Oncotice Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of

the most recent authorized product monograph are not listed.

Table of Contents ................................................................................................................... 2

1 Indications .................................................................................................................. 4

1.1 Pediatrics .............................................................................................................. 4

1.2 Geriatrics .............................................................................................................. 4

2 Contraindications ........................................................................................................ 4

4 Dosage and Administration ......................................................................................... 5

4.1 Dosing Considerations .......................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ..................................................... 5

4.3 Reconstitution ...................................................................................................... 5

4.4 Administration ...................................................................................................... 5

5 Overdose..................................................................................................................... 6

6 Dosage Forms, Strengths, Composition, and Packaging ............................................... 6

7 Warnings and Precautions ........................................................................................... 6

General ............................................................................................................................. 6

Driving and Operating Machinery .................................................................................... 7

Genitourinary ................................................................................................................... 7

Monitoring and Laboratory Tests ..................................................................................... 7

Reproductive Health: Female and Male Potential ............................................................ 7

Sensitivity ......................................................................................................................... 8

7.1 Special Populations ............................................................................................... 8

7.1.1 Pregnancy ......................................................................................................... 8

7.1.2 Breastfeeding ................................................................................................... 8

7.1.3 Pediatrics (< 18 years of age) ............................................................................ 8

7.1.4 Geriatrics .......................................................................................................... 8

8 Adverse Reactions ....................................................................................................... 8

8.1 Adverse Reaction Overview .................................................................................. 8

8.2 Clinical Trial Adverse Reactions ............................................................................ 9

8.3 Less Common Clinical Trial Adverse Reactions ................................................... 11

8.5 Post-Market Adverse Reactions ......................................................................... 12

9 Drug Interactions ...................................................................................................... 14

9.2 Drug Interactions Overview ................................................................................ 14

9.4 Drug-Drug Interactions ....................................................................................... 14

10 Clinical Pharmacology ............................................................................................... 14

10.1 Mechanism of Action .......................................................................................... 14

10.2 Pharmacodynamics ............................................................................................ 14

10.3 Pharmacokinetics ............................................................................................... 14

11 Storage, Stability, and Disposal ................................................................................. 15

12 Special Handling Instructions .................................................................................... 15

Part 2: Scientific Information ................................................................................................ 16

13 Pharmaceutical Information ...................................................................................... 16

14 Clinical Trials ............................................................................................................. 16

14.1 Clinical Trials by Indication ................................................................................. 16

15 Microbiology ............................................................................................................. 19

16 Non-Clinical Toxicology ............................................................................................. 19

Patient Medication Information ........................................................................................... 20

Part 1: Health Professional Information

1 Indications

OncoTICE® (Bacillus Calmette-Guérin [BCG], Strain TICE®) is indicated for:

• treatment of primary or relapsing flat urothelial cell carcinoma in situ (CIS) of the urinary bladder.
• adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage T_A (grade 2 or 3) or T₁ (grade 1, 2, or 3). It is only recommended for stage T_A grade 1 papillary tumours when there is judged to be a high risk of tumour recurrence.

OncoTICE® is not indicated for the treatment of invasive bladder cancer. It is not recommended for papillary tumours of stages higher than T₁.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness (see 4 Dosage and Administration, 7.1.4 Geriatrics, and 14 Clinical Trials).

2 Contraindications

• OncoTICE® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• OncoTICE® should not be used in patients with impaired immune response irrespective of whether this impairment is congenital or caused by disease, drugs, or other therapy (see 9 Drug Interactions).
• OncoTICE® should be avoided in patients with a positive HIV serology.
• Clinical evidence of existing active tuberculosis should be ruled out in individuals who are purified protein derivative (PPD) positive before starting treatment with OncoTICE®.
• OncoTICE® should not be used concomitantly with antituberculosis drugs like streptomycin, para-amino-salicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol because a potential loss of the antitumour activity of BCG may result (see 7 Warnings and Precautions and 9 Drug Interactions).
• In patients with urinary tract infections, therapy with OncoTICE® should be postponed or interrupted until the bacterial culture from urine becomes negative and the therapy with antibiotics and/or urinary antiseptics is stopped.
• In case of gross hematuria, OncoTICE® therapy should be stopped or postponed until the hematuria has been successfully treated or has resolved.

4 Dosage and Administration

4.1 Dosing Considerations

• OncoTICE® must not be administered intravenously, subcutaneously or intramuscularly (see 7 Warnings and Precautions).

4.2 Recommended Dose and Dosage Adjustment

• Prior to instillation into the urinary bladder, the contents of one vial of OncoTICE® (Bacillus Calmette-Guérin [BCG], Strain TICE®) are reconstituted and diluted as indicated (see 4.3 Reconstitution).
• Induction treatment: Weekly instillation with OncoTICE® for 6 consecutive weeks.
• Maintenance treatment: Additional instillations of OncoTICE® at week 8 and 12 and monthly from months 4 to 12.
• Health Canada has not authorized an indication for pediatric use.

4.3 Reconstitution

Perform the following procedures under aseptic conditions: See 12 Special Handling Instructions regarding optional transfer device products.

Reconstitution-Suspension for Bladder Instillation

• Add 1 mL of a sterile, pyrogen-free and preservative-free physiological saline solution to the vial of OncoTICE® by means of a sterile syringe. Ensure that the needle is inserted through the center of the rubber stopper of the vial. Allow to stand for a few minutes. Then gently swirl the vial until a homogeneous suspension is obtained. Caution: avoid forceful agitation. See 11 Storage, Stability, and Disposal.

Preparation of the Solution for Instillation:

• Dilute the reconstituted suspension in sterile physiological saline up to a volume of 49 mL. Rinse the vial with another 1 mL of sterile, pyrogen-free and preservative-free physiological saline. Add the rinse fluid to the suspension for a final volume of 50 mL. Mix the suspension carefully.
• If a needleless closed-system transfer device product is used, dilute the reconstituted suspension in sterile physiological saline up to a volume of 50 mL, and do not rinse the vial.
• Note: The suspension must not be filtered.
• This suspension is now ready for instillation; it contains a total of 1 to 8 x 10⁸ CFU of TICE® BCG.

Incompatibilities

• OncoTICE® is incompatible with hypotonic and hypertonic solutions. OncoTICE® should be mixed with physiological saline as described above under Reconstitution. Other incompatibility studies have not been performed.

4.4 Administration

Insert a catheter via the urethra into the bladder and drain the bladder completely. The 50 ml OncoTICE® suspension is instilled into the bladder via the catheter by gravity flow (or gentle pressure if a syringe is used).

After instillation, remove the catheter.

The instilled OncoTICE® suspension must remain in the bladder for a period of 2 hours. After 2 hours, have the patient void the instilled suspension in a sitting position. Urine should be voided in a sitting position for 6 hours after treatment, and two cups of household bleach should be added to the toilet before flushing. The bleach and urine should be left to stand in the toilet for 15 minutes before flushing.

Note: The patient is not allowed to ingest any fluid during a period of 4 hours prior to instillation, or during the time that the OncoTICE® suspension remains in the bladder after instillation (2 hours).

If a spill or contamination occurs, area should be cleaned by covering the area with paper towels soaked with tuberculocidal disinfectant for at least 10 minutes. Wastes should be treated as biohazardous and disposed of accordingly (see 12 Special Handling Instructions).

5 Overdose

Overdose occurs if more than one vial of OncoTICE® is administered per instillation. The patient should be closely monitored for signs of systemic BCG infection and treated with anti-tuberculous medication (see 8 Adverse Reactions).

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition, and Packaging

Table 1: Dosage Forms, Strengths, and Composition

OncoTICE® (Bacillus Calmette-Guérin [BCG], Strain TICE®), is supplied as a freeze-dried preparation in 2 mL vials; each vial contains 1 to 8 x 10⁸ CFU of TICE® BCG which is equivalent to approximately 50 mg wet weight. It is supplied in boxes containing 1 vial per box.

7 Warnings and Precautions

General

• OncoTICE® contains live, potentially pathogenic bacteria. Reconstitution, preparation of the

• OncoTICE® suspension for instillation and administration should be performed under aseptic conditions. Spillage of OncoTICE® suspension may cause TICE® BCG contamination. Any spilled OncoTICE® suspension should be cleaned by covering the area with paper towels soaked with tuberculocidal disinfectant for at least 10 minutes. Unused OncoTICE® and all equipment, supplies, and receptacles in contact with OncoTICE® should be handled and disposed of as biohazardous (see 12 Special Handling Instructions).
• Accidental exposure to OncoTICE® could occur through self-innoculation, by dermal exposure through an open wound or by ingestion of OncoTICE® suspension. OncoTICE® exposure should not produce significant adverse health outcomes in healthy individuals. However, in case of suspected, accidental self-innoculation, PPD skin testing is advised at the time of the accident and six weeks later to detect skin test conversion (see 12 Special Handling Instructions).
• Physicians that use this product should be familiar with the literature on the prevention and treatment of BCG-related complications and should be prepared in such emergencies to contact, when appropriate, infectious disease specialists with experience in treating the infectious complications of intravesical BCG. The treatment of infectious complications of BCG requires long term, multiple-drug antibiotic therapy.
• Patients should be monitored for the presence of symptoms of systemic BCG infection and for signs of toxicity after each intravesical treatment as death has been reported as a result of systemic BCG infections and sepsis.
• OncoTICE® should not be administered intravenously, subcutaneously or intramuscularly.
• OncoTICE® is not for oral or intradermal use.
• OncoTICE® is not a vaccine for the prevention of cancer, or for the prevention of tuberculosis.

Driving and Operating Machinery

Based on the pharmacodynamic profile of OncoTICE®, it is assumed that the product will not affect the ability to drive and to use machines.

Genitourinary

Care should be taken not to traumatize the urinary tract. Seven to 14 days should elapse before OncoTICE® is administered following TUR, biopsy, or traumatic catheterization.

Traumatic catheterization or other injuries to the urethra or bladder mucosa can promote systemic BCG infection. Delaying OncoTICE® administration should be considered in such patients until mucosal damage has healed.

Transurethral resection (TUR): When used as an adjuvant therapy after TUR of a superficial urothelial cell carcinoma of the bladder (see 1 Indications), treatment with OncoTICE® should be started between 10 and 15 days after performing the TUR. Treatment should not be started until mucosal lesions after TUR have healed.

Monitoring and Laboratory Tests

In patients with known risk factors for HIV infection, it is recommended to perform adequate HIV assays prior to therapy.

Before the first intravesical instillation of OncoTICE®, purified protein derivative (PPD) screening should be performed. In the event that this test is positive, the intravesical instillation of OncoTICE® is contraindicated only if there is supplementary medical evidence for an active tuberculosis infection (see 2 Contraindications).

Reproductive Health: Female and Male Potential

In order to protect the partner, the patient should be recommended to either refrain from intercourse for one week after OncoTICE® instillation, or to use a condom.

Sensitivity

The use of OncoTICE® may sensitize patients to tuberculin resulting in a positive reaction to PPD, therefore determination of tuberculin reactivity by PPD skin testing should be performed before starting the treatment with OncoTICE®.

7.1 Special Populations

7.1.1 Pregnancy

Animal reproduction studies have not been conducted with OncoTICE®. It is also not known whether OncoTICE® can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. OncoTICE® should be given to a pregnant woman only if clearly needed. Women should be advised not to become pregnant while on therapy (see 16 Non-Clinical Toxicology).

7.1.2 Breastfeeding

It is unknown if OncoTICE® is excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk (see 7.1.1 Pregnancy).

7.1.3 Pediatrics (< 18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness (see 4 Dosage and Administration, 7 Warnings and Precautions and 14 Clinical Trials).

8 Adverse Reactions

8.1 Adverse Reaction Overview

Adverse reactions are often localized to the bladder but may be accompanied by systemic manifestations.

Toxicity and side-effects appear to be directly related to the cumulative CFU count of BCG administered with the various instillations. Approximately 90% of patients develop local irritative symptoms in the bladder. Pollakiuria and dysuria are reported very frequently. The cystitis and typical inflammatory reactions (granulomas) which occur in the mucosa of the bladder after instillation of BCG, and which cause these symptoms, may be an essential part of the anti-tumour activity of the BCG. In most cases, the symptoms disappear within two days after instillation and the cystitis does not require treatment. During maintenance treatment with BCG, the symptoms of cystitis may be more pronounced and prolonged. Generally, there are no long-term urinary complications.

Irritative bladder adverse effects associated with OncoTICE® administration have been managed symptomatically with pyridium, propantheline bromide or oxybutin chloride, and acetaminophen or ibuprofen.

Also commonly observed is malaise, a low to medium grade fever and/or influenza-like symptoms (fever, rigors, malaise and myalgia) which may accompany the localized, irritative toxicities that often reflect hypersensitivity reactions and can be treated symptomatically. These symptoms usually appear within 4 hours after instillation and last for 24 to 48 hours. Fever higher than 39.0°C typically resolves within 24 to 48 hours when treated with antipyretics (preferably acetaminophen) and fluids. However, it is frequently not possible to distinguish these uncomplicated febrile reactions from early systemic BCG infections. Therefore, it is recommended that fever above 39.0°C that does not resolve within 12 hours despite antipyretic therapy must be considered as systemic BCG-infection, necessitating clinical confirmatory diagnosis and treatment. See 7 Warnings and Precautions – General.

Systemic adverse effects such as malaise, fever, and chills may reflect hypersensitivity reactions and can be treated with antihistamines. The “flu-like” syndrome of 1-2 days duration that frequently accompanies OncoTICE® administration should be treated symptomatically. Systemic BCG infections could be due to traumatic catheterization, bladder perforation or premature BCG instillation after extensive TUR of a superficial carcinoma of the bladder. See 7 Warnings and Precautions – Genitourinary. These systemic infections may be manifested by pneumonitis, hepatitis cytopenia, vasculitis, infective aneurysm and/or sepsis after a period of fever and malaise during which symptoms progressively increase. The presentation of systemic infections may also be delayed by months to years.

Patients with manifest symptoms of therapy-induced BCG infections should be adequately treated with anti-tuberculous agents following regular treatment schedules used for tuberculosis infections: when systemic infection is present, the triple drug therapy (isoniazid-rifampicin-ethambutol) with or without cycloserine is given first for several weeks and is followed by therapy with isoniazid and rifampicin; rifampicin plus isoniazid are given when there are signs of an active BCG infection without systemic involvement. In these cases, further instillations of OncoTICE® are contraindicated.

Deaths have been reported as a result of systemic BCG infections and sepsis. There have been two cases of nephrogenic adenoma, a benign lesion of bladder epithelium, associated with intravesical BCG therapy.

In general, the adverse effects of BCG therapy in bladder carcinoma have been of short duration and moderate morbidity. The side effects of intravesical OncoTICE® therapy are generally mild and transient.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug. See 14 Clinical Trials.

A summary of the incidence and severity of adverse effects observed in a study of 674 patients with superficial bladder cancer treated intravesically with OncoTICE® is presented in Table 2 below. The adverse events reported in other studies have been similar.

Table 2: Local Adverse Effects

Flu-like syndrome (which includes fever, shaking chills, malaise and myalgia) had an incidence of 33.2%, of which 9.0% were severe. Severe was ECOG Grade 3 or 4.

8.3 Less Common Clinical Trial Adverse Reactions

Blood and lymphatic system disorders: Anemia, coagulopathy, leukopenia, thrombocytopenia

Cardiac disorders: Cardiac

Gastrointestinal disorders: Diarrhea, gastrointestinal (Unclassified)

Hepatobiliary disorders: Hepatic granuloma, hepatitis

Immune system disorders: Allergy

Infections and infestations: BCG Sepsis, epididymitis/prostatitis, orchitis, pyuria, urethritis, urinary tract infection

Metabolism and nutrition disorders: Anorexia/weight loss

Musculoskeletal and connective tissue disorders: Arthritis/myalgia

Renal and urinary disorders: Urinary Incontinence, Urinary Debris, urinary obstruction, contracted bladder

Nervous system disorders: Headache/dizziness, neurologic

Reproductive system and breast disorders: Genital Inflammation/abscess

Respiratory, thoracic and mediastinal disorders: Respiratory (Unclassified); pneumonitis

Skin and subcutaneous tissue disorders: Rash

8.5 Post-Market Adverse Reactions

The following adverse reactions (Table 3) are reported from the post-market surveillance as serious and unexpected. This information is based on clinical experience and/or published clinical data.

Table 3: Post-Market Adverse Reactions

¹ High Level Term instead of Preferred Term

² Granuloma NOS has been observed in various organs including the aorta, bladder, epididymis, gastrointestinal tract, kidney, liver, lungs, lymph nodes, peritoneum, prostate

³ Identified in isolated case reports in the published literature during post marketing surveillance

9 Drug Interactions

9.2 Drug Interactions Overview

Immunosuppressants and/or bone marrow depressants and/or radiation may interfere with the development of the immune response and thus with the anti-tumour efficacy and should, therefore, not be used in combination with OncoTICE®.

9.4 Drug-Drug Interactions

The drugs listed in Table 4 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4: Established or Potential Drug-Drug Interactions

10 Clinical Pharmacology

10.1 Mechanism of Action

OncoTICE® has anti-tumour activity but the exact mechanism of action is not known. Study data suggest that an active non-specific immune response takes place. BCG invokes a local inflammatory response involving a variety of immune cells such as macrophages, natural killer cells and T cells.

10.2 Pharmacodynamics

OncoTICE® is an immunostimulating agent (ATC code L03AX03).

10.3 Pharmacokinetics

For the treatment and recurrence prophylaxis of bladder cancer, the attachment of BCG to the bladder wall after voiding has been shown to be important. This allows a targeted pharmacological effect at the site of application. It is known that TICE® BCG can bind specifically to fibronectin in the bladder wall. However, most instilled OncoTICE® will be excreted with the first urine void two hours after the instillation.

11 Storage, Stability, and Disposal

Intact OncoTICE® vials containing freeze-dried BCG, must be stored at 2 – 8° C and protected from light. The expiry date indicated on the label of the vials only applies if the vials are stored under these conditions.

The reconstituted solution for bladder instillation can be stored for up to 2 hours when refrigerated at 2 – 8° C and protected from light. Unused solution should be discarded after 2 hours.

Please refer to more detailed safe disposal instructions under 12 Special Handling Instructions.

12 Special Handling Instructions

OncoTICE® contains live attenuated mycobacteria. Reconstitution, preparation of the OncoTICE® suspension for instillation and administration should be performed under aseptic conditions. The use of needleless closed-system transfer device products may be considered when transferring OncoTICE® from primary packaging to instillation equipment.

Spillage of OncoTICE® suspension may cause TICE® BCG contamination. Any spilled OncoTICE® suspension should be cleaned by covering the area with paper towels soaked with tuberculocidal disinfectant for at least 10 minutes. Unused OncoTICE® and all equipment, supplies, and receptacles in contact with OncoTICE® should be handled and disposed of as biohazardous.

Accidental exposure to OncoTICE® could occur through self-innoculation, by dermal exposure through an open wound or by ingestion of OncoTICE® suspension. OncoTICE® exposure should not produce significant adverse health outcomes in healthy individuals. However, in case of suspected, accidental self-innoculation, PPD skin testing is advised at the time of the accident and six weeks later to detect skin test conversion (see 7 Warnings and Precautions).

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: Bacillus Calmette-Guérin (BCG), Strain TICE®

Chemical name: Bacillus Calmette-Guérin (BCG), Strain TICE®

Physicochemical properties: OncoTICE® - freeze-dried preparation in a glass vial, each containing 1 to 8 x 10⁸ CFU, which is equivalent to approximately 50 mg wet weight.

Pharmaceutical standard: [for biologics] Professed

Product Characteristics:

OncoTICE® (Bacillus Calmette-Guérin [BCG], Strain TICE®), is a freeze-dried preparation containing Bacillus Calmette and Guérin (BCG), Strain TICE® which is a live, attenuated strain of Mycobacterium bovis. The culture medium from which the freeze-dried cake is prepared has the following relative composition: lactose 150 grams, Sauton medium 250 mL and water 750 mL.

The freeze-dried BCG preparation is delivered in vials, each containing 1 to 8 x 10⁸ colony forming units (CFU) of TICE® BCG which is equivalent to approximately 50 mg wet weight. No preservatives have been added.

14 Clinical Trials

14.1 Clinical Trials by Indication

Trial Design and Study Demographics

Table 5: Summary of Patient Demographics for Clinical Trials in Carcinoma in situ

To evaluate the efficacy of intravesical administration of BCG Bacillus Calmette-Guérin (BCG), Strain TICE® in the treatment of carcinoma in situ, patients were identified who had been treated with BCG, Strain TICE® under 6 different studies in which the most important shared aspect was the use of an induction plus maintenance schedule. Patients received BCG, Strain TICE® (50 mg; 1 to 8 x 108 CFU) intravesically, once weekly for at least 6 weeks and once monthly thereafter for up to 12 months. A longer maintenance was given in some cases.

The study population consisted of 153 patients, 132 males, 19 females, and 2 unidentified as to gender. Thirty patients lacking baseline documentation of CIS and 4 patients lost to follow-up were not evaluable for treatment response. Therefore, 119 patients were available for efficacy evaluation. The mean age was 69 years (range: 38-97 years).

There were 2 categories of clinical response: (1) Complete Histological Response (CR), defined as complete resolution of carcinoma in situ documented by cystoscopy and cytology, with or without biopsy; and (2) Complete Clinical Response Without Cytology (CRNC), defined as an apparent complete disappearance of tumour upon cystoscopy. The results of an analysis of the evaluable patients conducted in 1987 are shown in Table 6.

Table 6: The Response of Patients With CIS Bladder Cancer in 6 Studies

An updated analysis of these data conducted in 1989 is presented in Table 7. The median duration of follow-up was 47 months.

Table 7: Follow-up Response of Patients With CIS Bladder Cancer in 6 Studies -–1989 Status of 90 Responders (CR or CRNC)

There was no significant difference in response rates between patients with or without prior intravesical chemotherapy. The median duration of response, calculated from the Kaplan-Meier curve as median time to recurrence, is estimated at 4 years or greater. The incidence of cystectomy for 90 patients who achieved a complete response (CR or CRNC) was 11%. The median time to cystectomy in patients who achieved a complete response (CR or CRNC) exceeded 74 months.

The efficacy of intravesical BCG, Strain TICE® in preventing the recurrence of a T_AT₁ bladder cancer after complete transurethral resection of all papillary tumours was evaluated in 2 open-label, randomized phase III clinical trials. Initial diagnosis of patients included in the studies was determined by cystoscopic biopsies. One was conducted by the Southwestern Oncology Group (SWOG) in patients at high risk of recurrence. High risk was defined as 2 occurrences of tumour within 56 weeks, any stage T1 tumour, or 3 or more tumours presenting simultaneously. The second study was conducted at the Nijmegen University Hospital; Nijmegen, The Netherlands. In this study patients were not selected for high risk of recurrence. In both studies treatment was initiated between 1 and 2 weeks after transurethral resection (TUR).

In the SWOG trial (study 8795) patients were randomized to BCG, Strain TICE® or mitomycin C (MMC). Both drugs were given intravesically weekly for 6 weeks, at 8 and 12 weeks, and then monthly for a total treatment duration of 1 year. Cystoscopy and urinary cytology were performed every 3 months for 2 years. Patients with progressive disease or residual or recurrent disease at or after the 6 month follow-up were removed from the study and were classified as treatment failures.

A total of 469 patients were entered into the study: 237 to the BCG, Strain TICE® arm and 232 to the MMC arm. Twenty-two patients were subsequently found to be ineligible, and 66 patients had concurrent CIS, and were analyzed separately. Four patients were lost to follow-up, leaving 191 evaluable patients in the BCG, Strain TICE® arm and 186 in the MMC arm. Of the patients, 84% were male and 16% were female. The average age of these patients was 65 years old.

The Kaplan-Meier estimates of 2-year disease-free survival are shown in Table 8. The difference in disease-free survival time between the 2 groups was statistically significant by the log rank test (P=0.03). The 95% confidence interval of the difference in 2-year disease-free survival was 12% ± 10%. No statistically significant differences between the groups were noted in time to tumour progression, tumour invasion, or overall survival.

Table 8: Results of SWOG Study 8795

In the Nijmegen study, the efficacy of 3 treatments was compared: BCG, Strain TICE®, Rijksinstituut voor Volksgezondheid en Milieuhygiene substrain BCG (BCG-RIVM), and MMC.

BCG, Strain TICE® and BCG-RIVM were given intravesically weekly for 6 weeks. In contrast to the SWOG study, maintenance BCG was not given. Mitomycin C was given intravesically weekly for 4 weeks and then monthly for a total duration of treatment of 6 months. Cystoscopy and urinary cytology were performed every 3 months until recurrence.

A total of 469 patients were enrolled and randomized. Thirty-two patients were not evaluable, 17 were ineligible, 15 were withdrawn before treatment, and 50 had concurrent CIS and were analyzed separately, leaving 387 evaluable patients: 117 in the BCG, Strain TICE® arm, 134 in the BCG-RIVM arm, and 136 in the MMC arm. Twenty-eight patients (24%) in the BCG, Strain TICE® arm, 32 patients (24%) in the BCG-RIVM arm, and 24 patients (18%) in the MMC arm had T_AG1 tumours. The median duration of follow-up was 22 months (range: 3-54 months).

The Kaplan-Meier estimates of 2-year disease-free survival are shown in Table 9. The differences in disease-free survival among the 3 arms were not statistically significant by the log-rank test (P=0.08).

Table 9: Results of Nijmegen Study

In both the SWOG 8795 study and the Nijmegen study, acute toxicity was more common, and usually more severe with BCG, Strain TICE® than with MMC.

15 Microbiology

No microbiological information is required for this drug product.

16 Non-Clinical Toxicology

Carcinogenicity: OncoTICE® has not been evaluated for the potential to cause carcinogenicity.

Genotoxicity: OncoTICE® has not been evaluated for the potential to cause genotoxicity.

Reproductive and Developmental Toxicology: OncoTICE® has not been evaluated for the potential to affect fertility in males or females.