Verity-BCG Product Monograph

RECENT MAJOR LABEL CHANGES

Not Applicable

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .......................................................................................... 2

TABLE OF CONTENTS ............................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4

1 INDICATIONS ............................................................................................................. 4

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

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

2 CONTRAINDICATIONS ................................................................................................ 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................... 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 ......................................................................................................... 6

4.5 Missed Dose ............................................................................................................. 6

5 OVERDOSAGE ............................................................................................................ 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 7

7 WARNINGS AND PRECAUTIONS ................................................................................. 7

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

7.1.1 Pregnant Women ............................................................................................... 8

7.1.2 Breast-feeding .................................................................................................... 8

7.1.3 Pediatrics ............................................................................................................ 9

7.1.4 Geriatrics ............................................................................................................ 9

8 ADVERSE REACTIONS................................................................................................. 9

8.1 Adverse Reaction Overview ..................................................................................... 9

8.2 Clinical Trial Adverse Reactions ............................................................................. 10

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

9 DRUG INTERACTIONS .............................................................................................. 12

9.2 Drug Interactions Overview ................................................................................... 12

9.3 Drug-Behavioural Interactions ............................................................................... 13

9.4 Drug-Drug Interactions .......................................................................................... 13

9.5 Drug-Food Interactions .......................................................................................... 13

9.6 Drug-Herb Interactions .......................................................................................... 13

9.7 Drug-Laboratory Test Interactions......................................................................... 13

10 CLINICAL PHARMACOLOGY ...................................................................................... 13

10.1 Mechanism of Action ....................................................................................... 13

10.2 Pharmacodynamics .......................................................................................... 13

10.3 Pharmacokinetics ............................................................................................. 13

11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 13

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 14

PART II: SCIENTIFIC INFORMATION ..................................................................................... 15

13 PHARMACEUTICAL INFORMATION .......................................................................... 15

14 CLINICAL TRIALS ...................................................................................................... 15

14.1 Trial Design and Study Demographics ............................................................. 15

14.2 Study Results .................................................................................................... 15

PATIENT MEDICATION INFORMATION ................................................................................ 16

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

VERITY-BCG (Bacillus Calmette-Guérin (BCG): Strain Russian BCG-I) is indicated for:

• Adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage Ta (grade 2 or 3) or T1 (grade 1, 2, or 3), without concomitant carcinoma in situ. It is only recommended for stage Ta grade 1 papillary tumors, when there is judged to be a high risk (>50%) of tumor recurrence.

Marketing authorization with conditions was based on recurrence free survival rates in single arm studies in patients with stage T1 disease only (see Part II: CLINICAL TRIALS).

1.1 Pediatrics

Pediatrics (< 18 years of age): No studies of VERITY-BCG have been performed in pediatric patients; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

There are limited data for patients aged 65 years and older. (see 4 Error! Reference source not found., 7 Error! Reference source not found. and 14 Error! Reference source not found.).

2 CONTRAINDICATIONS

• VERITY-BCG is contraindicated in patients who are hypersensitive to Bacillus Calmette-Guérin

  (BCG), 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, and COMPOSITION AND PACKAGING.

• VERITY-BCG is not indicated for the treatment of invasive bladder cancer.
• VERITY-BCG should not be used in patients with an impaired immune response irrespective of whether this impairment is congenital or caused by disease, drugs or other therapy.

• VERITY-BCG should not be given to patients with positive HIV serology (see 7 WARNINGS AND

  PRECAUTIONS, Monitoring and Laboratory Tests).

• VERITY-BCG is contraindicated during pregnancy and lactation (see 7 WARNINGS AND

  PRECAUTIONS, 7.1.1 Pregnant Women).

• VERITY-BCG should not be used for patients with active tuberculosis disease. Patients undergoing treatment with antituberculosis drugs for latent or active infection should not receive VERITY-BCG.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• When used as adjuvant therapy after Transurethral Resection (TUR) of a superficial urothelial cell carcinoma of the bladder (See 1 INDICATIONS), treatment with VERITY-BCG should be started 2 to 3 weeks after performing TUR. Treatment should not be started until mucosal lesions have healed (see 7 WARNINGS AND PRECAUTIONS – Genitourinary).
• Traumatic catheterization or other injuries to the urethra or bladder mucosa can promote systemic BCG infection, so treatment must be delayed. (See 7 WARNINGS AND PRECAUTIONS)
• In case of gross hematuria, therapy should be stopped or postponed until the hematuria has been successfully treated or has resolved.
• VERITY-BCG should not be administered to patients with fever without prior evaluation and treatment. (See 8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview)
• In patients with urinary tract infections, treatment with VERITY-BCG should be withheld until the urine culture becomes negative and antibiotic therapy is stopped.
• Clinical evidence of active tuberculosis disease should be ruled out in individuals who react to the Tuberculin Skin Test (TST) with purified protein derivative (PPD), prior to starting treatment with VERITY-BCG. (See 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

VERITY-BCG is an antineoplastic agent for bladder instillation only.

VERITY-BCG must not be administered intravenously, subcutaneously, intradermally or intramuscularly.

Delay treatment in patients who experience traumatic catheterization until mucosal damage has healed.

In cases of significant toxicity, the physician may elect to terminate treatment with BCG.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose per instillation of VERITY-BCG is 80 mg (two 4 mL vials each containing 40 mg).

Treatment should be started two to three weeks after performing Trans Urethral Resection (TUR).

Induction treatment: The induction treatment schedule consists of 6 consecutive weekly instillations with VERITY-BCG.

Maintenance treatment: Maintenance may include 3 consecutive weekly instillations at 3, 6 and 12 months if 1-year maintenance planned (15 instillation). If 3-year maintenance is planned, 3 consecutive weekly instillations at 3 and 6 months, and then every 6 months up to 36 months (27 instillations), are given.

The duration and frequency of maintenance treatment should be evaluated on the basis of tumour classification (grade, stage and size) and clinical diagnosis. Risk stratification is recommended to determine length of maintenance therapy, whereby patients with intermediate-risk disease are treated with maintenance until 12 months and patients with high-risk disease, 36 months.

Health Canada has not authorized an indication for pediatric use (See 1 INDICATIONS, Pediatrics).

4.3 Reconstitution

Add 1 mL of sterile isotonic preservative free saline (0.9% NaCl) using a sterile syringe to the contents of one vial of VERITY-BCG and allow to stand for few minutes. Then gently swirl the vial until a homogenous suspension is obtained (Caution: Avoid forceful agitation). Repeat the above procedure to reconstitute each subsequent vial used. To achieve the recommended dose of 80 mg, two vials (each of 40 mg) should be reconstituted; each reconstituted vial contains Bacillus Calmette-Guerin Russian strain BCG-I (40 mg/mL [between 1-8 X 10⁸ Colony Forming Units (CFU)]).

Transfer the reconstituted suspension from the first vial into a 50 mL syringe. Rinse the empty vial with 1 mL sterile isotonic saline. Add the rinse fluid to the reconstituted suspension in the 50 mL syringe. Repeat the above procedure for the second vial. Finally, dilute the contents of the 50 mL syringe (by adding sterile physiological saline solution) up to a total volume of 50 mL. Mix the suspension carefully. The suspension is now ready to use.

Although it is recommended to use VERITY-BCG immediately after reconstitution, the reconstituted solution can be stored for up to 2 hours when refrigerated at 2 to 8° C and protected from light. Any unused portion should be discarded as biohazardous waste (see 11 STORAGE, STABILITY AND DISPOSAL).

Table 1 - Reconstitution

4.4 Administration

Insert a catheter by aseptic technique through the urethra into the bladder and drain completely. Attach a 50 mL syringe containing the prepared solution to the catheter and instill into the bladder by gravity flow or gentle pressure, where it should be retained for 2 hours. After instillation, remove the catheter. Patients should not ingest any fluid 4 hours before and 2 hours after instillation and should lie on their stomach for the first 15 minutes after instillation. Patients should be advised to change positions frequently (i.e., every 15 minutes) to distribute the medication properly throughout the bladder. Thereafter, patients should be made to void the instilled contents in a sitting position. See PATIENT MEDICATION INFORMATION for post-procedure precautions.

4.5 Missed Dose

If a patient misses a dose, resumption of therapy is recommended, if benefits outweigh the risks. When possible, a missed dose should be replaced so that the patient receives a total of 15 instillations (for intermediate-risk) or 27 instillations (for high-risk) (see section 4 Error! Reference source not found., RECOMMENDED DOSE AND DOSE ADJUSTMENT).

5 OVERDOSAGE

In case of overdose, patients should be monitored closely for signs of systemic BCG infection and treated with anti-tuberculosis medications if clinically warranted.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

VERITY-BCG is supplied as 40 mg freeze-dried powder containing Bacillus Calmette-Guérin with 1-8 X 10⁸ Colony Forming Units (CFU) in amber colored glass vials.

Presentation: Pack of two monocartons (one carton containing two monocartons). Each monocarton contains one 40 mg vial of freeze-dried Bacillus Calmette-Guérin with 1-8 X 10⁸ Colony Forming Units (CFU).

Table 2 – Dosage Forms, Strengths, Composition and Packaging

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

VERITY-BCG is for intravesical instillation only. Do not inject subcutaneously, intradermally, or intravenously.

VERITY-BCG is not for oral or intradermal use.

VERITY-BCG is not a vaccine for the prevention of cancer, or for the prevention of tuberculosis.

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.

Contamination

VERITY-BCG contains live, potentially pathogenic bacteria. Reconstitution, preparation of the VERITY-BCG suspension for instillation and administration should be performed under aseptic conditions. Unused VERITY-BCG and all equipment, supplies, and receptacles in contact with

VERITY-BCG should be handled and disposed of as biohazardous. Urine voided for 6 hours after instillation also needs to be properly disinfected (see 4.3 RECONSTITUTION, 4.4 ADMINISTRATION and 12 SPECIAL HANDLING INSTRUCTIONS).

Genitourinary

Traumatic catheterization or other injuries to the urethra or bladder mucosa can promote systemic BCG infection. VERITY-BCG administration should be delayed until mucosal damage has healed.

Monitoring and Laboratory Tests

Before the first intravesical instillation of VERITY-BCG, a Tuberculin Skin test with PPD should be performed. In the event that this test is positive, the intravesical instillation of VERITY-BCG is contraindicated only if there is clinical evidence of active tuberculosis disease.

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

Peri-Operative Considerations-Transurethral Resection (TUR)

When used as adjuvant therapy after TUR of a superficial urothelial cell carcinoma of the bladder (see 1 INDICATIONS), treatment with VERITY-BCG should be started 2 to 3 weeks after performing TUR. Treatment should not be started until mucosal lesions have healed.

Reproductive Health: Female and Male Potential

To protect their partners, patients should be advised to either refrain from sexual intercourse for one week after VERITY-BCG instillation, or to use a condom with intercourse throughout the treatment period and for one week after VERITY-BCG instillation. Women should be advised not to become pregnant while on therapy (see 2 CONTRAINDICATIONS, 7.1.1 Pregnant Women).

Sensitivity/Resistance

The use of VERITY-BCG may sensitize patients to tuberculin skin testing and result in a positive reaction to PPD, therefore determination of tuberculin reactivity by PPD skin testing should be performed before starting the treatment with VERITY-BCG.

The stopper of the vial for this product is latex free.

7.1 Special Populations

7.1.1 Pregnant Women

Animal reproduction studies have not been conducted with VERITY-BCG. It is also not known whether VERITY-BCG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. As safety of VERITY-BCG in pregnant women has not been evaluated, it should not be given to a pregnant woman.

7.1.2 Breast-feeding

Safety of VERITY-BCG in nursing women has not been evaluated. It is not known whether VERITY-BCG is excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions from VERITY-BCG in

nursing infants, it is advisable to discontinue breastfeeding if the mother’s condition requires treatment with VERITY-BCG.

7.1.3 Pediatrics

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

7.1.4 Geriatrics

There are limited data for patients aged 65 years and older (see 4 DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and 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.

Frequent adverse reactions (>10%) include hematuria, dysuria, urinary frequency and urgency. The symptoms usually resolve within 2 days but during maintenance treatment, symptoms may be prolonged.

Fever less than 39°C, malaise and and/or influenza-like symptoms (fever, rigors, malaise and myalgia) are common. These symptoms usually occur 4 hours after instillation and fever usually resolves within 24 to 48 hours with antipyretics and fluids. Fever higher than 39°C for more than 12 hours or any fever lasting more than 24 to 48 hours requires further evaluation for potential systemic BCG infection.

Systemic BCG infection resulting from BCG immunotherapy is a serious complication that may lead to death. Systemic BCG infections may be manifested by pneumonitis, hepatitis, cytopenia, vasculitis, infective aneurysm or sepsis. Contributing factors include traumatic catheterization, perforation of bladder or early BCG instillation after extensive TUR. Localized BCG infection may present as infection in the genitourinary tract (such as granulomatous prostatitis, epididymitis, orchitis or renal granulomatosis) or infection in other sites (such as eye, peritoneum, liver or bone). Presentation of BCG infection may be acute or delayed by months to years.

Treatment with antituberculosis therapies should be considered for severe cystitis, localized BCG infection and systemic BCG infection. Severe cystitis may be treated with single-agent Isoniazid, but systemic infection requires triple drug therapy (isoniazid-rifampicin-ethambutol) with or without cycloserine. Anti-tuberculosis treatment may be prolonged and require discontinuation of VERITY-BCG. Consultation with infectious diseases specialist may be necessary to determine optimal treatment regimen and duration.

Arthritis, renal failure, nephritis, urinary retention, or bladder contraction may occur.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Safety of VERITY-BCG was studied in 259 patients in three post-marketing surveillance studies. Adverse reactions were recorded and evaluated after each instillation. In addition, laboratory investigations (hematological, renal, and hepatic), chest x-rays, USG, and CT/MRI were performed in two of these studies. In these studies, 37/259 patients were lost to follow-up and reasons for dropping out were not available. Adverse reactions were reported as ‘mild’, but no formal classification of severity was used. No serious adverse reactions were reported in any of the studies.

Table 3 - List of studies on VERITY-BCG to evaluate safety

Study 01

In the 120 mg cohort, there were 476 episodes of dysuria (36%) and 475 episodes of fever (36%) whereas in the 80 mg cohort, there were 383 episodes of fever (29%) and 297 episodes of dysuria (22%).

Table 4 - Adverse Reactions Observed after Administration of VERITY-BCG in Study 01

*N represents the number of instillations

Study 02

Very common adverse reactions (≥ 10%) were dysuria (23%) and fever (18%). Common adverse reactions (≥ 1% and ≤10%) were urinary frequency (9%) and hematuria (7%).

Study 03

This post-marketing surveillance study was conducted to assess the safety of VERITY-BCG in patients with intermediate and high-risk Ta, T1 Transitional Cell Carcinoma (TCC) of the urinary bladder. VERITY-BCG was administered intravesically in patients 10 to 14 days after transurethral resection (TUR).

A total of 549 doses of VERITY-BCG were administered to 105 patients. VERITY-BCG was instilled intravesically at a dose of 80 mg or 120 mg per instillation.

Very common adverse reactions (≥ 10%) reported after the first treatment were hematuria (21%) and dysuria (19%). Common adverse reactions were fever (8%), urgency/frequency (7%), bladder cramps (4%), pain (3%), urinary tract infection (3%), influenza-like symptoms (2%), and cystitis (2%).

8.5 Post-Market Adverse Reactions

The following table summarizes serious and non-serious adverse reactions from post-market surveillance of VERITY-BCG. Other uncommon adverse reactions to BCG have been reported in the literature and are not confined to a particular BCG strain. These include pulmonary infection, hepatitis, ocular disorder (uveitis/conjunctivitis), arthralgia/myalgia, and fatigue.

Table 5 – Post-Marketing Adverse Reactions

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 VERITY-BCG.]

9.3 Drug-Behavioural Interactions

Although there is evidence that smoking worsens bladder cancer outcomes, there is no direct evidence for the need to quit smoking or vaping while undergoing treatment with Verity-BCG.

9.4 Drug-Drug Interactions

VERITY-BCG is sensitive to most antibiotics and in particular, to the routinely used anti-tuberculous agents, like streptomycin, para-aminosalicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol except for pyrazinamide. Therefore, the anti-tumour activity of VERITY-BCG may be decreased by concomitant therapy with antibiotics. If a patient is being treated with an antibiotic it is recommended to postpone the intravesical instillation until the end of the antibiotic treatment (see also 2 CONTRAINDICATIONS).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

VERITY-BCG has anti-tumor activity, but the exact mechanism of action is not known. Study data suggest that an active nonspecific 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

VERITY-BCG is an immunostimulating agent.

10.3 Pharmacokinetics

Studies to evaluate pharmacokinetic properties of VERITY-BCG were not conducted.

11 STORAGE, STABILITY AND DISPOSAL

Vials of VERITY-BCG are stable for up to 24 months when stored at 2 to 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.

12 SPECIAL HANDLING INSTRUCTIONS

VERITY-BCG contains live attenuated mycobacteria. Reconstitution, preparation of the VERITY-BCG suspension for instillation and administration should be performed under aseptic conditions in a biohazardous containment cabinet, wearing appropriate personal protective equipment.

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

For up to six hours after treatment, once a patient urinates, bleach should be poured into the toilet. The bleach should be allowed to stand for 15 minutes prior to flushing. Clothing that is soiled within six hours of treatment should be laundered and dried separately at a high temperature. Incontinence pads should be soaked in bleach, wrapped separately in a plastic bag and disposed of.

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

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Product Characteristics:

VERITY-BCG is prepared from a culture of Bacillus Calmette-Guérin (BCG) Russian strain BCG-I. Product is provided in freeze-dried form, with each 40 mg vial containing 1-8 X 10⁸ CFU.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Two post-marketing studies of efficacy and safety were conducted in patients with stage T1 urothelial cell carcinoma of the bladder between 2006 and 2012 to fulfil regulatory requirements in India. Recurrence free survival and progression free survival were evaluated as study endpoints; however, due to the single arm nature of the studies, there are limitations in the interpretation of the study results. Therefore, a confirmatory clinical trial in Canada is a condition of authorization.

Table 6 - Summary of patient demographics for clinical trials in patients with stage 1 urothelial cell carcinoma of the bladder

14.2 Study Results

Study 01

A total of 51 patients were enrolled in the 80 mg dose group. One patient was lost to follow up during the maintenance course of treatment. Out of the remaining 50 patients, 8 (16%) patients had muscle