not to introduce contaminants into the urinary tract nor to traumatise unduly the urinary mucosa. If the physician believes that the bladder catheterisation has been traumatic (e.g. associated with bleeding), then ImmuCyst^® 81 mg should not be administered and there must be a treatment delay of at least 10 days. Subsequent treatment should be resumed as if no interruption in the schedule had occurred.

Intravesicular treatment with ImmuCyst^® 81 mg 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^® 81 mg may therefore be desirable.

For patients with small bladder capacity, increased risk of bladder contracture should be considered in decisions to treat with ImmuCyst^® 81 mg.

If a bacterial urinary tract infection (UTI) occurs during the course of ImmuCyst^® 81mg treatment, ImmuCyst^® 81 mg instillation should be withheld until complete resolution of the bacterial UTI for two 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^® 81 mg.

Patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of ImmuCyst^® 81 mg.

BCG infection of aneurysms and prosthetic devices (including arterial grafts, cardiac devices, and artificial joints) have been reported following intravesicular administration of BCG. The risk of these ectopic BCG infections has not been determined, but is considered to be very small. The benefits of BCG therapy must carefully be weighed against the possibility of an ectopic BCG infection in patients with pre-existing arterial aneurysms or prosthetic devices of any kind.

Patients must be advised that drug combinations containing bone marrow depressants and/or immunosuppressants and/or radiation may impair the response to ImmuCyst^® 81 mg and/or increase the risk of disseminated BCG infection. For patients with a condition that may in future require mandatory immunosuppression (e.g. awaiting an organ transplant, myasthenia gravis), the decision to treat with ImmuCyst^® 81 mg should be considered carefully.

Limited in-vitro testing of bacteriostatic lubricants and BCG has shown a reduction in the number of BCG CFU. However, it has been shown in patients that when a bacteriostatic lubricant was used for catheterisation before instillation, the BCG CFU count remained above the required minimum microbial count and there was no significant reduction in the clinical efficacy of BCG therapy.

Animal reproduction studies have not been conducted with ImmuCyst^® 81 mg. It is also not known whether ImmuCyst^® 81 mg can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ImmuCyst^® 81 mg should be given to a pregnant woman only if clearly needed.

A nursing woman 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 ImmuCyst^® 81 mg is administered to a nursing woman.

There are no indications that ability to drive and use machines is impaired.

Administration of intravesicular ImmuCyst^® 81 mg causes an inflammatory response in the bladder and has been frequently associated with transient fever, haematuria, urinary frequency and dysuria. Such reactions may to some degree be taken as evidence that BCG is evoking the desired response, but patients should be carefully monitored for serious adverse events. Serious adverse events have occurred in <1% of ImmuCyst^® 81 mg recipients.

Local:

The most common local reactions are transient dysuria and urinary frequency. During the induction course, these reactions occurred on at least one occasion in 26% and 14% of patients, respectively. This rose to 46% and 34% respectively, among patients during maintenance therapy. Gross hematuria has occurred among 11-19% of ImmuCyst^® 81 mg recipients, while more serious genitourinary adverse events have occurred in <0.5% of recipients. Infrequent associations include bacterial UTI, bladder contracture, symptomatic granulomatous prostatitis, epididymo-orchitis, urethral obstruction, and renal abscess.

Systemic:

Transient fever of <38.5°C of < 48 hours duration has occurred among 17% of ImmuCyst^® 81 mg recipients during induction and among 31% during maintenance.

Skin rash, arthralgia, and migratory arthritis are rare, and are considered to be strictly allergic reactions.

Ocular symptoms (including uveitis, conjunctivitis, iritis, keratitis, and granulomatous choreoretinitis) alone, or in combination with joint symptoms (arthritis or arthralgia), urinary symptoms and/or skin rash, have been reported following administration of intravesicular BCG. The risk seems to be elevated among patients who are positive for HLA-B27.

BCG Infection

Systemic BCG infection is a serious side effect of ImmuCyst^® 81 mg administration and fatalities have occurred.

BCG infection may be more common after traumatic bladder catheterisation or bladder perforation. BCG treatment should be delayed in such patients until mucosal damage has healed.

Treatment should be delayed for 10-14 days after TUR or biopsy of bladder lesions.

All patients receiving the product should be carefully monitored and advised to report all incidences of fever and other events outside the urinary tract. Fever lasting over 24 hours and any unusual event should be investigated to exclude another cause and to try and isolate organisms. Blood cultures and samples from affected sites should be cultured for BCG.

The infection may manifest as pneumonitis, hepatitis and/or cytopenia after a period of fever and malaise.

Fever lasting more than 48 hours for which there is no explanation and any other unexplained reactions should be treated with antituberculous therapy, following the regular treatment schedules for tuberculosis.

ImmuCyst^® 81 mg is sensitive to Isoniazid, Rifampicin and Ethambutol.

No further treatment with BCG should be given.

Treatment of undesirable effects:

Table 1 summarises the recommended treatment of adverse events.

Irritative bladder side effects associated with ImmuCyst^® 81 mg administration can be managed symptomatically with propantheline bromide. Paracetamol 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 anti-tuberculosis drugs with the exception of pyrazinamide. Accordingly, for more serious reactions other than a systemic BCG infection (e.g., severe urinary tract adverse events or allergic reaction), Isoniazid with or without Rifampicin should be administered for 3-6 months.

If a systemic BCG infection occurs, an Infectious Diseases consultation should be sought. ImmuCyst^® 81 mg should be permanently discontinued, and triple anti-tuberculosis therapy should be initiated promptly and continued for 6 months. Commonly, this will comprise Isoniazid (300 mg daily), Rifampicin (600 mg daily), and Ethambutol (1000 mg daily). In the presence of signs of septic shock as a manifestation of a systemic BCG infection, the addition of short-term corticosteroids (e.g. Prednisolone, 40 mg daily) has been shown to be beneficial, and should be considered.

If a systemic BCG infection 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^® 81 mg, the symptoms and signs of the BCG infection, the treatment administered for the reaction, and the response to this treatment.

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 the urine; painful or frequent urination lasting> 2 days; nausea and vomiting;fever and chill lasting> 24 hours.

Rare: Cough; skin rash; high or persistent fever; joint pains; jaundice; eye complaints.

Table 1

Recommended Treatment of Adverse Events Associated with ImmuCyst^® 81mg

In case of overdose, patients should be monitored closely, and any adverse events should be treated according to the recommendations in “Treatment of undesirable effects”, above.

ATC Code: LO3AX

ImmuCyst^® 81 mg promotes a local acute inflammatory and immunological reaction, and sub-acute granulomatous reaction with macrophage and lymphocyte infiltration in the urothelium and lamina propria of the urinary bladder.

ImmuCyst^® 81 mg has been administered intravesically with concomitant percutaneous administration. Acid-fast bacteria have been observed in the urine. Cultures and strains for acid-fast bacilli at other sites have usually been negative even in the cases of suspected systemic BCG infection. However, traumatic catheterisation or treatment following extensive tumour resection or bladder perforation could result in systemic BCG infection.

ImmuCyst^® 81 mg administered intravesically induced no serious systemic toxicity in studies in guinea pigs and monkeys. Studies in animals suggest that there is a possibility of a potential for allergenicity to the product.

No animal reproduction studies have been performed. Studies on mutagenicity and carcinogenicity have also not been performed.

Monosodium glutamate

BCG bacilli are sensitive to a wide variety of antibiotics. Antimicrobial administration may therefore diminish the efficacy of ImmuCyst^® 81 mg. Patients undergoing antimicrobial therapy for infections should be evaluated to assess whether the therapy might diminish the efficacy of ImmuCyst^® 81 mg.

ImmuCyst^® 81 mg is contraindicated in persons receiving immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents or cytotoxic drugs because of risk of disseminated BCG infection.

Twenty-four months from the date of initiation of the viability (potency:viable count) test when stored between 2° and 8° C.

ImmuCyst^® 81 mg 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 or reconstituted ImmuCyst^® 81 mg be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

The lyophilisate is contained in a 5 ml type 1 amber glass vial sealed with a grey butyl silicone stopper and held closed with an aluminium seal with a blue flip-off plastic top.

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 low traffic, high airflow 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^® 81 mg should not be handled by persons with an immune deficiency.

ImmuCyst^® 81 mg is to be reconstituted only with sterile preservative-free normal saline to ensure proper dispersion of the organisms.

Using a 5 ml sterile syringe and needle, draw up 3ml of saline from an ampoule.

Prepare the surface of the ImmuCyst^® 81 mg vial using a suitable antiseptic and using a 5 ml syringe containing 3ml of saline, pierce the stopper of the vial. Holding the vial upright 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 saline from the syringe into the vial. After all the saline has passed into the freeze-dried material, remove the needle and syringe.

Shake the vial gently.

Two options for intravesicular administration are possible:

Option 1:

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

The reconstituted product is then transferred to a bladder syringe.

Option 2:

The entire contents from the reconstituted vial is added to a saline bladder irrigation bag.

The product should be used immediately after reconstitution. In the event of a delay between reconstitution and administration, the reconstituted and diluted suspension may be stored, protected from light, for up to 8 hours at room temperature (up to 25º C). 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 product, packaging, and all equipment and materials used for instillation should be sterilised or disposed of properly as with any other biohazardous waste.

Urine voided over 6 hours following ImmuCyst^® 81 mg instillation should be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to stand for 15 minutes before flushing.

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

UK

Trading as: Cambridge Laboratories, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB, United Kingdom.

PL 16853/0120

19 September 2001

10/01/2011